Strategies for immunotherapy of cancer

IMMUNOLOGY V75 - AP - 5003(D) / c6-235 / 04-11-00 09:50:45

ADVANCES IN IMMUNOLOGY, VOL. 75

Strategies for Immunotherapy of Cancer CORNELIS J. M. MELIEF, RENE´ E. M. TOES, JAN PAUL MEDEMA, SJOERD H. VAN DER BURG, FERRY OSSENDORP, AND RIENK OFFRINGA Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

I. Introduction

The prevailing mood among immunologists and oncologists concerning immunotherapy of cancer is still one of gloom. Indeed, as of this writing, the impact of immunotherapy on oncological practice is modest at best. Nevertheless, as this review will illustrate, many of the reasons for the failures can now be understood on the basis of which strategies can be shifted. These insights and the undeniable striking successes in defined clinical conditions and animal models can lead to more rationally designed and sophisticated forms of immunotherapy. Let us first examine some of the striking clinical successes. Despite the fact that many human cancerassociated viruses establish persistent infection in a high proportion of infected individuals, preventive vaccination against such viruses can be highly effective. This was first demonstrated by preventive vaccination of young children against hepatitis B virus (HBV). This vaccine reduced the rate of chronic infection from 10% to less than 1% and was associated with a striking reduction in the incidence of hepatocellular carcinoma many years later (Chang et al., 1997). The important message from this work is that preventive vaccination against tumor viruses, which are associated with 15–20% of all cancers, can be successful, whereas so-called therapeutic. vaccination in patients with advanced virus-associated cancer is likely to fail miserably. An exception to this rule is the cancer patient whose tumor burden has been reduced significantly by conventional therapy. In this situation of minimal residual disease, vaccination could be used as adjuvant therapy, provided that neither the disease process nor the prior therapy has compromised the patient’s capacity to respond to the vaccine. Preventive vaccines against human tumor viruses other than HBV are being developed. A case in point is human papilloma virus (HPV), oncogenic variants of which constitute a leading cause of cancer-related death among women in less developed countries. Large field trials of preventive HPV vaccination are likely to start soon (WHO report, 1999). These HPV vaccines are based on the immunizing potency of viruslike particles (VLP), constituting naturally folded viral envelopes without the viral genome. Preventive vaccination for the major human cancer types not associated with viruses is not 235

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feasible at present. However, as subgroups of cancer induced on the basis of known genetic predisposition are being identified, this situation may change, and preventive vaccines may be directed against prospective tumor constituents that are likely to be overexpressed or mutated. The only current form of therapy that may be effective against tumor burdens larger than minimal residual disease in a high proportion of patients is therapy with specific T cells. This is illustrated by the successful therapy of relapsed chronic myelogenous leukemia (CML). Of the CML patients treated by allogeneic bone marrow transplantation, approximately 20% show leukemia recurrence. Full remission in most of these patients can subsequently be achieved by adoptive immunotherapy involving the infusion of lymphocytes from the marrow donor. The beneficial effect of lymphocyte transfusion is intimately connected to the anti-leukemic activity of transplanted T cells (Kolb and Holler, 1997). Similarly, EBV-induced lymphomas in recipients of allogeneic bone marrow were treated successfully by adoptive transfer of donor-derived T cells enriched for EBVspecific cells (O’Reilly et al., 1998; Rooney et al., 1998). EBV-specific cytotoxic T lymphocytes (CTL) were shown to be responsible for the therapeutic efficacy of the infused T cell populations (Heslop et al., 1996; O’Reilly et al., 1998; Rooney et al., 1998), bearing out the remarkable capacity of adoptively transferred CTL to eradicate large tumor masses in mouse models (Kast et al., 1989; Greenberg, 1991; Melief, 1992). Adoptively transferred CD4⫹ T cells also possess substantial antitumor activity, even against MHC class II-negative tumors (Greenberg, 1991; Toes et al., 1999). Adoptive transfer of T cells thus can serve as rescue therapy in individual patients when other forms of therapy have failed or are futile by current technology because the disease is too far advanced. On the other hand, this type of therapy is tailored to the individual patient, is laborious and costly, and may not work as efficiently with autologous expanded T cells directed against tissue-specific tumor-associated antigens, because the most potentially reactive therapeutic T cells may have been deleted by tolerance-inducing mechanisms. Traditionally, tumor escape mechanisms such as production by tumor cells of immunosuppressive factors (e.g., TGF웁, IL-10) and loss of MHC expression or tumor-associated antigens have been considered the greatest enemies of successful immunotherapy. Although tumor escapes are well documented, it seems likely that an even more formidable barrier to immunotherapy is successful maintenance of (self ) tolerance by cancers. In this respect tumors do not differ from the normal tissues in which they arose. In particular, high-dose antigens in normal tissues are probably processed and presented in a continuous fashion by a phenomenon known as ‘‘cross-presentation’’ (see following), leading to both MHC class I- and

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II-restricted peptide display on professional antigen-presenting cells (APC) (Heath et al., 1998). Because normal tissues and many early-stage tumors do not provide the inflammatory stimuli required to turn the professional APC into T-cell-activating agents, and therefore keep them in a resting tolerizing state, T cells recognizing the cross-presented antigens will be tolerized or anergized (Matzinger, 1994; Heath et al., 1998; Toes et al., 1999). A large part of this review will therefore be spent on a discussion of strategies to counteract immunological tolerance induced by tumors. If tumor cells express lower doses of antigens, chances are that the immune system simply ignores antigen expression by the tumor or preneoplastic lesions, even in the case of virus-induced tumors. This state of ‘‘immunological ignorance’’ differs from tolerance in that T cells from such individuals behave as virgin lymphocytes that have never encountered antigen (Starzl and Zinkernagel, 1998). To what extent tumor antigens induce tolerance or are associated with ignorance (indifference) is unclear at present. Our own bias is that there is much more active tolerance induction going on than previously realized, particularly because the sensitivity of the exogenous pathway for processing of MHC class I-presented antigens has been grossly underestimated. For example, infection by oncogenic human papillomaviruses (HPV) is considered to be associated with immunological ignorance (Starzl and Zinkernagel, 1998), but this does not explain why many young women apparently manage to eradicate early HPV-induced lesions and become completely virus negative (Ho et al., 1998). Perhaps the balance between ignorance and immunity is very delicate, because many other women do not manage to rid themselves of the virus and some go on to develop preneoplastic lesions which may progress to cervical cancer. Another example of the importance of cross-presentation for class I-restricted responses is the exquisite efficiency by which professional APC acquire exogenous antigen for priming of CTL responses following intramuscular gene vaccination (Tighe et al., 1998). Transgene-encoded antigens expressed by the muscle cells apparently have no problem in arriving in professional APC of draining lymph nodes. This might go unnoticed if strong immunostimulatory sequences in DNA vaccines, causing APC activation, would not make sure that CTL immunity rather than tolerance is the outcome (Tighe et al., 1998). The inescapable concept thus stands out that, depending on their state of activation, professional APC, also named dendritic cells (DC), either tolerize or activate T cells. CD4⫹ helper T cells appear somewhat easier to activate than CD8⫹ cytotoxic T lymphocyte precursors. Indeed, activated CD4⫹ cells appear to be required to activate DC into a state permitting CTL induction (‘‘license to kill’’ concept,’’ see following) in a remarkable three-cell-type interaction (Schoenberger et al., 1998b; Bennett et al., 1998; Ridge et al., 1998). Novel therapeutic ap-

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proaches must deal with this model. While the exact DC activation state required for optimal protective T cell response remains to be identified, the realm of molecularly defined adjuvants that directly activate DC to the desired state in vivo comes within view. In two recent studies addressing this issue, in vivo triggering of CD40 converted tolerance of CD8⫹ or CD4⫹ tumor-specific T cells into protective immunity (Diehl et al., 1999; Sotomayor et al., 1999). Rather than focusing on improved performance of DC, one might also consider taking the brakes off costimulation at the T cell level by blockade of the inhibitory receptor CTLA-4 on T cells (Hurwitz et al., 1998). This approach has been shown to act synergistically with vaccination by GM–CSF-transduced tumor cells (Hurwitz et al., 1998; Van Elsas et al., 1999). In the ensuing pages we discuss the several aspects of antitumor immunity, ranging from natural protective immunity against cancer to the multiple immunoregulatory mechanisms that must be considered in developing effective immunotherapeutic strategies for patients in whom such natural immunity is lacking or failing. II. Natural Protective Immunity against Cancer

Evidence that natural immune responses protect against cancer comes from two main sources. First, for tumors of different histologic types, including melanoma, medullary breast carcinoma, gastric carcinoma, bladder carcinoma, seminoma, choriocarcinoma, neuroblastoma, and glioblastoma, the presence of T lymphocytes constitutes an important prognostic factor (reviewed in Clemente et al., 1998). Recently, infiltration of human colorectal cancer tissue by CD8⫹ T cells was also found to be a favorable prognostic sign. The impact of this was similar to—but independent of— Duke’s staging (Naito et al., 1998). Although with some exceptions, particularly melanoma, the identity of nonviral tumor antigens recognized by tumor-specific T cells has not been elucidated, these data provide a strong impetus to the search of tumor antigens recognized by T cells of the autochthonous host in human cancers of diverse histologic types. In melanoma patients, tumor-specific CD8⫹ T cells usually coexist with the tumors. Apart from the evidence already cited, it is therefore hard to prove that these CD8⫹ T cells are beneficial. However, if CD8⫹ T cell responses are stimulated, e.g., by vaccination with HLA class I-binding peptides with or without additional interleukin-2 (IL-2) (Rosenberg et al., 1998; Nestle´ et al., 1998; Marchand et al., 1995), significant therapeutic responses are seen. Favorable responses are often associated with depigmentation reminiscent of autoimmune vitiligo (Rosenberg et al., 1998). Indeed, high frequencies of skin-homing melanocyte-specific CTL are found in auto

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immune vitiligo (Ogg et al., 1998), suggesting that these CTL are at least in part responsible for the destruction of skin melanocytes in this disease. CTL against melanocyte differentiation antigens can also be retrieved from healthy donors (Visseren et al., 1995; Bakker et al., 1995; Van Elsas et al., 1996; Chen et al., 1998). This suggests that these CTL, like those in nonregressing melanoma patients, are checked and balanced in vivo, too low in numbers, or of insufficient affinity to mediate significant destruction. Assays are therefore needed to better monitor T cell responses in cancer patients, particularly assays that identify truly in vivo tumoricidal CTL and distinguish these from tumor-reactive CTL, sometimes referred to as tumor-observing lymphocytes, that lack biting force or at least need additional prodding. The second major line of evidence for natural protective immunity against cancer comes from the observation that immunodeficient or immunosuppressed patients suffer from a markedly increased cancer incidence, particularly cancer induced by tumor viruses. Patients with AIDS exhibit a strongly increased incidence of EBV-induced lymphomas and of Kaposi sarcomas associated with the sexually transmitted human herpesvirus type 8 (HHV8; Kedes et al., 1996; Gao et al., 1996). EBV-induced lymphomas also emerge frequently in the immunodeficient period following bone marrow transplantation. These tumors, in contrast to the rare EBV lymphomas arising in immunocompetent individuals, express a wide array of EBVassociated antigens and can therefore efficiently be treated with adoptive transfer of donor-derived EBV-specific T cells (Heslop et al., 1996; O’ Reilly et al., 1998; Rooney et al., 1998). Patients receiving long-term immunosuppressive treatment following renal allograft transplantation also experience a markedly increased incidence of malignancies, which has risen further since the introduction of cyclosporin A (Hiesse et al., 1997; Newstead, 1998). Again, many of these appear to have a viral etiology. Particularly frequent are skin cancers, which are likely the result of failure of immunosurveillance against ultraviolet light- and HPV-induced neoplasia, EBV-induced lymphomas, HHV8-associated Kaposi sarcoma, and HPVpositive cervical cancer (Newstead, 1998). The fields of tumor immunity and autoimmunity converge in the case of the so-called paraneoplastic neurologic disorders. Patients affected typically carry a malignancy of neuroendocrine origin, such as small-cell lung carcinoma or certain types of gynecologic cancer, in the course of which they develop severe paraneoplastic cerebellar degeneration (PCD). In these patients both antibody and CTL responses are found against the antigen cdr2, which is shared between neuronal tissues and tumor (Darnell, 1996; Albert et al., 1998). Cancer patients with PCD appear to have a more favorable clinical course than patients without it, supporting the notion

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that the same effector mechanisms are involved in both autoimmunity and antitumor responses. In some patients PCD-associated tumors even regress coincident with the onset of autoimmune neurologic disease (Darnell and DeAngelis, 1993). III. Antigens Eliciting T Cell Responses Expressed by Virus-Associated Tumors

A list of currently known human cancer-inducing viruses and the viral antigens expressed by the cancer cells is provided in Table I. An extensive description of these antigens, including literature references, is provided elsewhere (Van der Burg et al., 1999). TABLE I ANTIGENS EXPRESSED BY VIRUS-INDUCED HUMAN CANCER Virus EBV

Disease

Antigen Expression

Burkitt’s lymphoma Hodgkin’s lymphoma Nasopharyngeal carcinoma T cell lymphoma Immunoblastic lymphoma In immunocompromised individuals

冧

HTLV-1

Adult T cell leukemia

HHV-8

Kaposi’s sarcoma Primary effusion lymphoma

HBV

Hepatocellular carcinoma in HBV surface antigen (HbsAg) positive patients Hepatocellular carcinoma in HbsAg negative patients

HCV

Hepatocellular carcinoma

HPV

Cervical intraepithelial neoplasia Cervical carcinoma

冎

EBNA-1 EBNA-1 LMP-1*, LMP-2a*, LMP-2b* EBNA-1, 2*, 3* EBNA leader protein* LMP1*, LMP2a*, LMP2b* Gag*, envelope*, reversetranscriptase, integrase, protease, tax*, rex HHV-8 shows sequence Similarity to two other oncogenic 웂herpes viruses: Herpes virus saimiri (HVS) and EBV, similarly early and late antigens will probably be expressed. Pre-S, HbsAg* (surface) HbeAg, HbcAg* (core) HbxAg, polymerase* HbxAg (HbeAg and HbcAg are detected in numerous tumors) Core*, Envelope 1* and Envelope 2*, Nonstructural proteins: NS2*, NS3*, NS4* and NS5* E1, E2, E4, E5, E6, E7*, L1 and L2 E6 and E7*

* Antigens against which natural T cell responses in patients have been observed.

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IV. Antigens Eliciting T Cell Responses Expressed by Non-Virus-Induced Tumors

A list of the most important currently known human cancer antigens on non-virus-induced tumors is provided in Table II. Most of these antigens were indentified in melanomas. The antigens of the MAGE, BAGE, and GAGE families as well as the genes encoding them have been reviewed elsewhere (Boon et al., 1994; Van den Eynde and Van der Bruggen, 1997; Rosenberg, 1999). The LAGE-1 gene was identified by representational difference analysis (Lethe et al., 1998). It is closely related to NY-ESO-1 (Chen et al., 1997), which was originally detected by antibodies in the serum of cancer patients (Chen et al., 1997). Importantly, naturally processed HLA–A2-restricted epitopes derived from NY–ESO-1/LAGE-1 have now been reported ( Ja¨ ger et al., 1998; Aarnoudse et al., 1999). The PRAME antigen was originally identified as a melanoma-associated antigen recognized by a CTL clone expressing the NK inhibitory receptor p58.2. This clone could therefore recognize only the HLA–A24-presented PRAME peptide on a melanoma metastasis lacking HLA–Cw7 (Ikeda et al., 1997). Nevertheless, PRAME expression is found on a variety of cancers, including TABLE II COMMON ANTIGENS RECOGNIZED BY T CELLS ON NONVIRAL HUMAN CANCERS Tumor type Differentiation antigens Tyrosinase Gp 100 MART/1 (Melan-A) TRP-1 (gp 75) TRP-2 CEA (carcinoembryonic antigen) Testis tumor antigens MAGE-1 MAGE-2 MAGE-3 BAGE GAGE RAGE LAGE-1 NY-ESO-1 PRAME Overexpressed antigens (as a result of mutation) P53 HER-2/neu

Melanoma Melanoma Melanoma Melanoma Melanoma Colorectal carcinomas Melanoma and variety of carcinomas Melanoma and variety of carcinomas Melanoma and variety of carcinomas Melanoma and variety of carcinomas Melanoma and variety of carcinomas Renal cancer and variety of carcinomas Melanoma and variety of carcinomas Melanoma and variety of carcinomas Melanoma and variety of carcinomas and leukemias Variety of cancers Breast, ovary, and colorectal carcinomas

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leukemias, in particular, more than 50% of the M2 and M3 types of acute myelogenous leukemias and approximately 20% of common ALL (Van Baren et al., 1998). In our laboratory we have raised CTL clones against two HLA–A2-presented PRAME peptides that lysed a wide variety of PRAME expressing HLA–A2-positive cancer cell lines, including melanoma lines, renal cancer lines, non-small-cell lung cancer lines, and leukemia lines (our unpublished data). Autoreactive CTL against an HLA–A2-presented CEA-encoded peptide have been generated and shown to lyse HLA–A2-compatible, CEA-overexpressing tumor cells (Tsang et al., 1997). A CEA peptide with enhanced A2-binding ability as a result of single amino acid substitution also showed improved immunogenicity (Zaremba et al., 1997). A similar observation was made for the GP 100 melanoma antigen, and this peptide was used for clinical vaccination (Rosenberg et al., 1998). Accordingly, we have shown that stability of MHC class I/peptide complexes is directly correlated with immunogenicity of the peptide epitopes (Van der Burg et al., 1996). It is conceivable that the T cell immune system exhibits a certain degree of tolerance against ‘‘naturally optimal’’ epitopes derived from tumorassociated auto-antigens, leaving particularly the subdominant and cryptic determinants from these proteins as targets for immunotherapy (Schoenberger and Sercarz, 1996; Sherman et al., 1998). By using optimized variants of such epitopes, it may be possible to elicit a T cell response with maximal antitumor reactivity and minimal reactivity to normal tissue. Because melanoma-associated antigens have received ample attention in recent reviews, we have opted to discuss several other categories of tumor-associated antigens in greater detail. A. p53 AS A TUMOR ANTIGEN p53 was originally identified by antibodies found in the serum of mice bearing chemically induced sarcomas (De Leo et al., 1979). Mutation of the p53 gene is one of the most frequent events in human oncogenesis. Aberrant expression of p53 is found in approximately 50% of all human malignancies (Hollstein et al., 1991; Lane, 1994). Formation of antibodies against p53 occurs only in cancer patients, not in healthy people (Lubin et al., 1995a; Hammel et al., 1997). The highest prevalence of these antibodies is found in lung cancer patients (30%), and such antibodies are early markers of disease (Lubin et al., 1995b). Antibodies against p53 are also frequently (26%) detected in sera of patients with colorectal cancer, where p53 mutation is common, but not all patients with p53 overexpression have demonstrable serum antibodies (Houbiers et al., 1995; Hammel et al., 1997). Many of the p53 antibodies are of the IgG class (Lubin et al., 1995a), indicating an underlying CD4⫹ T helper cell response. Such helper

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cells proliferating to wild-type p53 have indeed been found (Tilkin et al., 1995). CTL responses of healthy donor T cells against both mutant and wild-type p53 sequences have been reported (Houbiers et al., 1993). One of the CTL lines generated in this study, directed against the HLA–A2binding sequence LLGRNSFEV (p53 wild-type AA 264–272), also recognized endogenously processed wt p53 on HLA-A*0201-positive human cancer lines (Ro¨ pke et al., 1996). This suggests that tolerance to wild-type p53, like tolerance to the melanoma-associated self antigens discussed earlier, is not complete. On the other hand, it is much more difficult to generate high-affinity CTL against H-2- or HLA–A2-binding sequences of wild-type mouse p53 in, respectively, normal C57BL/6 or HLA-A2 transgenic mice than in their p53-deficient counterparts (Vierboom et al., 1997; Theobald et al., 1998). Irrespective of this tolerance issue, the difference in expression of p53 between tumors carrying mutant p53 and normal tissues is such that large tumors can be eradicated by adoptive transfer of cloned wild-type p53-specific CTL and IL-2 in the absence of any demonstrable toxicity to normal tissues (Vierboom et al., 1997). This makes a strong case for wild-type p53-directed CTL therapy to be explored further for human cancer, provided the tolerance issue can be adequately addressed. One possibility for circumventing this problem involves exploitation of the allogeneic T cell repertoire. This approach is based on the observation that T cell tolerance is self MHC-restricted. Stauss and coworkers were the first to demonstrate that allogeneic murine T cell cultures can be enriched for T cells that recognize the ‘‘self ’’ MHC/peptide complex of interest and that the resulting CTL exhibit antitumor reactivity in vitro and in vivo (Sadovnikova and Stauss, 1996). Of note, the frequent observation of p53-specific IgG responses in cancer patients (see above) indicates that self tolerance seems less pronounced with respect to the p53-specific Th response. Because the relevance of the tumor-specific Th response is becoming more and more apparent (e.g., Ossendorp et al., 1998), future investigation of p53-directed immunotherapy should also include the Th arm of the immune system. Various other aspects of this immunotherapy are discussed elsewhere (Vierboom et al., 1999; Chen and Carbone, 1997; DeLeo, 1998; McCarty et al., 1998). Because of its pivotal role as a tumor suppressor, gene p53 is also used for nonimmunologically oriented (gene) therapies (Gallagher and Brown, 1999). B. CEA AS A TUMOR ANTIGEN Like p53, CEA was originally detected as an overexpressed antigen, this time in human tumors, against which serum antibodies accumulate spontaneously (Gold, 1967). For a long time CEA-directed immunotherapy did not receive the attention it deserves, because considerable quantities

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of the antigen are shed in the circulation. As a result, antibody-mediated therapy was considered futile, because therapeutic antibodies would be trapped by circulating antigen long before they might reach the tumor. However, these considerations do not apply to processed CEA peptides recognized by T cells, in particular CTL. Tolerance of the T cell immune system to CEA, as shown for other self antigens, again appears incomplete. This was illustrated by the fact that CTL specific for an HLA–A2-presented CEA peptide, and capable of tumor cells lysis, could be generated in patients immunized with recombinant vaccinia–CEA tumor vaccine (Tsang et al., 1997). Furthermore, CEA-specific vaccination of (human) CEAtransgenic mice was shown to induce protective T cell immunity against a challenge with CEA-expressing tumor cells (Kass et al., 1999). C. HER-2/NEU AS A TUMOR ANTIGEN The HER-2/neu oncogene-encoded protein is a member of the tyrosine kinase family of growth factor receptors. Overexpression, which is correlated with poor prognosis, is found frequently in adenocarcinomas of breast, ovary, and colorectum (Slamon et al., 1987). CTL isolated from cancer patients or generated in vitro against several HLA–A2-binding peptides of HER-2/neu were found to specifically kill antigen-positive HLA–A2matched cancer cell lines (Yoshino et al., 1994; Brossart et al., 1998; Rongcun et al., 1999). However, in the hands of another group of investigators, CTL against one of these peptides, raised in secondary stimulation in vitro of PBL from patients vaccinated with HER-2/neu peptide AA369– 377, despite excellent peptide specificity, failed to lyse HLA–A2-matched HER-2/neu-overexpressing or even vaccinia-HER-2/neu recombinant virus-infected target cells (Zaks and Rosenberg, 1998). A possible explanation for this latter failure is bias for low-affinity peptide-specific CTL selection by the peptide vaccination approach. However, in other examples of clinical peptide vaccination, CTL recognizing endogenously processed MHC class I peptides were readily found (Rosenberg et al., 1998; Nestle´ et al., 1998). D. MUCIN AS A TUMOR ANTIGEN Tumor-associated mucins, in particular, MUC1, which is highly expressed at the surface of human cancer cells, can elicit both antibody (IgM) and CD4⫹ T cell responses (Kotera et al., 1994; Hiltbold et al., 1998). Until recently, the search for anti-MUC1 immune responses, as well as the development of MUC1-specific antitumor vaccines, has been focused on the large tandem repeat (TR) region of MUC1, mainly because most of the above-mentioned responses were found to be directed against epitopes in this region. CD8⫹ T cell responses have also been observed

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against this TR region, although it should be noted that the peptides identified showed only low-affinity binding to the restricting MHC molecules (HLA–A11 and A2) and did not contain the preferred binding motifs (Domenech et al., 1995; Apostolopoulos et al., 1997). Yet other MUC1specific CD8⫹ T cells that recognized their targets in an MHC-unrestricted fashion were described (Magarian-Blander et al., 1998). Since then, a number of classical, HLA–A2-restricted CTL epitopes have been identified. Of note, these epitopes map outside the MUC1 TR region (Brossart et al., 1999; our unpublished data). Although human MUC1-transgenic mice were shown to exhibit tolerance for MUC1, this tolerance could be broken by a dendritic cell-based vaccine (Tempero et al., 1998; Gong et al., 1998). On the other hand, MUC1 was found to be expressed at considerable levels on activated human T cells (Agrawal et al., 1998). The significance of MUC1 as a target antigen for immunotherapy of cancer is therefore unclear at present. E. IDIOTYPE IG AS A TUMOR ANTIGEN A significant number of B cell non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM) patients do not benefit from chemo- and radiotherapy. Because the immunoglobulin (Ig) produced by the malignant B cell clone comprises a tumor-specific marker, it appears a highly attractive target for immunotherapy of NHL. Experiments in mouse models of myeloma and NHL have shown that idiotypic vaccination can induce protective antitumor immunity (Lynch et al., 1972; Campbell et al., 1987; King et al., 1993). Although both humoral and cellular anti-idiotype responses were observed, more recent evidence suggests that the tumor-protective effect of this vaccination can be largely attributed to the humoral response (Campbell et al., 1990; Syrengelas and Levy, 1999). In clinical studies, patients with B cell lymphoma have been vaccinated with tumor lg protein purified from custom-made tumor-derived hybridomas. The antigen was either coupled to keyhole limpet hemocyanin and emulsified in adjuvant or pulsed onto autologous dendritic cells. In the study with the KLH-based vaccine, 50% of the patients generated anti-idiotype humoral responses, whereas in the study with the DC-based vaccine all patients (4/4) were shown in addition to exhibit cellular immunity (Hsu et al., 1996, 1997). Importantly, several of the vaccinated patients showed complete or partial tumor regression. In a similar study, 2 of 12 MM patients that received idiotype-specific vaccination were shown to develop idiotype-specific humoral and cellular immunity, which correlated with the fact that these patients remained in complete remission (Reichardt et al., 1999). Taken together, these data show that idiotype-specific vaccination constitues a highly promising immunotherapeutic approach against Ig-expressing tu-

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mors. So far, vaccination studies have been performed with patients from whom tumor cells could be harvested for generation of idiotype-producing hybridomas. It is conceivable that the PCR methodology used for detection and identification of tumor-specific idiotypes (e.g., van Belzen et al., 1997) can also be used to clone idiotype-encoding genes and to incorporate those into expression vectors for production of recombinant idiotype protein (McCormick et al., 1999). Alternatively, such a vaccine could consist of a set of synthetic peptides covering the idiotype-specific sequence (approx, 100 residues). This would permit idiotype-specific vaccination of patients for which hybridomas cannot be generated. F. DISCOVERY OF NEW TUMOR ANTIGENS ON NON-VIRUS-INDUCED HUMAN TUMORS BY SEROLOGY Undoubtedly, molecular cloning of tumor antigens recognized by CTL has strongly revitalized tumor immunology (Boon et al., 1994; Van den Eynde and van der Bruggen, 1997). Similar methodology allows the cloning of genes encoding proteins recognized by serum antibodies of tumorbearing patients (Sahin et al., 1995). In fact, many of the gene products eliciting antibody responses are also likely targets of tumor-specific autoreactive T cells, as exemplified by the aforementioned results with the NYESO-1 antigen (Chen et al., 1997). A recent survey of sera from 234 cancer patients showed that antibodies to proteins of the testis cancer family of antigens can be found regularly, whereas antibodies to the MART-1/MelanA and tyrosinase, antigens expressed by both melanoma cells and their normal counterparts, were not demonstrable in sera of 127 melanoma patients (Stockert et al., 1998; York and Rock, 1996). V. Processing of Tumor Antigens

Processing of exogenous antigens for presentation by MHC class I molecules is now a widely recognized second pathway of class I-restricted antigen presentation, next to the well-known endogenous route (for reviews see Bevan, 1995; Rock, 1996; York and Rock, 1996; Jondal et al., 1996; Reimann and Kaufmann, 1997; Heath et al., 1998). By a variety of routes, including delivery of apoptotic bodies, antigen enters into the cytoplasm and hence into the proteasome–TAP-dependent pathway. In particular, immature DC possess this capacity and ingest apoptotic cells via 움v웁5 integrin and CD36 for cross-presentation to CTL (Albert et al., 1998b). Conceivably, the normal outcome of cross-presentation is CTL tolerance, unless APC activation by CD4⫹ T cells or inflammatory stimuli takes place (Kurts et al., 1997; Matzinger, 1998). Processing of exogenous antigen into MHC class I appears to be a capacity of dendritic cells but not of

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macrophages, whereas both cell populations are capable of processing exogenous antigen into MHC class II (Mitchell et al., 1998). Some class I-restricted viral epitopes may be exclusively generated by exogenous processing, whereas others arise commonly from exogenous as well as endogenous processing (Gil-Torregrosa et al., 1998; Stolze et al., 1998; Geier et al., 1999). Recently, priming of CTL immunity to virus-infected nonhematopoietic cells was found to require processing of exogenous antigen by professional APC (Sigal et al., 1999). It is hoped that continued analysis of the specificity of the proteasome complex and other processing enzyme systems will allow more accurate prediction of processing (Nussbaum et al., 1998). The identity of MHC class I-restricted tumor peptides can also be determined by direct elution of peptides from class I molecules and mass spectrometry sequencing (Henderson et al., 1993; Flad et al., 1998; Schirle et al., 1999; Skipper et al., 1999). Processing of exogenously derived proteins and long peptides has long been recognized as a major pathway for presentation by MHC class II molecules (reviewed in Lindner and Unanue, 1996; Nelson et al., 1997). Ingested antigens are broken down within endosomes or lysosomes where MHC class II loading with peptides takes place. Proteolytic cleavage is mediated by lysosomal cathepsins. Recently, an asparaginyl endopeptidase was found to be another important processing activity for class II peptide generation (Manoury et al., 1998). Interestingly, incubation of dendritic cells with interleukin-6 (IL-6) was shown to alter the hierarchy by which class II-restricted epitopes derived from a model antigen were processed and presented. Dendritic cells modified in this manner were capable of activating T cells against determinants that were otherwise cryptic because of poor presentation (Drakesmith et al., 1999). Defective antigen processing and MHC expression in tumor cells are discussed in Section VIII. VI. Pivotal Role of Dendritic Cells and Tumor-Specific CD4ⴙ Helper Cells in Tumor Immunity

As discussed in Section I (Introduction), bone-marrow-derived APC, conceivably DC, can either tolerize or prime T cell responses (Heath et al., 1998; Sallusto and Lanzavecchia, 1999). DC that tolerize CD8⫹ CTL precursors could be either a specialized lineage of so-called lymphoid DC (Kronin et al.,1996) or resting and activated forms (immature and mature) of the same DC lineage. Appreciation of the fundamental role of the DC activation state to tune the outcome of T cell responsiveness helps to explain why CTL responses against tumors, including those induced by noninflammatory persistent tumor viruses such as HBV, HCV, HPV, HHV8, and EBV and murine leukemia virus (MuLV), are dependent on T

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cell help, whereas CTL responses against acute disease-causing cytopathic viruses, such as influenza virus, are without a clear need for CD4⫹ Th activity (Allan et al., 1990). In a well-defined MuLV tumor model, the need for tumor-specific help for protection against an MHC class IInegative tumor was well characterized (Ossendorp et al., 1998). Crucial CD4⫹ T cell help for CTL-mediated protection was also documented in other tumor models in mice (reviewed in Hung et al., 1998, and Toes et al., 1999). How does this CD4⫹ help operate? Assembled evidence shows that for induction of MHC class I-restricted tumor-specific immunity crosspresentation of antigens captured by DC plays a dominant role (Seung et al., 1993; Huang et al., 1994; Toes et al., 1996a). Analysis of the cellular interactions involved in CTL priming revealed that Th cells must recognize antigen on the same APC that cross-presents the CTL epitope (Bennett et al., 1997). This explains the requirement for epitope linkage between Th epitopes and CTL epitopes for induction of CTL responses (Cassel and Forman, 1988). The traditional explanation for the need of this proximity is that the CD4⫹ T cell, upon recognition of antigen on MHC class II, releases cytokines such as IL-2, which allow more pronounced activation and proliferation of CD8⫹ CTL precursors recognizing antigen presented by MHC class I. Some evidence indicates that this is not the major mechanism of CD4⫹ help for CTL, although factors released by CD4⫹ cells such as IFN-웂 do have an additional role (see following). The decisive events, however, are of a cell–cell cognate nature, in which CD40L on CD4⫹ T helper cells, which becomes upregulated on CD4⫹ cells during activation, triggers CD40 on DC (Schoenberger et al., 1998b; Bennett et al., 1998). These results confirm a central role for CD40–CD40L interactions in the generation of protective T-cell-mediated tumor immunity (Mackey et al., 1997, 1998). CD4⫹ T cell–DC interaction via CD40L–CD40 most likely empowers the DC to prime CTL, because help for CTL priming can be bypassed by activation of DC through CD40 in vitro (Ridge et al., 1998) or in vivo (Schoenberger et al., 1998; Bennett et al., 1998). Other lines of evidence indicate that CD40 signaling is part of an important pathway in T-cell-dependent APC activation. Recombinant soluble CD40L stimulates human monocytes to release proinflammatory cytokines (Kiener et al., 1995), whereas ligation of CD40 on DC or interaction between CD4⫹ T cells, notably T helper 1 cells, and DC triggers the production of IL-12 (Koch et al., 1996; Ria et al., 1998). This IL-12 production can be inhibited by blockade of CD40L on the CD4⫹ T cell (Koch et al., 1996). Although CD40 engagement is essential, IFN-웂 is required as a second signal for induction of IL-12 secretion (Snijders et al., 1998). CD40 signaling is also a robust stimulus to upregulate expression of the adhesion molecule ICAM-1

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and the costimulatory molecules CD80 and CD86 (Cella et al., 1996; Shinde et al., 1996). Expression of these molecules is important for CTL priming by DC, but for full induction of protective CTL responses associated with longterm memory, CD40 ligation alone, either naturally through CD40L on CD4⫹ helper cells or by CD40 activating antibody, is unlikely to be sufficient. Although we have succeeded in overcoming peptide-induced peripheral CTL tolerance and augmenting antitumor peptide vaccine efficacy by monoclonal antibody-mediated CD40 activation in vivo (Diehl et al., 1999), this burst of tumor-specific CTL activity appears not to be long-lasting (our unpublished observations), in contrast to the long-term CTL memory associated with vaccination with the same peptide delivered by peptide-loaded DC or by adenovirus (Toes et al., 1997a, 1998a). Nonetheless, CD40 ligation led to markedly improved results of therapeutic MHC class I- or II-presented peptide vaccines, allowing complete eradication of established tumors in the absence of toxicity, whereas the same peptide vaccines in the absence of CD40 ligation had no impact on the tumors or even caused peptide-induced tolerance (Diehl et al., 1999; Sotomayor et al., 1999). Thus CD40 ligation acts as a molecularly defined adjuvant. This can reverse the induction of T cell tolerance, which appear to be an early event in tumor progression (Staveley-O’Carroll et al., 1998). Triggering or blocking of other defined molecules on DC or T cells may help to tip the balance further toward tumor eradication. CD40 is a member of the tumor necrosis factor receptor (TNF-R) super family, whereas CD40L is a member of the TNF family. Other members of both families can have profound effects on the regulation of T cell responses and T cell survival (see next paragraph). Another important target molecule for immunotherapy of cancer is the regulator of costimulation cytotoxic Tlymphocyte-associated antigen 4 (CTLA-4; see Section XI). VII. Fine Tuning of T Cell Responses by TNF(-R) Family Members

TNF-R family molecules and their ligands of the TNF family profoundly affect T cell responses and in defined cases also T cell effector function. In this review we restrict ourselves to a brief discussion of the TNF-R molecules CD95, CD40, CD30, 4-1BB, and OX-40. Detailed reviews of these molecules and their ligands can be found elsewhere (Krammer, 1999; Gravestein and Borst, 1998; Vogel and Noelle, 1998; Toes et al., 1998; Horie and Watanabe, 1998; Weinberg et al., 1998; Vinay and Kwon, 1998). Initiation of T cell responses requires proper duration and intensity of TCR-mediated signals (Lezzi et al., 1998; Hamad et al., 1998; Boniface et al., 1998; Motta et al., 1998; Delon et al., 1998). Full activation of naive T cells also requires costimulation of T cells through engagement of CD28

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by CD80 or CD86 on DC (reviewed in Allison, 1994). However, even in successful CD4⫹ or CD8⫹ T cell activation, for instance, following infection by LCMV or influenza virus, many of the immune T cells eventually die or become inactivated (Belz et al., 1998; Oxenius et al., 1998). It is increasingly clear that the ultimate fate of T cells is determined to a large extent by subtle signaling events involving TNF-R family members and their ligands. All TNF-R family molecules just mentioned have a proven role in this regulation, and an important role of other family members is likely to become apparent in the near future. A. CD95 CD95-mediated T cell death is necessary to prevent splenomegaly, lymphoadenopathy, and autoimmunity, as can be deduced form lpr/lpr mice, which carry a mutation in the CD95 gene, as well as from the CD95L-mutated gld/gld mice (Krammer, 1999). Upon activation, T cells express both CD95 and CD95L, yet it is only later when the T cells have exerted their function that they actually become sensitive to CD95-induced apoptosis (Klas et al., 1993; Peter et al., 1997). Clearly, resistance and sensitivity to CD95 need to be carefully regulated to allow the T cells to function, yet to prevent them from inducing autoimmunity. Several mechanisms that govern CD95-induced apoptosis have been proposed over the years. For instance, the expression of Bcl-2 is higher in resistant T cells than in sensitive ones. Costimulation through CD28 increases this expression even further (Boise et al., 1995). However, T cells from Bcl-2 transgenic mice are not resistant to CD95-induced apoptosis, indicating that expression of Bcl-2 may be required but is not sufficient for complete resistance (Strasser et al., 1995). An alternative mechanism involves the anti-apoptotic molecule cFLIP, which efficiently inhibits CD95-induced apoptosis. cFLIP was shown to be induced in resistant T cells and almost absent in the senstive cells (Irmler et al., 1997). Although this would provide an elegant way to warrant resistance of T cells, it was subsequently shown that resistant T cells fail to form a death-inducing signaling complex upon CD95 triggering (Peter et al., 1997), Since cFLIP requires this complex to exert its function (Scaffidi et al., 1999), it is conceivable that other factors are needed to guarantee a CD95-resistant status of T cells. Whatever the mechanism may be, it should endow peripheral T cells with resistance to CD95-mediated apoptosis early in the immune response, while allowing deletion of most activated T cells, except for the memory cells, when their target has been eliminated. CD95 expression and CD95induced apoptosis in lymphoid cells thus limit clonal expansion and seem to preserve tolerance, as is exemplified by the phenotype of CD95/CD95L mutant mice.

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In tissues such as testis and the eye, CD95L expression is essential to maintain immune privilege (Griffith et al., 1995; Nagata 1997), which seems to be due to elimination of the infiltrating T cells. However, CD95L expression is in itself not sufficient to obtain privilege but requires additional factors. For instance, TGF-웁 was shown to inhibit the infiltration/ activation of neutrophils, which are attracted by CD95L (Chen et al., 1998). Moreover, this immune privilege is not absolute since we have recently shown that adoptive CTL therapy of intraocular tumors in mice was very efficient in the absence of any toxicity. These data suggest that the immune privilege of ocular tumors is related to their low immunogenicity rather than to the failure of effector cells to track down and destroy such tumors (Schurmans et al., 1999). The CD95/CD95L pair is essential not only for (auto-) regulation of the T cell system but also for its effector function. CD95-expressing targets can be efficiently eradicated by CTL through this mechanism (Lowin et al., 1994; Hanabuchi et al., 1994; Ka¨ gi et al., 1994). In certain cases CD95L-induced cytotoxicity even appears to dominate over the perforin/granzyme B pathway (see following). B. CD40 The pivotal role of CD40 on DC in cognate interactions between CD4⫹ Th cells, immature DC, and CD8⫹ CTL precursors has been discussed in the previous paragraph, but CD40 has much broader biological effects as could be anticipated from its wide tissue distribution, including not only DC and monocytes but also B cells and a variety of other cell types outside the immune system. CD40 on B lymphocytes is required for B cell activation, proliferation, isotype switching, germinal center formation, and memory cell generation (Vogel and Noelle, 1998). In contrast to CD95, which is also expressed on B cells, CD40 prevents apoptosis of activated B cells. B cells that have received signals through the B cell receptor become resistant to CD95-mediated apoptosis, allowing a full display of the stimulatory effects of CD40 triggering (Vogel and Noelle, 1998) and of the helper activity of CD95L positive CD4⫹ helper cells. Inappropriately triggered B cells die at the hands of the latter cells. CD40 is also expressed in a variety of human lymphomas and epithelial cancers, including breast cancer. Although CD40 signaling promotes normal B cell responses, it can inhibit neoplastic B cell growth both in vitro and in vivo, the latter in SCID mice (Funakoshi et al., 1994; Murphy et al., 1995). In the same SCID model, treatment with soluble CD40L caused significantly increased survival of mice bearing CD40-expressing human breast cancer tumors (Hirano et al., 1999). Although CD40 triggering can induce apoptosis in its own right, prior exposure of a fibroblast line to anti-CD40 antibody

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rendered the cells resistant to TNF-mediated apoptosis, again pointing to opposing effects of TNF-R family members (Hess et al., 1998). C. CD30 CD30 is expressed by activated, but not by resting, B or T cells, as well as on a subset of thymocytes (Horie and Watanabe, 1998). Mice deficient in CD30 experience an impairment of thymic negative selection (Amakawa et al., 1996). The T-cell-dampening role of CD30 is also borne out by the fact that signaling through CD30 protects against autoimmune diabetes mediated by CD8⫹ CTL (Kurts et al., 1999). CD30-deficient pancreatic islet-specific CTL were roughly 6000-fold more auto-aggressive. Complete destruction of islets and diabetes were induced by the transfer of a few as 160 CD30-deficient T cells (Kurts et al., 1999). Whereas the same group of investigators had previously shown that autoreactive CD8⫹ CTL induced by cross-presentation of self antigens are deleted by a mechanism involving signaling through CD95 (Kurts et al., 1998), CD30 signaling is apparently a second distinct mechanism for deletion of autoreactive T cells. In tumor immunology, however, control of tumor-specific T cell proliferation by CD30 interacting with its ligand is highly undesirable, and ways to block this interaction, perhaps at the expense of (temporary) autoimmunity, are attractive. Interplay between different TNF-R members is illustrated by the finding that CD30 is a CD40-inducible molecule that negatively regulates CD40-mediated immunoglobulin class switching in non-antigen-selected human B cells (Cerutti et al., 1998). This suggests that CD30 dampens the effects not only of CD40-triggered T cell responses, but also of B cell responses. D. 4-1BB 4-1BB is specifically expressed on T cells. Whereas CD40 ligation provides activation and survival stimuli for DC and B cells, 4-1BB triggering promotes activation and survival of T cells, in particular, Th1 cells and CD8⫹ CTL. It thus provides a CD28-independent costimulation pathway for T cells (De Benedette et al., 1997; Kim et al., 1998; Saoulli et al., 1998; Vinay & Kwon, 1998; Takahashi et al., 1999). Entirely in line with these findings, agonistic monoclonal antibody to 4-1BB caused eradication of established poorly immunogenic tumors, accompanied by a marked augmentation of tumor-selective CTL activity (Melero et al., 1997). Conceivably, because CD40 signaling activates DC to promote CTL activation whereas 4-1BB signaling directly triggers CD8⫹ CTL, simultaneous activation of these two TNF-R members might act synergistically in promoting tumor-specific CD8⫹ CTL responses. Preliminary studies in our laboratory indicate that this is indeed the case (our unpublished observations). 4-1BB

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ligand (4-1BBL) is expressed on mature B cells and macrophages, as well as on activated B cells and DC (Vinay and Kwon, 1998). 4-1BBL is upregulated on B-cells by CD40 ligation and on DC by culture-induced maturation (De Benedette et al., 1997) and possibly also by CD40 ligation. E. OX-40 The Ox-40 TNF-R family member is expressed on the surface of activated CD4⫹ T cells. This appears to be yet another receptor on T cells that inhibits activation-induced T cell death, thereby enhancing both effector and memory CD4⫹ responses (Weinberg et al., 1998). Ox-40L is expressed on activated professional APC. Its expression is upregulated on B cells by activation through the antigen receptor and through CD40, and on DC through CD40. As described for 4-1BB in the previous section, ligation of Ox-40 (through a soluble Ox-40L : Ig fusion protein) enhances tumor immunity in murine tumor models (Weinberg et al., 1998; Muy-Rivera et al., 1998). F. OTHER TNF-R FAMILY MEMBERS A role for other TNF-R family members in the regulation of T cell responses is less well defined. An intriguing and potentially important player in the field is CD27, next to its ligand CD70 (Loenen, 1998; Lens et al., 1998). CD27 clearly is a costimulatory receptor on both T and B cells (Lens et al., 1998). CD70 is largely confined to lymphoid cells. Since both molecules are absent from dendritic cells, this receptor–ligand pair is not thought to be involved in T cell priming, but rather appears to control size and function of lymphocyte populations following antigen triggering (Loenen, 1998; Lens et al., 1998) VIII. Escape Mechanisms of Tumors

As has been argued, two of the most powerful escape mechanisms of tumors may be either to be ignored by the immune system (Starzl and Zinkernagel, 1998; Sogn, 1998) or to induce peripheral T cell tolerance. Tolerance occurs in particular because the majority of the tumors, like most normal tissue, lack costimulatory properties themselves and, following cross-presentation of tumor antigens by DC, fail to activate the DC to an immunizing state and instead leave them in their normal tolerizing state. In doing so, tumors do not need to develop any special feature. Just by masquerading as normal tissues, cancer lesions can cause tolerance following cross-presentation of tumor antigens (Heath et al., 1998). Other escape mechanisms of tumors usually depend on their genetic instability, thus allowing loss or gain of gene expression permitting specific

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immune evasion strategies. Such mechanisms may be especially important for tumors that fail to tolerize—or fail to become ignored by—the immune system, perhaps because they express highly immunogenic antigens and/ or because their expansion causes inflammation. Once tumor-specific T cell immunity has been elicited, loss of MHC class I expression (H-2 or HLA) is a frequent route of escape from CTL-mediated immune attack (reviewed in Garrido et al., 1995, 1997; Ruiz-Cabello and Garrido, 1998). MHC class I expression can be of various kinds, ranging from loss of a single HLA locus to total HLA loss (Garrido et al., 1997). Loss of 웁2microglobulin synthesis is a frequent cause of total HLA loss. Even in tumor types not considered to be strongly immunogenic, loss of HLA class I expression of one type or another is very frequent (Cabrera et al., 1998). In melanoma HLA-B locus downregulation was found in association with HLA–haplotype loss (Real et al., 1998). Recently, 웁2-microglobulin gene mutations were shown to result in lack of HLA class I molecules on melanoma cells of two patients immunized with MAGE peptide (Benitez et al., 1998). Further studies are required to establish a causal relationship between vaccination and loss of HLA class I expression. Loss of HLA class I expression and melanocyte differentiation antigen expression were shown to be independent events in metastatic melanoma ( Ja¨ ger et al., 1997). In addition to loss of MHC class I or 웁2-microglobulin genes or defects in MHC class I regulation, human cancer cell lines were frequently shown to exhibit deficiencies in genes involved in antigen processing ( Johnson et al., 1998). Affected gene products included the TAP1/ TAP2 peptide transporter and the LMP2, LMP7, and LMP10 (MECL-1) proteasome components. Importantly, most of these deficiencies could be restored by treatment with interferon-웂. However, cancer cells can develop unresponsiveness to IFN-웂 or even all interferons by deficiencies in, respectively, expression of the IFN-웂 receptor or the STAT protein that is involved in transducing the intracellular signal (Garrido et al., 1997). Indeed, human cancer lines that are resistant to MHC induction by IFN-움 and/or 웂 have been described (Garrido et al., 1997; Abril et al., 1998). The importance of IFN-induced antigen processing and MHC expression in cancer immunosurveillance was recently demonstrated in mice lacking either the IFN웂 receptor or the STAT1 protein (Kaplan et al., 1998). These mice showed both increased spontaneous tumor incidence and more rapid tumor development following application of the chemical carcinogen methycholanthrene. In particular, the lack of IFN-웂 responsiveness appears to decrease the tumor immunogenicity and might conceivably also act at the effector cell level by decreased sensitivity to IFN-웂-deficient T cells and NK cells. Tumor viruses can evade proteasome-mediated processing in various ways. In the case of EBV-induced Burkitt lymphomas, all viral antigens with

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the exception of EBNA-1 are switched off. EBNA-1 shrewdly subverts proteasome-mediated class I processing through a glycine–alanine repeat sequence that prevents the interaction of ubiquitinated polypetides with the proteasome, effectively inhibiting proteolysis and thereby MHC class I epitope generation (Shapiro et al., 1998). We have observe two instances of epitope-specific immune evasion events affecting proteasome-mediated antigen processing of a tumorvirus (MuLV)-encoded CTL epitope. One virus variant contained a single amino acid substitution within the viral epitope which caused a novel major cleavage site within the epitope. This led to premature destruction of the viral sequence (Ossendorp et al., 1996). In the second example a single amino acid substitution immediately flanking the C terminus of the viral epitope prevented precise C-terminal cleavage of the epitope which is required for proteasome-mediated generation of CTL epitopes (Beekman et al., 1999). Similarly, a mutation in p53 flanking a CTL epitope precluded proper proteasome-mediated generation of this epitope, protecting cells from lysis by specific CTL (Theobald et al., 1998). Additional strategies utilized by (human) cancer viruses to evade specific immune responses have been reviewed by us (Van der Burg et al., 1999). Another level of immune escape is production by tumor cells of immunosuppressive factors such as TGF-웁 and IL-10. IL-10 production leads to strongly reduced levels of TAP and MHC by the tumor cells (Petersson et al., 1998). Finally, tumors sometimes develop mechanisms that directly interfere with their demise by the action of cytolytic T lymphocytes. One strategy is the production of a soluble decoy receptor, termed decoy receptor 3 (DcR3), that binds to CD95L and inhibits CD95L-induced apoptosis (Pitti et al., 1998). In this study, the DcR3 gene was amplified in about half of 35 primary lung and colon cancers studied. Another strategy involves overexpression of an apoptosis-inhibiting protein called FLICE inhibitory protein (c-FLIP). This protein is the most receptor-proximal inhibitor of CD95-induced apoptosis and interferes with CD95- but not perforindependent killing by CTL in vitro (Kataoka et al., 1998). We have demonstrated that overexpression of c-FLIP in two murine tumors, whose eradication critically depends on CTL induction, results in their escape from this response. Moreover, these tumors were found to be selected for elevated c-FLIP expression in immunocompetent but not immunodeficient hosts (Medema et al., 1999). The c-FLIP-overexpressing tumor cells were normally lysed in vitro in the usual assays, for which the perforin pathway apparently sufficed. These results indicate that the CD95-dependent pathway is more important for tumor cell killing in vivo than is to be anticipated from in vitro cytolytic assays. Furthermore, our data demonstrate that blockade of the CD95 pathway through overexpression of c-FLIP, as was

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found in human melanomas (Irmler et al., 1997; Griffith et al., 1998), can indeed serve as an efficient mechanism of immune-escape by tumors. IX. Cancer Therapy by Adoptive Transfer of T Cells

The marked success of adoptive T cell therapy in tumor eradication in a setting of allogeneic bone marrow or stem cell transplantation has already been mentioned. How can we capitalize on these findings and achieve success in a wider variety of cancers? First, we should realize that the eradication of the highly antigenic EBV lymphomas that arose in immundeficient hosts is light years away from dealing with EBV lymphomas that arose in immunocompetent hosts, which express much less or even no antigens detectable by tumor-specific CTL and likely have evolved a variety of other immune evasion strategies. Nevertheless, some EBV-encoded antigens against which CTL responses have been recorded are expressed on Reed–Sternberg cells in Hodgkin’s diseases (Table 1), and CTL against these antigens could be used for immunotherapy of Hodgkin’s disease (Sing et al., 1997). Poor antigen expression and immune evasion do not apply, however, to relapsed CML in allogeneic stem cell recipients. CML constitutes a disease involving all hemopoietic lineages, including DC. It is tempting to speculate that inclusion of DC among the leukemia population contributes to the success of allogeneic T cell therapy in relapsed CML. These DC may fulfill all of the criteria for successful expansion and survival of infused therapeutic T cells, including CD40, CD28, 4-1BB, and Ox-40 signaling, preventing premature death, or lack of expansion of therapeutic T cells. In addition, allogeneic T cells have the advantage of not having undergone self MHC-restricted negative selection in the thymus. Moreover, positive selection in the context of a certain MHC molecule does not seem to be required to generate high-avidity TCR that are restricted by the same molecule. Based on this principle, high-avidity peptide-specific CTL against viral and tumor antigens can be generated from allogeneic donors in both mouse (Sadovnikova and Stauss, 1996; Obst et al., 1998) and human (Sadovnikova et al., 1998; Mu¨ nz et al., 1999). From the allogeneic repertoire of T cells, highly specific T cells can therefore be retrieved not only against leukemias but also against solid tumors. The likelihood that this will be successful against solid tumors is already indicated by results of polyclonal allogeneic cell therapy in a mouse mammary carcinoma model (Morecki et al., 1998). Provided that MHC-restricted epitopes are known, advanced cell-sorting technology, involving, for instance, MHC tetramers (see Section XIII), can be employed to select and expand T cells from the allogeneic donors (Dunbar et al., 1998), minimizing the risk of graft versus

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host disease mediated by irrelevant alloreactive T cells among the desired tumor-specific T cells. A category of tumor antigens of particular usefulness in the allogeneic setting are minor histocompatibility antigens with restricted expression to the hemopoietic system (Goulmy 1997; Simpson et al., 1998). The feasibility of expanding human CTL against such antigens from the blood of healthy allogeneic donors has been reported (Mutis et al., 1999). If the effectiveness of T cell culture and expansion from allogeneic donors can be made sufficiently high, HLA-mismatched or minor H-mismatched allogeneic stem cell transplantation with highly purified stem cells, in combination with high avidity specific T cell therapy, has much to offer and could be applied to both leukemias/lymphomas and solid tumors. Interestingly, in a murine model graft versus host disease could be suppressed and graft versus tumor effects amplified by infusion of activated NK cells following allogeneic bone marrow transplantation (Asai et al., 1998). One of the challenging questions with respect to adoptive T cell therapy is whether therapeutic T cells can be obtained in sufficient quantity and quality from tumor-bearing patients. Scanty experience from melanoma studies indicates that this is possible (Rosenberg et al., 1994). Another case in point is virus-induced cancers such as HPV-induced cervical carcinomas which express non-self antigens. Although in patients bearing HPV-positive malignancies a certain level of tumor-induced tolerance cannot be excluded, deletion of high-avidity T cells by professional APC that crosspresent antigens from normal tissues is not an issue here. In accordance with this notion, specific CD8⫹ CTL and CD4⫹ T helper cells have been observed in patients with HPV-16-induced lesions (Ressing et al., 1996; Evans et al., 1997; De Gruijl et al., 1996, 1998; Luxton et al., 1996). In the years to come proof of concept of tumor eradication with T cells retrieved from the autochthonous host will have to be delivered. These efforts should include cloning and expansion of CD4⫹ tumor-specific T cells for therapy trials by adoptive transfer. As outlined in the previous section, effective T cell immunity, even against MHC class II-negative tumors, depends heavily on tumor-specific CD4⫹ T cells, in both the induction and effector phases (Ossendorp et al., 1998). Adoptive transfer of tumor-specific CD4⫹ cells, in particular IFN-웂-producing Th1 cells, can be expected to activate DC both locally and in the draining lymph nodes. This can strongly promote the activity and expansion of preexistent or simultaneously transferred tumor-specific CD8⫹ T cells. Quite apart from this, tumor-specific CD4⫹ T cells can be expected to themselves exert effector function, because cytokines produced by Th1- or Th2-type CD4⫹ cells can recruit and activate macrophages and eosinophils, respectively (Hung et al., 1998). In this study, protection against tumor challenge was

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strongly associated with the presence of eosinophil granulocytes and the production of oxygen radicals by tumoricidal macrophages. Of note, these CD4⫹-dependent effector mechanisms should also operate in the case of tumors that have lost MHC class I expression. Although adoptive T-cellmediated immunotherapy seems a highly promising approach, major hurdles remain in establishing technologies for the efficient and reliable expansion of specific T cells. The major problems are limitation in the number of cell divisions (life span), induction of apoptosis rather than proliferation as a result of an inappropriate ensemble of growth factors and stimuli, and loss of antigen specificity due to overgrowth of the culture by nonspecific rapidly growing lymphocytes. All tricks discussed in the preceding pages should be tried to obtain sufficient cell numbers for adoptive T cell therapy. Undoubtedly, this will lead to major biotechnological advances in adoptive T cell therapy and it is hoped, will make this therapy available to more than the handful of patients who profit by it today. X. Design of Rational Cancer Vaccines Including Molecularly Defined Adjuvants

The area of cancer vaccines has been reviewed by several investigators (Toes et al., 1997b; Offringa et al., 1999; Pardoll, 1998; Restifo and Rosenberg 1999). This discussion will therefore be restricted to what future tumor vaccines might look like and to the feasibility of therapeutic rather than preventive vaccines. Processing of exogenous protein not only for MHC class II but also for class I presentation is now a widely recognized fact. Previous failure to view exogenous class I processing as an important and efficient pathway is probably due to the fact that much exogenous class I processing and presentation were never visualized, because APC presenting the epitopes were not appropriately stimulated for CD8⫹ CTL induction. The signals for appropriate DC stimulation are now being uncovered (Sections VI and VII) and several DC and/or CD8⫹ stimuli (adjuvants) have been found capable of supporting CD8⫹ CTL responses following exogenous antigen delivery. Indeed, appropriate delivery of exogenous antigens in different formulations, including synthetic peptides in incomplete Freund’s adjuvant (IFA), proteins in IFA or other adjuvants, denatured protein, and liposome or particle-associated proteins, leads to efficient CTL induction and protection (reviewed in Jondal et al., 1996, and Offringa et al., 1999). In our hands excellent protection against murine HPV16 tumors associated with CTL memory was achieved by different types of vaccination. Effective vaccines include HPV16 synthetic peptides of the exact MHC class I fitting length (9-mer) or a 19-mer peptide with the same epitope in the middle, delivered in IFA (Feltkamp et al., 1993) or loaded onto ex vivo-activated DC (Mayordomo et al., 1995; Ossevoort

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et al., 1995). Recently we showed that an E7 32-mer peptide with the epitope in the middle induced a level of CTL-mediated protection similar to that of the minimal MHC class I-binding 9-mer if delivered in IFA (our unpublished obervations). HPV16 E7 recombinant protein delivered in the MF 59 adjuvant or in IFA also induced protective T cell immunity (Zhu et al., 1995; De Bruijn et al., 1998). The immune system is apparently capable of excising the exact MHC class I-binding peptides from exogenously offered proteins and long peptides. On the basis of these results, we favor long peptides or proteins for future anticancer vaccination trials. The advantage of such an approach is that, if delivered in the appropriate adjuvant (with DC stimulatory capacity), all potential MHC class II and class I epitopes within the delivered peptides or protein will be processed and presented to host T cells. These vaccines will thus become independent of MHC binding motif prediction or processing algorithms and can be administered to subjects independent of their HLA type. Moreover, we have observed that downregulation of CTL responses, observed by us in the case of two exact MHC class I-binding adenovirus E1 peptides (Toes et al., 1996b,c), probably because the short peptides rapidly leak out of the adjuvant depot and fail to become loaded on activated DC (Diehl et al., 1999), does not occur if these epitopes are delivered as middle portions of long 32-mer peptides (our unpublished observations). The main message from this work is that, as long as proper adjuvanticity is ensured, MHC class I-restricted protective responses will be induced, regardless of the length of the peptide/protein sequences offered. The same holds in fact for DNA vaccines and viral vector-based vaccines. DNA vaccines need to have immunostimulatory sequences that activate DC. In most cases of DNA vaccination, the DC probably acquire the antigen via exogenous processing (Tighe et al., 1998). In certain cases, however, when DNA was delivered in mice via gene gun or by scarification of the ear, a major involvement in T cell priming of direct presentation by gene-transduced DC was demonstrated (Porgador et al., 1998; Akbari et al., 1999). An alternative approach to obtaining direct presentation of the antigen of interest involves DC that are transfected or infected in vitro prior to their application in vivo (e.g., Kim et al., 1997; Tuting et al., 1998; Nair et al., 1998). Is it possible to further improve the potency of peptide/protein-based cancer vaccines by the use of improved molecularly defined adjuvants? The answer is probably yes. Mouse studies have indicated that prophylactic or tolerizing peptide vaccines acquire therapeutic tumor-eradicating potential by antibody-mediated CD40 signaling (Diehl et al., 1999; Sotomayor et al., 1999). CD40–ligand trimer constitutes an alternative to CD40 signaling monoclonal antibody (Gurunathan et al., 1998). Further improvements

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can be expected from agonistic signaling through 4-1BB (Melero et al., 1997) and Ox-40 (Weinberg et al., 1998) and from blockade of CD30. If applied clinically, these measures should be monitored carefully for induction of autoimmune disease (see, for instance, Roskrow et al., 1999; Overwijk et al., 1999). The idea to temporarily shift the T cell activation and survival balance within the immune system by signaling and blocking of TNFR family members and their ligands (see Section VII) appears useful not only for tumor vaccine strategies but also for adoptive T-cell-based cancer therapies. Eventually it should be possible to design small molecular compounds that mimic agonistic or blocking action of individual TNFR family members. A second mode of improvement of peptide/protein-based cancer vaccines is to offer epitopes with improved immunogenicity to the immune system. This has been achieved by Rosenberg et al. (1998), who used a gp100 peptide vaccine with a methionine instead of a threonine at position 2 of the peptide. This ensured increased binding to the HLA-A *0201 molecule and resulted in CTL responses in 91% of vaccinated patients and objective clinical responses in combination with IL-2. A similar strategy to break tolerance against gp100 was used in a mouse melanoma model. The CTL elicited with a high-affinity altered peptide ligand crossreacted with self gp100, lysed tumor cells, and were therapeutically active (Overwijk et al., 1998). Improved immunogenicity was also obtained with an HLA-A*0201-binding CEA peptide, this time by substituting a TCR contact residue in the peptide, thus more easily breaking tolerance and eliciting CTL that cross-reacted with the wild-type CEA peptide and lysed CEA-overexpressing cancer cells (Zaremba et al., 1997). Recombinant viruses used in cancer vaccines include attenuated influenza or vaccinia viruses, avian poxviruses, which do not replicate in mammalian cells, or gene-deleted adenoviruses. Such viruses, encoding either entire tumor antigens (reviewed in Offringa et al., 1999; Restifo and Rosenberg, 1999) or string-of-beads arrangements of several tumor-associated CTL epitopes (Toes et al., 1997a), have been shown to elicit tumor-specific CTL responses associated with tumor protection. In one phase I vaccination study with recombinant avipox CEA virus in advanced cancer patients, CEA-specific CTL responses were induced and the vaccine was well tolerated (Marshall et al., 1999). As argued previously for the peptide/protein vaccines, disruption of tolerizing or downregulatory T cell circuits is probably required for optimal in vivo effects of these antitumor vaccines. It is unlikely that this can be achieved alone by incorporation of additional immunostimulatory sequences within the recombinant vaccines. The effects of the vaccine will be local and very temporary, particularly upon boosting with the same vaccine because of accompanying immune responses against the virus

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vector, whereas a prolonged systemic T cell expansion and survival strategy is needed. Therefore, vaccination strategies are being developed that involve subsequent vaccination with different vectors encoding the same antigen (e.g., Irvine et al., 1997; Hodge et al., 1997). Furthermore, stringof-beads constructs (polyepitope constructs) can be substantially improved by the incorporation of CTL epitopes with increased binding ability as well as of tumor-specific T helper epitopes (Toes et al., 1999; Topalian et al., 1996; Manici et al., 1999; Pieper et al., 1999; Chaux et al., 1999) and perhaps by incorporation of cytokine genes such as IL-12. Like recombinant viruses, DNA vaccination also induced CTL-mediated tumor protection (e.g., Schreurs et al., 1998), although it should be noted that DNA vaccination can also result in strong T cell responses against immunodominant epitopes encoded by the vector backbone (Van Hall et al., 1998). An interesting variant of the genetic vaccination concept is the use of a selfreplicating RNA vaccine. In this vaccine design, the function of the naked nucleic acid immunogen was amplified by the incorporation of a geneencoding and RNA replicase from Semliki Forest virus. A single injection of this vaccine elicited antibody and CD8⫹ tumor-specific CTL responses, protected mice from tumor challenge, and prolonged survival of mice bearing established tumors (Ying et al., 1999). XI. Tumor Immunotherapy Based on Improved Costimulation via the CD28 Pathway

Expression of the costimulatory molecules CD80 and CD86 on professional APC is required for initiation of T cell responses. These molecules costimulate TCR-triggered lymphocytes via the CD28 costimulatory molecule. The same ligands downregulate T cell responses by binding to the CTLA-4 molecule on T cells, serving as a brake on CD28-mediated T cell costimulation. Like TNFR-mediated T cell homeostasis, this costimulatory event and its downregulation are finely regulated (Chambers and Allison, 1997). Tumor cells show enhanced immunogenicity when transfected with CD80 or CD86 (Hellstro¨ m et al., 1995). Mouse embryo cells transfected with CD80 and a construct expressing an endoplasmatic reticulumtargeting signal sequence followed by a tumor-associated CTL epitope sequence, associated with very high specific peptide/MHC expression, even completely bypass professional APC for in vivo CTL induction and are capable of direct CTL-priming (Schoenberger et al., 1998a). Such a strategy overcomes poor antigen uptake by professional APC and can be useful for therapeutic purposes. Indeed, established spontaneous mammary carcinoma metastases could be eliminated or reduced following immunotherapy with a cellular vaccine consisting of tumor cells transfected with a combina-

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tion of CD80 and MHC class II genes. However, the primary tumor was not affected by this treatment. Still such a strategy would be useful if the primary tumor is resectable or sensitive to irradiation treatment (Pulaski and Ostrand-Rosenberg, 1998). Another sophisticated strategy is to use a single-chain monoclonal antibody recognizing a tumor antigen and couple this to the signal transduction domain of CD28. Human primary T cells retrovirally transduced with this construct proliferated and produced IL2 upon recognition of the antigen (Krause et al., 1998). Although similar ‘‘T-bodies’’ expressing tumor-specific antibody domains fused to the CD3␨ signaling domain have been shown to effectively eliminate tumor cells in vitro (review: Eshhar, 1997), true in vivo efficacy of such engineered effector cells remains to be demonstrated. The successful treatment of established poorly immunogenic tumors by combined vaccination with GM–CSF-producing tumor cells and CTLA-4 blockade (Hurwitz et al., 1998; Van Elsas et al., 1999) has already been referred to in the introduction of this review. XII. Enhancement of Tumor-Specific T Cell Responses by Cytokines and by Cytokine-Transduced Tumor Cells

The antitumor effects of IL-2 alone or in combination with adoptive CTL therapy are well known and have been reviewed elsewhere (Rosenberg et al., 1997). High-dose IL-2, however, causes severe toxicity. Other cytokines that have received considerable attention for immunotherapy of cancer are IL-12 and GM–CSF. In a murine tumor model, tumor cells transfected by IL-12 and IL-18 acted synergistically in protection against concurrently injected tumor cells (Coughlin et al., 1998b). The mechanism of action involves inhibition of angiogenesis. Tumor cells defective in IFN-웂 receptor 1 are less responsive to IL-12 therapy in vivo (Coughlin et al., 1998a). The most potent cytokine gene to enhance tumor-specific responses, if used to transfect tumor cells to create a cellular vaccine, is GM–CSF (Dranoff et al., 1993). Although GM–CSF transduction does not enhance the immunogenicity of all murine tumors, a recent clinical phase I study using GM–CSF-transduced irradiated autologous melanoma cells showed much more densely infiltrated tumor lesion after vaccination than prior to vaccination in 11 of 16 patients examined. The infiltrates included T cells and plasma cells as well as granulocytes (eosinophils and neutrophils) and were associated with evidence of substantial tumor destruction (Soiffer et al., 1998). In addition, local pharmacological administration of GM–CSF in patients with colorectal cancer enhanced antibody and proliferative T cell responses to recombinant carcinoembryonic antigen (Samanci et al., 1998). Systemic

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administration of GM–CSF enhanced CTL and DTH responses to MHC class I-binding tumor-associated peptides in melanoma patients ( Ja¨ ger et al., 1996). XIII. Monitoring of Tumor-Specific T Cell Responses

It has been notoriously difficult to sensitively monitor tumor antigenspecific CTL responses in cancer patients and thus document the effect of vaccination and other forms of immunotherapy. An important step forward is TCR staining with fluorescent tetrameric high-avidity peptide/ MHC complexes (Altman et al., 1996). This technology has already allowed sensitive and reliable detection of melanoma peptide-specific CTL in the blood of melanoma patients and in metastatic lymph nodes (Romero et al., 1998a, b; Dunbar et al., 1998). Alternatively, the frequency of specific T cells (either CTL or Th) can be monitored by measuring cytokine production at the single cell level, through Elispot assays (Herr et al., 1997; Romero et al., 1998a), intracellular cytokine staining (Murali-Krishna et al., 1998), or staining of secreted cytokines that have been captured at the surface of the secreting cells through bispecific antibodies (Manz et al., 1995). An advantage of tetramer staining is the possibility of discriminating between low- and high-affinity T cells (Davis, 1999), the latter of which are likely to have more impact on the eradication of tumors in vivo. On the other hand, the cytokine staining techniques can discriminate between responsive and hyporesponsive (anergic) T cells. Although tetramer and cytokine staining, at least in certain settings, yielded the same outcome in numbers of antigen-specific T cells (Murali-Krishna et al., 1998), it is very likely that this will not always be the case. For instance, in patients with advanced cancer tumor, reactive T cells may have become anergic. Such T cells would still be visible with tetramers, but not through cytokine staining. It seems therefore advisable to use both detection approaches in parallel. Of note, both tetramers and staining of extracellularly captured cytokines allow sorting of live cells on the basis of their antigen specificity. The resulting T cell populations can subsequently be expanded in vitro and are of potential interest for adoptive immunotherapy (as discussed in Section IX). XIV. Immunotherapy with Monoclonal Antibodies

While not the chief subject of this review, the impact of monoclonal antibody therapy is important and calls for intensified efforts to improve it. Anti-CD20 antibodies have shown significant clinical responses in many B cell lymphoma patients who have failed chemotherapy (Maloney et al.,

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1997). Anti-CD20 is now a registered anti cancer therapeutic compound. Conceivably, the therapeutic effect can be further improved by activation of Fc-receptor-bearing effector cells with cytokines such as IL-2 (Hooijberg et al., 1995). Postoperative adjuvant treatment of patients with colorectal cancer with the monoclonal antibody 17-1A, specific for epithelial cell adhesion molecule (Ep-CAM), led to an approximately 30% reduction in mortality from Duke’s stage C colorectal cancer 7 years later (Riethmu¨ ller et al., 1998). Apparently this monoclonal antibody dealt effectively with micrometastases, despite the fact that it was an intact mouse monoclonal antibody with less than optimal interaction with human Fc receptors for maximal effector function. XV. Epilogue

This review shows that a plethora of different immunotherapeutic strategies mediates considerable biological effects in a variety of experimental systems and clinical studies. It will be an art to extract from these approaches those therapies that will be effective in the various clinical situations with a minimum number of toxic side effects. Probably we have to live with at least some autoimmunity if we are to cure patients with a significant burden of tumors expressing tumor-associated autoantigens. An alternative is allogeneic bone marrow transplantation in combination with immunotherapy. After the current phase of extensive phase I trials in patients with advanced cancer, the odds for success are by far the best in patients with early cancer and with minimal residual disease. Substantial reduction of the high incidence of virally induced cancer in many countries by preventive vaccination is an achievable goal. Rescue therapies for patients suffering from tumors that have escaped T cell immunity, for example, by loss of MHC expression, must be considered. CD4⫹ T cells may be active in this case, next to monoclonal antibodies. What about NK cells, whose therapeutic potential in human disease remains largely unexplored? Monoclonal antibody therapy, adoptive transfer of T cells, and various vaccination strategies must all be rigorously explored without prejudice for—or against—any particular strategy. Progress is likely to be slow and based on a shrewd combination of animal experiments and clinical trials. It can no longer be denied that this is a most exciting area of immunology. Malignant tumors are the ultimate challenge to immunologists, posing profound and basic questions concerning tolerance, escape, stimulation, death, and survival. REFERENCES Aarnoudse, C. A., van den Doel, P. B., Heemskerk, B., and Schrier, P. I. (1999). Interleukin2-induced, melanoma-specific T cells recognize CAMEL, an unexpected translation product of LAGE-1. Int. J. Cancer 82, 442–448.

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