Antibody-based vaccines for the treatment of melanoma

Antibody-Based Vaccines for the Treatment of Melanoma Jose Lutzky, Ana M. Gonzalez-Angulo, and Jennifer A. Orzano Malignant melanoma remains a difficult clinical problem. Chemotherapy is not effective and immunotherapy has long been contemplated as the preferred approach to this disease. Extensive passive and active immunotherapy trials have been conducted. Active vaccination with whole cells or defined antigens, administered with a panoply of techniques to increase immunogenicity, has yielded inconsistent results. The development of antibody-based vaccines has allowed vaccination without the need for tumor tissue material or purified antigens. The idiotype network theory originally proposed by Lindemann and by Jerne provided the basis for the development of anti-idiotype (anti-Id) antibody vaccines, which mimic the internal image of the epitope targeted for immunization. Preclinical and phase I clinical data are available for various malignancies. In melanoma, some of the anti-Id vaccines have targeted gangliosides. One of these vaccines, TriGem, has been successful in generating a robust and specific humoral immunity in melanoma patients. Phase II data suggest this anti-Id vaccine has clinical activity. Semin Oncol 29:462-470. Copyright 2002, Elsevier Science (USA). All rights reserved.

D

ESPITE THE RAPID progress in cancer therapeutics realized during the last decade, melanoma remains one of the most difficult solid tumors to treat effectively with standard chemotherapy and/or radiation. The incidence of melanoma in the United States continues to increase with 53,600 new cases and 9,600 deaths estimated in 2002; the lifetime risk of melanoma is now 1:58 for men and 1:82 for women.1 Melanomas were targeted early on for immunotherapeutic approaches because of the documented instances of spontaneous regressions and influence of the host’s underlying immunologic integrity on the progression of the disease. Immunotherapy is an attractive option for the treatment of certain types of malignant tumors because of its potential for achieving maximal therapeutic benefit with minimal toxicity. Immunologic interven-

From the Melanoma Multidisciplinary Program, Mount Sinai Comprehensive Cancer Center, Miami Beach, FL; and the University of Miami, Miami, FL. Address reprint requests to Jose Lutzky, MD, FACP, Melanoma Multidisciplinary Program, Mount Sinai Comprehensive Cancer Center, 4306 Alton Rd, Miami Beach, FL 33140. Copyright 2002, Elsevier Science (USA). All rights reserved. 0093-7754/02/2905-0005$35.00/0 doi:10.1053/sonc.2002.35241 462

tions may be achieved through the induction of an immune response (active immunotherapy) or by the administration of antibodies (passive immunotherapy). Another approach is the stimulation of effector cells with cytokines, encompassing both active and passive mechanisms. There are two approaches to active immunotherapy, based on whether or not they utilize tumor-derived material such as tumor cells or tumorassociated antigens (TAAs) to induce antitumor immunity. Several studies have shown that melanoma may be responsive to treatment based on stimulation of T-cell immunity by TAAs.2-4 Various vaccination strategies are possible. Autologous or allogeneic intact tumor cells or antigen-supplemented tumor cells have been used frequently. Defined antigen vaccines include purified peptides, proteins, gangliosides, and anti-idiotypes. Genetic manipulation of tumor cells, viruses, or dendritic cells transfected with cytokines or with antigen genes is also a major area of focus in cancer vaccine development. The generation of anti-idiotype (anti-Id) monoclonal antibody (mAb) vaccines is the major antibody-based tumor-specific active approach that does not utilize tumor-derived material and will be the main focus of this review. We will discuss the principles of the anti-Id network theory and its application to antibody-based vaccine therapy. We will review the clinical experience with anti-Id vaccination therapy in malignancies other than melanoma and summarize the available data on anti-Id antibody treatment for melanoma. THE ANTI-IDIOTYPE NETWORK THEORY

Active immunotherapies such as vaccination with tumor-derived material have encountered a number of potential limiting factors. TAAs are often weakly immunogenic, since most are modified self-antigens to which immune tolerance has developed. One strategy to break immune tolerance is to present the critical epitope to the tolerant host in a different molecular environment. This approach has been successful with well-defined antigens such as haptens. However, most tumor antigens are chemically ill defined and difficult to purify.5 Some investigators have taken an alternative Seminars in Oncology, Vol 29, No 5 (October), 2002: pp 462-470

ANTIBODY VACCINES FOR MELANOMA

463

Fig 1. The anti-Id network and generation of anti-Id vaccines. Reprinted with permission from the American Association for Cancer Research.

approach by generating anti-Id mAbs that mimic the natural TAA. In the early 1970s, Lindemann6 proposed that the immune system consists of a network of interacting antibodies and lymphocytes. Jerne, in an elaborate discussion paper,7 provided further support for widespread acceptance of the network hypothesis, postulating that the interaction of the Id and anti-Id regulates the immune response of the host to a given antigen. The network hypothesis predicts that within the immune network, the universe of external antigens is mimicked by idiotypes expressed by antibodies and T-cell receptors in a stochastic fashion. In the words of Lindenmann, “the world of antigenic determinants is represented in the world of immunoglobulin molecules in two different manners: as negative images located in the combining sites (antibody) and as positive images located in the idiotypic sites (anti-idiotype).” Two different approaches to tumor immunotherapy apply the principles of the anti-Id network theory. The first approach relies on the presence of internal antigen images in the idiotype repertoire. The internal image idiotypes mimic the threedimensional shapes of antigens and are not genetically restricted. The antigens may be presented in a different molecular environment (such as in a murine antibody molecule), thereby enhancing their immunogenicity. The approach proposed by Paul and Bona8 implied the existence of regulatory idiotypes, a special class of idiotypes with unique regulatory functions prior to antigenic stimulation. These regulatory idiotypes could potentially be used to control tumor growth immunologically.

Immunization with a given TAA will generate antibodies against this TAA that are termed Ab1. Subsequently, Ab1 can be used to generate a series of anti-Id antibodies against the Ab1, termed Ab2. Some of these Ab2 molecules can effectively mimic the three-dimensional structure of the TAA recognized by the Ab1. These particular antibodies, called Ab2-␤, fit into the combining sites (paratopes) of Ab1 because they portray the internal image of the TAA. The Ab2-␤ are able to induce specific immune responses similar to those induced by the original TAA and can therefore be used as surrogate TAAs. Immunization with Ab2-␤ can lead to the generation of anti–anti-Id antibodies (Ab3) that recognize the corresponding original TAA identified by the Ab1 (Fig 1).5,9 Immunization with an anti-Id antibody begins with the endocytosis and processing of the antibody by antigen-presenting cells (Fig 2). Subsequently, the peptides are presented in conjunction with major histocompatibility complex (MHC) class II antigens to Th2 CD4 helper T cells. The latter will stimulate Ab3-activated B cells to produce antibody directed at the original antigen. Parallel activation of Th1 CD4 helper T cells results in secretion of interleukin-2 (IL-2) and interferon gamma with further activation of T cells, macrophages, and natural killer (NK) cells. These effector cells directly lyse the tumor and potentiate antibody-dependent cellular cytotoxicity (ADCC). The anti-Id may also be presented to CD8 cells along with MHC class I antigens to generate a cytotoxic CD8 response, amplified by IL-2 from activated Th1 CD4 helper T cells.9,10

464

LUTZKY, GONZALEZ-ANGULO, AND ORZANO

Fig 2. Mechanisms of generation of immune response to anti-Id vaccines. Reprinted with permission from the American Association for Cancer Research.

CLINICAL APPLICATIONS OF THE IDIOTYPE NETWORK MODEL

The application of the principles from the anti-Id network theory allows the transformation of epitope structures into idiotypic determinants expressed on the surface of antibodies. The recurrent nature of the complementary binding sites and idiotypes provides the framework for the generation of anti-Id vaccines. This concept has been employed to induce specific and protective immunity against infectious agents; a role for anti-Id antibodies in the treatment of autoimmune disorders has also been postulated.11-18 A variety of such anti-Id antibodies for the treatment of cancer have been investigated, first in animal studies and more recently in clinical trials. Experimental immunization of animals with anti-Id antibodies mimicking cancer antigens has induced antigen-specific humoral, cellular, and protective immune responses. The use of a carrier or an adjuvant has been shown to enhance the strength and specificity of the immune response. These preclinical studies, including experimental tumor systems and studies performed in animals with anti-Id antibodies mimicking human tumorassociated antigens, have been reviewed elsewhere and fall beyond the scope of this article.19-29

Significant tumor inhibition and improved survival has been observed in animals. These results have provided the basis for the development of clinical protocols to study anti-Id vaccine therapy in cancer patients. CLINICAL EXPERIENCE WITH ANTIIDIOTYPE VACCINES IN TUMORS OTHER THAN MELANOMA

The main advantage of anti-Id vaccines is their ability to allow specific epitope immunization even when tumor or tumor-derived materials are not available, or when the antigen is difficult to purify. Moreover, anti-Id vaccines can be generated with nonprotein antigens. Anti-Id vaccines appear to be quite effective in certain animal model systems and therefore have been used to treat human cancers. Anti-Id antibodies that mimic distinct TAA expressed by malignant cells or distinct determinants of a TAA have been used to implement active specific immunotherapy in patients with malignant diseases. A number of anti-Ids to a variety of tumor antigens have demonstrated active immune responses in patients with colon, ovarian, and breast cancer. Early clinical data in neuroblastoma have been

ANTIBODY VACCINES FOR MELANOMA

reported. These studies are not reviewed here, but they are referenced for the interested reader.30-53 ANTI-IDIOTYPE ANTIBODY VACCINATION IN MALIGNANT MELANOMA

While non-ganglioside anti-Id vaccines for melanoma have been reported, as described later, the bulk of the clinical experience in active immunotherapy for melanoma with anti-idiotypes has focused on the use of gangliosides as a target. Gangliosides are glycolipids composed of a ceramide linked to a sialic acid– containing oligosaccharide. Gangliosides are located in a strategic position within the plasma membrane with the carbohydrate moiety exposed on the outer layer contributing significantly to the antigenic surface profile of the cell. However, the exact function of these molecules remains unclear. Malignant transformation may lead to altered ganglioside biosynthesis. These changes may include incomplete synthesis with accumulation of precursor gangliosides, synthesis of novel gangliosides, structural changes in specific gangliosides, alterations in the ceramide portion, altered ganglioside epitope exposure, and changes in the density of expression in the cell membrane. Certain malignancies display a high level of ganglioside expression. As a rule, the latter are cancers of neuroectodermal origin such as melanoma, neuroblastoma, glioblastoma, astrocytoma, soft tissue sarcoma, and small cell lung cancer. The carbohydrate moiety in neuroectodermal tumors is usually of the ganglio series. The most commonly expressed ganglioside antigens in melanoma are GD3, GD2, and GM2. Because melanoma cells express high-density ganglioside antigens, a large number of studies have focused on passive immunotherapy with antiganglioside antibodies and active immunization with purified gangliosides. Significant clinical responses have been observed after treatment with such mAbs against gangliosides with generation of an inflammatory response with CD8⫹ T lymphocytes. The problems encountered with these treatments have included occasional toxicity and the rapid development of human anti-mouse antibodies (HAMA).54 Active vaccination with purified gangliosides has also been a challenge. Gangliosides are carbohydrate antigens and therefore fail to induce a significant T-cell response. The gangliosides GM2 and GD2 have been the target of most studies.

465

Purified gangliosides injected alone do not induce an antibody response. An extensive literature documents the elegant attempts over the years to increase the immunogenicity of purified ganglioside vaccines.55 Most studies of vaccination with purified or modified gangliosides have been able to demonstrate induction of moderate to high titers of Ab3 IgM antibodies and increased T-cell help for the carbohydrate-specific antibody response. This approach has failed to generate high tumorspecific IgG titers consistently. The induction of an IgG antibody response is desirable because IgG antibodies exhibit better affinity and penetrate tissues more easily; they can mediate ADCC and remain detectable for longer periods. Clinically, the considerable body of vaccination studies using purified gangliosides suggests that melanoma patients with spontaneous or immunotherapy-induced antiganglioside antibodies have a better clinical outcome.56-58 The extensively studied GM2-KLH/QS-21 vaccine has been compared to high-dose interferon alpha-2b (IFN) in patients with resected stage IIB-III melanoma in a large, prospective randomized trial. While antibody responses to GM2 were associated with a trend towards improved relapsefree and overall survival, the study was stopped prematurely after a planned interim analysis demonstrated superiority of the IFN arm.59 It was felt that one of the mechanisms of action of passive immunotherapy and purified ganglioside vaccines could be activation of the anti-Id network and the interest in anti-Id vaccines developed concurrently with these approaches. Mittelman et al administered the mouse anti-Id monoclonal antibody MF11-30, which bears the internal image of human high molecular weight melanoma-associated antigen (HMW-MAA) without adjuvants to patients with stage IV malignant melanoma.60 In the phase I trial, three of 16 patients had minor responses, without significant toxicity. A phase II trial with 21 patients demonstrated HAMA in 17 of 19 evaluable patients; 16 patients developed Ab3. One complete response and three minor responses were reported.60 Twenty-five patients with stage IV melanoma were immunized with the mouse anti-Id mAb MK2-23, which bears the internal image of the determinant defined by anti–HMW-MAA mAb 763.74. Twenty-three patients were evaluable. Only 14 patients developed Ab3 antibodies de-

466

fined by serologic and immunochemical assays to recognize the same or a spatially close determinant as the anti–HMW-MAA monoclonal antibody 763.74. Side effects consisted of erythema, induration, and ulceration at the sites of the injections. Occasionally, flu-like symptoms, arthralgias, and myalgias were noted. Three of the patients who developed anti–HMW-MAA antibodies achieved a partial response. Survival of the 14 patients who developed anti–HMW-MAA antibodies was longer than that of the nine patients without detectable humoral anti–HMW-MAA immunity development.61 A series of sequential protocols with the purpose of enhancing the immunogenicity of the anti-Id MK2-23 vaccine suggested that conjugation with KLH and coadministration with BCG was the best strategy to induce Ab3 (anti– anti-Id).62,63 BEC2 is an anti-idiotypic mAb that mimics GD3 and is able to induce anti-GD3 IgG production but is weakly immunogenic when given alone.64,65 McCaffery et al66 conducted a small clinical trial with BEC2 in combination with either BCG (14 patients) or QS21 (six patients) given to high-risk melanoma patients rendered disease-free after surgical resection. All patients developed high-titer IgG antibodies against BEC2 but anti-GD3 antibodies were induced in only three of 14 patients immunized with BEC2/BCG and in none of the patients immunized with BEC2/QS21. After a median follow-up of 2.4 years, 71% of the patients immunized with BEC2/ BCG remain alive and 64% are free of disease. Many of the long-term survivors did not demonstrate anti-GD3 antibodies. Since data from Mittelman had suggested increased immunogenicity when anti-Id antibodies were conjugated to KLH, another trial with BEC2-KLH/BCG was undertaken. Eighteen high-risk stage III and completely resected stage IV patients were treated; four patients developed IgM anti-GD3 antibodies. No IgG antibodies were detected in contrast to the previous trial.67 Melimmune-2 (IDEC Pharmaceuticals, La Jolla, CA) is the murine anti-Id antibody I-Mel-2, which mimics an epitope of the melanoma-associated high molecular weight proteoglycan antigen. Melimmune-2 was administered to 26 patients with metastatic melanoma in conjunction with the Syntex (Biocine, Emeryville, CA) adjuvant in its microfluidized form (SAF-m). Fever, myalgias,

LUTZKY, GONZALEZ-ANGULO, AND ORZANO

fatigue, headache, and nausea were reported. Patients developing HAMA and anti–I-Mel-2 antibody response fared better clinically. Six patients responded, one with a complete response, two with minor responses, and three with stable disease. The complete responder had measurable titers of Ab3.68 Another trial in 21 patients with resected melanoma was conducted with a dual preparation containing Melimmune-2 and another murine anti-Id antibody mimicking another epitope of the melanoma-associated high molecular weight proteoglycan antigen (Melimmune-1) along with SAF-m. Immune cellular and antibody responses were observed in 12 of the 13 patients in whom detailed studies were performed.69 The same vaccine was used at the M.D. Anderson Cancer Center in 28 patients with high-risk melanoma. Specific cytotoxic T-lymphocyte responses with elevated interferon gamma levels were generated in 43% of patients. Clinical follow-up data have not been published.70 Hastings et al reported the cloning and characterization of a human/murine chimeric anti-Id antibody mimicking the internal image of a GM3 antigen by transfection of the VH and VL DNA from 4C10, a murine anti-Id antibody.71 No further preclinical or clinical data have been published on this anti-Id. The anti-Id antibody 1A7 (TriGem, Titan Pharmaceuticals, South San Francisco, CA), generated against the mAb 14G2a (Ab1), functionally mimics the TAA disialoganglioside GD2, which is overexpressed on the surface of a number of neuroectodermal tumors such as melanoma, neuroblastoma, soft tissue sarcoma, and small cell carcinoma of the lung. When cynomolgus monkeys were vaccinated with 1A7 mixed with the adjuvant QS21, high titers of IgG anti–anti-Id were detected. The specificity of the antibodies for GD2 was confirmed by dot blot analysis and by lysis of GD2-positive target cells in the ADCC assay. The induction of anti-GD2 responses in monkeys was devoid of side effects and clinical trials were initiated.72-74 Forty-seven patients with advanced melanoma received either 1-, 2-, 4-, or 8-mg doses of anti– 1A7 idiotype antiboby vaccine mixed with QS-21 adjuvant (Aquila Biopharmaceuticals, Worcester, MA) given subcutaneously weekly for 4 weeks and then monthly until disease progression. Fortythree percent of patients had undergone prior

ANTIBODY VACCINES FOR MELANOMA

467

Table 1. Clinical Trials With anti-Id mAb Vaccines in Melanoma

Anti-Id

Molecular mimicry

Stage

No. treated

Ab3 Generation

Clinical Response

References 60 60

14/23 3/14 4/18 1/26

3 minor 1 CR; 3 minor 3 PR, suggestion of 1 OS Suggestion of 1 OS Not reported 1 CR, 2 minor, 3 SD

61 66 67 68

21

12/13

Not reported

69

High-risk adjuvant

28

Not reported

70

GD2

IV

47

40/47

GD2

High-risk adjuvant

69

69/69

Not reported ICR;12 SD, suggestion of 1 OS Suggestion of 1 RFS and OS

MF11-30 MF11-30

HMWMAA HMWMAA

IV IV

16 21

Not reported 16/19

MK2-23 BEC2 BEC2 Melimmune2 Melimmune2 Melimmune1 Melimmune2 Melimmune1

HMWMAA GD3 GD3 MA-HMWPA

IV High-risk adjuvant High-risk adjuvant IV

25 20 18 26

MA-HMWPA

High-risk adjuvant

MA-HMWPA

TriGem TriGem

75 77, 78

Abbreviations: HMWMAA, high molecular weight melanoma-associated antigen; MA-HMWPA, melanoma-associated high molecular weight proteoglycan antigen; CR, complete response; PR, partial response; SD, stable disease; OS, overall survival; RFS, relapse-free survival.

therapy for metastatic disease, 55% had disease confined to soft tissue, and 45% had visceral metastasis. Toxicity consisted of local reaction at the site of injection and mild fever and chills. Hightiter GD2-specific IgG responses were documented in 40 patients. One patient achieved a complete response that lasted more than 24 months and 12 patients had stable disease for a median of 18⫹ months. Thirty-two patients progressed. Response status was not available for two patients. The median survival for the 21 patients with visceral disease was 13 months. The median survival for the 26 patients with only soft tissue disease had not been reached at the time of publication.75 A phase II trial of TriGem adjuvant vaccination in 69 patients with stage III melanoma has been recently reported. Twenty-eight patients had one positive node, 26 had two or three positive nodes, and eight had four or more positive nodes. Twenty-five patients received high-dose interferon alpha in addition to vaccine. The toxicity of the vaccine consisted of mild local reaction with swelling and pruritus for 24 to 48 hours. All patients generated robust IgG anti-GD2 responses. Patients who received interferon were able to mount a response similar to patients who were treated with vaccine alone. Either QS-21, granulocyte macrophage colony-stimulating factor (GM-CSF),76 or aluminum hydroxide (AluGel)

was used as an adjuvant. All generated appropriate antibody responses. AluGel was the least toxic. At a median follow-up of 2 years, the overall survival and relapse-free survivals were 82% and 62%, respectively. Interestingly, in the subgroup of patients receiving both interferon and TriGem, the overall and relapse-free survivals were 96% (1/25) and 80% compared to patients receiving TriGem alone at 72% (7/44) and 50%, respectively.77,78 A planned phase III adjuvant trial in patients with stage III melanoma will randomize patients to high-dose interferon alone or in combination with TriGem AluGel. FUTURE APLICATIONS

Most anti-Id vaccines are undergoing or have already undergone phase II trials (Table 1). Phase III trials comparing standard treatment to vaccination or standard treatment plus vaccination are currently active or in the late planning stages. If therapeutic value is demonstrated in phase III trials, anti-Id vaccines will then be tested in combination with other therapeutic modalities such as chemoradiotherapeutic agents, biologic agents (other vaccines, cytokines, immune stimulators), molecularly targeted drugs (signal transduction inhibitors, anti-angiogenics, tyrosine kinase inhibitors, pro-apoptotic drugs, etc), and others. Singleagent activity may warrant their use alone in

468

LUTZKY, GONZALEZ-ANGULO, AND ORZANO

situations where toxicity of conventional therapy is prohibitive or poorly tolerated, as in the elderly population. Vaccines are well suited for use in adjuvant therapy because of the minimal tumor burden and need for nontoxic therapy in this setting. The current and planned large adjuvant anti-Id vaccine trials in colon cancer, breast cancer, and melanoma will hopefully set the stage for their use in other settings and other malignancies. Combinations of anti-Id vaccines or multiple epitope vaccines may prove to be more effective.79 Additional manipulation of the anti-idiotypic sequences may lead to multifunctional molecules and the generation of DNA vaccines encoding one or more anti-Id antibodies. Anti-Id vaccination may have an important role to play in the future treatment approaches to malignant melanoma. If ultimately proven effective, antibody-based vaccines will provide a lowtoxicity option in a disease that has experienced little therapeutic progress in the last 30 years. REFERENCES 1. Jemal A, Thomas A, Murray T, et al: Cancer Statistics 2002. CA Cancer J Clin 52:23-47, 2002 2. Mastrangelo MJ, Maguire HC, Sato T, et al: Active specific immunization in the treatment of patients with melanoma. Semin Oncol 23:773-781, 1996 3. Wolchock JD, Livingston PO, Houghton AN: Vaccines and other adjuvant therapies for melanoma. Hematol Oncol Clin North Am 12:835-848, 1998 4. Weber JS, Aparicio A: Novel immunologic approaches to the management of malignant melanoma. Curr Opin Oncol 132:124-128, 2001 5. Bhattachary-Chatterjee M, Baral RN, Chatterjee SK, et al: Counterpoint. Cancer vaccines: Single-epitope anti-idiotype vaccine versus multiple-epitope antigen vaccine. Cancer Immunol Immunother 49:133-141, 2000 6. Lindenmann J: Speculations on idiotypes and homobodies. Ann Immunol (Paris) 124C:171-184, 1973 7. Jerne NK: Towards a network theory of the immune system. Ann Immunol (Paris) 125C:373-389, 1974 8. Paul WE, and Bona C: Regulatory idiotypes and immune networks: A hypothesis. Immunol Today 3:230-234, 1982 9. Foon KA, Bhattacharya-Chatterjee M: Are solid tumor anti-idiotype vaccines ready for prime time? Clin Cancer Res 7:1112-1115, 2001 10. Durrant LG, Parsons T, Moss R, et al: Human antiidiotypic antibodies can be good immunogens as they target FC receptors on antigen-presenting cells allowing efficient stimulation of both helper and cytotoxic T-cell responses. Int J Cancer 92:414-420, 2001 11. Beninati C, Oggioni MR, Boccanera M, et al: Therapy of mucosal candidiasis by expression of an anti-idiotype in

human commensal bacteria. Nat Biotechnol 18:1038-1039, 2000 12. Zhang W, Winkler T, Kalden JR, Reichlin M: Isolation of human anti-idiotypes broadly cross-reactive with antidsDNA antibodies from patients with systemic lupus erythematosus. Scand J Immunol 53:192-197, 2001 13. Alvarado-Flores E, Avalos-Diaz E, Diaz LA, et al: Antiidiotype antibodies neutralize in vivo the blistering effect of Pemphigus foliaceus IgG. Scand J Immunol 53:254-258, 2001 14. Shoenfeld Y, Amital H, Ferrone S, et al: Anti-idiotypes and their application under autoimmune, neoplastic, and infectious conditions. Int Arch Allergy Immunol 105:211-223, 1994 15. Calvanico NJ: The humoral immune response in autoimmunity. Dermatol Clin 11:379-389, 1993 16. Wraith DC, Smilek DE, Webb S: MHC-binding peptides for immunotherapy of experimental autoimmune disease. J Autoimmun 5:103-113, 1992 (suppl A) 17. Rico MJ, Hall RP: Idiotypes, anti-idiotypes, and autoimmunity. J Am Acad Dermatol 19:579-585, 1988 18. Grzych JM, Capron M, Lambert PH, et al: An antiidiotype vaccine against experimental schistosomiasis. Nature 316:74-76, 1985 19. Herlyn D, Somasundaram R, Li W, et al: Anti-idiotype cancer vaccines: Past and future. Cancer Immunol Immunother 43:65-76, 1996 20. Bhattacharya-Chatterjee M, and Foon KA: The antiidiotype vaccines for immunotherapy. Curr Opin Mol Ther 3:63-69, 2001 21. Raychaudhury S, Saeki Y, Fuji H, et al: Tumor-specific idiotype vaccines. I. Generation and characterization of internal image tumor antigen. J Immunol 137:1743-1749, 1986 22. Saeki Y, Chen JJ, Shi L, et al: Idiotypic intramolecular help. Induction of tumor-specific antibodies by monoclonal anti-idiotypic antibody with the help of Fc-specific T helper clones. J Immunol 142:2629-2634, 1989 23. Raychaudhuri S, Saeki Y, Chen JJ, et al: Tumor-specific idiotype vaccines. II. Analysis of the tumor-related network response induced by the tumor and by internal image antigens (Ab2beta). J Immunol 139:271-278, 1987 24. Raychaudhuri S, Saeki Y, Chen JJ, et al: Tumor-specific Id vaccines. III. Induction of T helper cells by anti-id and tumor cell. J Immunol 139:3902-3910, 1987 25. Raychaudhuri S, Saeki Y, Chen JJ, et al: Tumor-specific id vaccine IV: Analysis of the network in tumor immunity. J Immunol 139:2096-2102, 1987 26. Kennedy RC, Dreesman GR, Butel JS, et al: Suppression of in vivo tumor formation induced by simian virus 40-transformed cells in mice receiving anti-idiotypic antibodies. J Exp Med 161:1432-1449, 1985 27. Shearer MH, Lanford RI, Kennedy RC: Monoclonal anti-idiotypic antibodies induce humoral immune responses specific for simian virus 40 large tumor antigen in mice. J Immunol 145:932-939, 1990 28. Shearer MH, Bright RK, Kennedy RC: Comparison of humoral immune responses and tumor immunity in mice immunized with recombinant SV40 large tumor antigen and a monoclonal anti-idiotype. Cancer Res 53:5734-5739, 1993 29. Nelson KA, Georege E, Swenson C: Immunotherapy of murine sarcomas with auto-anti-idiotypic monoclonal antibod-

ANTIBODY VACCINES FOR MELANOMA

ies which bind to tumor-specific T cells. J Immunol 138:21102117, 1987 30. Riethmuller G, Holz E, Schlimok G, et al: Monoclonal antibody therapy for resected Dukes’ C colorectal cancer: Seven year outcome of a multi-center randomized trial. J Clin Oncol 16:1788-1794, 1998 31. Fagerberg J, Steinitz M, Wigzell H, et al: Human antiidiotypic antibodies induced a humoral and cellular immune response against a colorectal carcinoma-associated antigen in patients. Proc Natl Acad Sci USA 92:4773-4777, 1995 32. Herlyn D, Harris D, Zaloudik J, et al: Immunomodulatory activity of monoclonal anti-idiotypic antibody to anticolorectal carcinoma antibody CO171-A in animals and patients. J Immunother 15:303-311, 1994 33. Robins RA, Denton GWL, Hardcastle JD, et al: Antitumor immune response and interleukin-2 production induced in colorectal cancer patients by immunization with human monoclonal anti-idiotypic antibody. Cancer Res 51:5425-5429, 1991 34. Denton GWL, Durrant LG, Hardcastle JD, et al: Clinical outcome of colorectal cancer patients treated with human anti-idiotypic antibody. Cancer Res 57:10-17, 1994 35. Bhattacharya-Chatterjee M, Mukerjee S, Biddle W, et al: Murine monoclonal anti-idiotype antibody as a potential network antigen for human carcinoembrionic antigen. J Immunol 145:2758-2765, 1990 36. Pervin S, Chakraborty M, Bhattacharya-Chatterjee M, et al: Induction of antitumor immunity by an anti-idiotype antibody mimicking carcinoembryonic antigen. Cancer Res 57:728-734, 1997 37. Foon KA, John WJ, Chakraborty M, et al: Clinical and immune responses in advanced colorectal cancer patients treated with anti-idiotype monoclonal antibody vaccine that mimics the carcinoembryonic antigen. Clin Cancer Res 3:1267-1276, 1997 38. Foon KA, John WJ, Chakraborty M, et al: Clinical and immune responses in resected colon cancer patients treated with anti-idiotype monoclonal antibody vaccine that mimics the carcinoembryonic antigen. J Clin Oncol 17:2889-2895, 1999 39. Rohatgi N, Bhatnagar A, Lowy A, et al: CeaVac antiidiotype monoclonal antibody treatment for resected colorectal cancer: Results of a phase II trial. Proc Am Soc Clin Oncol 20:1080, 2001 (abstr) 40. Spendlove L, Li L, Potter V, et al: A therapeutic human anti-idiotypic antibody mimics CD55 in three distinct regions. Eur J Immunol 30:2944-2953, 2000 41. Durrant LG, Maxwell-Armstrong C, Buckley D, et al: A neoadjuvant clinical trial in colorectal cancer patients of the human anti-idiotypic antibody 105AD7, which mimics CD55. Clin Cancer Res 6:422-430, 2000 42. Bhattacharya-Chatterjee M, Mrozek E, Mukerjee S, et al: Anti-idiotypes as potential therapeutic agents for breast cancer, Ceriani RL (ed): Proceedings of the 5th International Workshop on Breast Cancer Therapy and Immunology. New York, NY, Plenum, 1994, pp 387-401 43. Chakraborty M, Mukerjee S, Foon KA, et al: Induction of human breast cancer-specific antibody responses in cynomolgus monkeys by a murine monoclonal anti-idiotype antibody. Cancer Res 55:1525-1530, 1995 44. Reece DE, Foon KA, Bhattacharya-Chatterjee M, et al:

469

Use of the anti-idiotype antibody vaccine TriAb after autologous stem cell transplantation in patients with metastatic breast cancer. Bone Marrow Transplant 26:729-735, 2000 45. Tripathi PK, Qin H, Bhattacharya-Chatterjee M, et al: Construction and characterization of a chimeric fusion protein consisting of an anti-idiotype antibody mimicking a breast cancer-associated antigen and the cytokine GM-CSF. Hybridoma 18:193-202, 1999 46. Baral R, Sherrat A, Das R, et al: Murine monoclonal anti-idiotypic antibody as a surrogate antigen for human Her2/neu. Int J Cancer 1:88-95, 2001 47. Wagner U, Schlebusch H, Kohler S, et al: Immunological responses to the tumor-associated antigen CA125 in patients with advanced ovarian cancer induced by the murine monoclonal anti-idiotype vaccine ACA125. Hybridoma 16:3340, 1997 48. Wagner U, Kohler S, Reinartz S, et al: Immunological consolidation of ovarian carcinoma recurrences with monoclonal anti-idiotype antibody ACA125: Immune responses and survival in palliative treatment. Clin Cancer Res 7:1154-1162, 2001 49. Cheung NK, Guo HF, Cheung IY: Correlation of antiidiotype network with survival following anti-G(D2) monoclonal antibody 3F8 therapy of stage 4 neuroblastoma. Med Pediatr Oncol 35:635-637, 2000 50. Handgretinger R, Baader P, Dopfer, et al: A phase I study of neuroblastoma with the anti-ganglioside GD2 antibody 14.G2a. Cancer Immunol Immunother 35:199-204, 1992 51. Yu AL, Eskenazi A, Strother D, et al: A pilot study of anti-idiotype monoclonal antibody as tumor vaccine in patients with high risk neuroblastoma. Proc Am Soc Clin Oncol 20:1470, 2001 (abstr) 52. Grant SC, Kris MG, Houghton AN, et al: Long survival of patients with small cell lung cancer after adjuvant treatment with the anti-idiotypic antibody BEC2 plus Bacillus CalmetteGuerin. Clin Cancer Res 5:1319-1323, 1999 53. Foon KA, Oseroff AR, Vaickus L, et al: Immune responses in patients with T-cell lymphoma treated with an anti-idiotype antibody mimicking a highly restricted T-cell antigen. Clin Cancer Res 1:1285-1294, 1995 54. Ritter G, Livingston PO: Ganglioside antigens expressed by human cancer cells. Semin Cancer Biol 2:401-409, 1991 55. Livingston P: Approaches to augmenting the immunogenicity of melanoma gangliosides: From whole melanoma cells to ganglioside-KLH conjugate vaccines. Immunol Rev 145: 147-166, 1995 56. Ritter G, Livingston PO: Ganglioside antigens expressed by human cancer cells. Semin Cancer Biol 2:401-409, 1991 57. Livingston P: Ganglioside vaccines with emphasis on GM2. Semin Oncol 25:636-645, 1998 58. Livingston PO, Wong GY, Adluri S, et al: A randomized trial of adjuvant vaccination with BCG versus BCG plus the melanoma ganglioside GM2 in AJCC stage III melanoma patients. J Clin Oncol 12:1036-1044, 1994 59. Kirkwood JM, Ibrahim JG, Sosman JA, et al: High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: Results of intergroup trial E1694/S9512/C509801. J Clin Oncol 19:2370-2380, 2001 60. Mittelman A, Chen ZJ, Kageshita T, et al: Active spe-

470

cific immunotherapy in patients with melanoma. A clinical trial with mouse antiidiotypic monoclonal antibodies elicited with syngeneic anti-high-molecular-weight-melanoma-associated antigen monoclonal antibodies. J Clin Invest 86:21362144, 1990 61. Mittelman A, Chen ZJ, Yang H, et al: Human high molecular weight melanoma-associated antigen (HMW-MAA) mimicry by mouse anti-idiotypic monoclonal antibody MK223: Induction of humoral anti-HMW-MAA immunity and prolongation of survival in patients with stage IV melanoma. Proc Natl Acad Sci USA 89:466-470, 1992 62. Ferrone S, Chen ZJ, Liu CC, et al: Human high molecular weight-melanoma associated antigen mimicry by mouse anti-idiotypic monoclonal antibodies MK2-23. Experimental studies and clinical trials in patients with malignant melanoma. Pharmacol Ther 57:259-290, 1993 63. Mittelman A, Chen GZ, Wong GY, et al: Human high molecular weight-melanoma associated antigen mimicry by mouse anti-idiotypic monoclonal antibody MK2-23: Modulation of immunogenicity in patients with malignant melanoma. Clin Cancer Res 1:705-713, 1995 64. Chapman PB, Houghton AN: Induction of IgG antibodies in patients against GD3 in rabbits by an anti-idiotypic monoclonal antibody. J Clin Invest 88:186-192, 1991 65. Chapman PB, Livingston PO, Morrison ME, et al: Immunization of melanoma patients with anti-idiotypic antibody BEC2 which mimics GD3 ganglioside: Pilot trials using no immunological adjuvant. Vaccine Res 3:59-69, 1994 66. McCaffery M, Yao TJ, Williams L, et al: Immunization of melanoma patients with BEC2 anti-idiotypic monoclonal antibody that mimics GD3 ganglioside: Enhanced immunogenicity when combined with adjuvant. Clin Cancer Res 2:679686, 1996 67. Yao TJ, Meyers M, Livingston PO, et al: Immunization of melanoma patients with BEC2-KLH plus BCG intradermally followed by intravenous booster immunizations with BEC2 to induce anti-GD3 ganglioside antibodies. Clin Cancer Res 5:7781, 1999 68. Quan WD Jr, Dean GE, Spears L, et al: Active specific immunotherapy of metastatic melanoma with an antiidiotype vaccine: A phase I/II trial of I-Mel-2 plus SAF-m. J Clin Oncol 15:2103-2110, 1997 69. Saleh MN, Lalisan DY Jr, Pride MW, et al: Immunologic response to the dual murine anti-Id vaccine Melimmune-1 and Melimmune-2 in patients with high-risk melanoma without evidence of systemic disease. J Immunother 21:379-388, 1998

LUTZKY, GONZALEZ-ANGULO, AND ORZANO

70. Pride MW, Shuey S, Grillo-Lopez A, et al: Enhancement of cell-mediated immunity in melanoma patients immunized with murine anti-idiotypic monoclonal antibodies (MELIMMUNE) that mimic the high molecular weight proteolycan antigen. Clin Cancer Res 4:2363-2370, 1998 71. Hastings A, Morrison SL, Kanda S, et al: Production and characterization of a murine/human chimeric anti-idiotype antibody that mimics ganglioside. Cancer Res 52:1681-1686, 1992 72. Sen G, Chakraborty M, Foon KA, et al: Induction of IgG antibodies by an anti-idiotype antibody mimicking disialoganglioside GD2. J Immunother 21:75-83, 1998 73. Sen G, Chakraborty M, Foon KA, et al: Preclinical evaluation in nonhuman primates of murine monoclonal antiidiotype antibody that mimics the disialoganglioside GD2. Clin Cancer Res 3:1969-1976, 1997 74. Foon KA, Sen G, Hutchins L, et al: Antibody responses in melanoma patients immunized with an anti-idiotype antibody mimicking disialoganglioside GD2. Clin Cancer Res 4:1117-1124, 1998 75. Foon KA, Lutzky J, Baral RN, et al: Clinical and immune responses in advanced melanoma patients immunized with an anti-idiotype antibody mimicking disialoganglioside GD2. J Clin Oncol 18:376-384, 2000 76. Nasi ML, Lieberman P, Busam KJ, et al: Intradermal injection of granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with metastatic melanoma recruits dendritic cells. Cytokines Cell Mol Ther 5:139-44, 1999 77. Chatterjee M, Lutzky J, Safa M, et al: Immune and clinical comparison of different adjuvants combined with TriGem: An anti-idiotype monoclonal antibody treatment for stage III melanoma. Proc Am Soc Clin Oncol 20:1400, 2001 (abstr) 78. Safa M, Lutzky J, Chatterjee M, et al: TriGem antiidiotype monoclonal antibody treatment for stage III melanoma: Results of a multicenter phase II trial. Proc Am Soc Clin Oncol 20:1008, 2001 (abstr) 79. Maruyama H, Zaloudik J, Li W, et al: Cancer vaccines: single epitope anti-idiotype vaccine versus multiple epitope antigen vaccine. Cancer Immunol Immunother 49:123-132, 2000 80. Zeytin HE, Tripathi PK, Bhattacharya-Chatterjee M, et al: Construction and characterization of DNA vaccines encoding the single-chain variable fragment of the anti-idiotype antibody 1A7 mimicking the tumor-associated antigen disialoganglioside GD2. Cancer Gene Ther 7:1426-1436, 2000