Minimal residual disease as the target for immunotherapy of cancer

Minimal residual disease as the target for immunotherapy of cancer

Standing by in Singapore The caning last week of an 18-year-old American in Singapore has been condemned by political leaders in the United States-bu...

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Standing by in Singapore The

caning last week of an 18-year-old American in Singapore has been condemned by political leaders in the United States-but not forcefully. It is easy to explain this low-key response. Many people in the US and in other countries where there is angry frustration over rising crime believe that Singapore has the answer. That small country retains corporal punishment, for males under 50, for various offences from attempted murder to vandalism, and it is relatively free from crime. This must be cause and effect, the argument runs. But in that island state not all manifestations of true democracy are fully developed: there are more ways of persuading a population into conformist behaviour than the threat of the cane. In August, 1991, Amnesty International urged doctors to write to the authorities in Singapore and to theSingapore Medical Association to protest against caning there as a "cruel, inhuman and degrading form of punishment" and against the of medical involvement that Section 231 Singapore’s Criminal Procedure Code stipulates. A medical officer has to certify that "the offender is in

fit state of health to undergo such punishment" and stands by in case the punishment needs to be stopped on medical grounds. Last month a Singapore Home Affairs spokesman stated that canings had averaged 1000 a year over the past decade. The official figure for 1987 and 1988 combined was 1218 (including 234 foreigners by the way). This form of punishment-which even those who retain a bizarre affection for the chastisements of their youth must recognise as brutal-seems to be on the increase. Last December Amnesty International mounted a similar campaign in respect of Malaysia, which uses the cane very much as Singapore does and was proposing to extend it to "white collar crime". One Malaysian prisoner describes being led from the examining doctor’s office to the punishment compound behind it, where another doctor stood as part of the supervising team. The Singapore Medical Association seems not to have responded to protests but the Malaysian Medical Association shares the sentiments of letter writers and has forwarded the matter to its Council. Medical people should have nothing to do with such punishments. a

The Lancet

COMMENTARY

Minimal residual disease as the immunotherapy of cancer

target for

See page 1177

Oscillating optimism and pessimism in tumour immunology have been amply documented.’ Initially there was confusion through misunderstanding of tumour-specific rejection versus allograft rejection. When inbred mice and rats became freely available for tumour transplantation studies, the fmding that carcinogeninduced tumours carried tumour-specific antigens and could immunise the host was greeted enthusiastically. Equally, the subsequent finding that spontaneous tumours were poorly immunogenic or non-immunogenic engendered despair. Nevertheless, much clinical experimentation on cancer vaccines followed. These investigations used irradiated cancer cells or preparations derived from them, together with viral, bacterial, or other adjuvants, to treat various metastatic cancers. Many anecdotal reports of spectacular remissions ensued. Unfortunately, these successes were mainly confined to a few types of cancer-eg, malignant melanoma, renal carcinoma, and acute myelogenous leukaemia, diseases in occur. remissions sometimes spontaneous the effects were Moreover, good unpredictable and confmed to a small minority of patients. Although a few groups struggled on, the widespread interest of the 1970s gradually waned. Yet in the 1990s there is renewed activity in specific immunotherapy of cancer,2 based on the molecular cloning of tumour rejection antigens,3 better quantification of cytotoxic T-cell responses, and new ways of rendering tumour cells more immunogenic.45

which

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The monoclonal antibody revolution provided analytical tools of razor-sharp precision to identify, characterise, and localise putative tumour-associated antigens. It lent Ehrlich’s idea of a "magic bullet" greater credence because unlimited

amounts

of

a

consistent

product could be provided. Unfortunately, many tumourassociated antigens proved to be constituents of normal cells, although sometimes expressed in abnormally large amounts or with unusual anatomical distribution. Despite this constraint there were many attempts to use monoclonal antibodies in cancer therapy, usually via tagging of antibody with radioisotope, toxin, or drug. Several phase I/II clinical trials have subsequently offered some encouragement. Two recent examples are presented by way of illustration. Welt et al6 conducted a phase I study of a "’I-labelled murine IgG2a monoclonal antibody directed against a high molecular weight glycoprotein homogeneously expressed by normal and malignant colonic epithelial cells but not by other epithelial tissues. In 19 of 20 assessable colorectal cancer patients with advanced disease, selective localisation of the antibody was noted in tumour tissue. The periphery of liver metastases was most strongly labelled but some concentration was noted even in the necrotic core. A trial more directed at establishing clinical efficacy has been completed and the results are awaited. Amlot et al’ reported results on 26 patients with relapsing B-cell lymphoma treated with a "second generation" immunotoxin consisting of a monoclonal antibody to the B-cell surface marker CD22 bound to a deglycosylated and thus non-hepatotoxic ricin A chain. Partial or complete responses were noted in 37’5% of

these very advanced patients, and the subgroup believed to have less than 100 g of tumour tissue showed most responses. The results were deemed sufficiently promising to warrant studies in less advanced patients. In the report of Riethmiiller et al in this issue a refreshingly different approach has yielded considerable encouragement. These researchers predicated their research on the following premises. First, the large antigenic load and physiological barriers to delivery of monoclonal antibodies limit the efficacy of treatment of advanced metastatic disease, so the micrometastases present at early stages of the cancer process may constitute more favourable targets. Second, and in particular because these patients are clinically well, immunotoxins with potentially serious side-effects may not be appropriate. Native antibodies can lead to cellular destruction-via complement-mediated lysis, antibodydependent cellular cytotoxicity, or opsonisation of cells and subsequent phagocytosis-and intravenous infusions of antibody are well tolerated. Third, a target antigen on normal epithelia may be partly shielded from antibody or accessory molecules and cells whereas that same antigen may be readily accessible on a cancer cell within a micrometastasis in mesenchymal tissue. Accordingly, 189 patients with Dukes stage C (UICC stage III) colorectal cancer were recruited for a prospective multicentre randomised and controlled trial to see whether the murine IgG2a monoclonal antibody 17-1A directed against a ubiquitously expressed 37-40 kDa epithelial cell surface glycoprotein could prolong life after apparently curative surgery. Patients were randomised before consent and the results were biased against a positive effect by the inclusion within the treatment group of 11 patients randomised to the treatment arm but who declined infusions. Patients received 500 mg of antibody postoperatively and then four monthly infusions of 100 mg. Median follow-up of 5 years (range 2-7-7-5 years) showed that 51% of patients in the observed (control) group and 36% of patients in the treatment group had died. The reduction in mortality was statistically significant. The treatment also reduced the 5-year recurrence rate from 66-5% to 48-7%. The recurrence-free interval was prolonged and, when recurrences were divided into distant metastases (noted as first recurrence) versus local relapses, the latter group showed no benefit from treatment and all the benefit could be ascribed to prevention or delay of distant metastases. The 6-year overall and disease-free survival data have confirmed the 5-year results. Toxic effects of treatment were minor and easily controlled. Despite the fact that 80% of treated antibodies mouse patients developed against first noted after or the second immunoglobulin, usually third infusion, only four anaphylactic reactions were encountered during 371 infusions. This trial was initiated in May, 1985, and since then adjuvant chemotherapy for colorectal cancer has become common practice. For Dukes stage C the reduction in mortality achieved is broadly similar to Riethmuller’s results. Although the latest data need confirmation in a larger trial, it is tempting to suggest that combination

relevant to future research. First, monoclonal antibodies in future will be "humanised"-ie, engineered to possess human constant regions and variable region framework portions, both to reduce anti-immunoglobulin antibody formation and to optimise accessory processes. Second, and taking a lead from cancer chemotherapy, a wellchosen cocktail of antibodies may be preferable in view of the cancer cells’ capacity for mutation and antigen loss. There is no shortage of other molecular targets, including A33, TAG-72, CEA, Muc-1, and mutated oncogene products. Third, surrogate markers of efficacy need to be developed so that possible benefit can be detected earlier. much Riethmuller’s used has group markers to detect colorectal8 or immunocytochemical breast9 carcinoma cells in bone marrow aspirates, and has shown that positivity at the time of primary surgery worsens the prognosis. A blood test would be preferable, but none of the existing tests for tumour-associated antigens in serum is either specific or sensitive enough. Little is known about how many cancer cells are present in the blood of relatively good prognosis patients, but very sensitive techniques such as immunobead polymerase chain reaction," which uses immunomagnetic beads to enrich for epithelial cells and the polymerase chain reaction to detect, for example, K-ras or p53 mutations, could rapidly fill this gap. The real and historic significance of Riethmuller’s study lies in the fact that it records the first example of an antibody with proven life-saving benefit in a common solid-organ cancer. This surely must engender a new wave of optimism in tumour immunology. The cancer cell is a formidable foe. Down-regulation of class I major histocompatibility complex (MHC) antigens, mutation or loss of tumour rejection antigens, and the practical problem of MHC polymorphism will delay progress in active immunotherapy. Heterogeneity in antigen difficulties with expression, accessibility, toxicity, and the formation of neutralising (including anti-idiotypic) anti-immunoglobulins are obstacles for passive antibody/immunotoxin approaches. Cost will be a very real hurdle. Nevertheless, tumour immunology seems

poised for an upswing. G J V Nossal Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia 1 2

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(adjuvant chemotherapy plus immunotherapy) to offer, since antibody can act on dormant or non-cycling cells that may be resistant to antiproliferative agents. Three suggestions may be may have much

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Klein G, Boon T. Tumor immunology: present perspectives. Curr Opin Immunol 1993; 5: 687-92. Bystryn J-C, Ferrone S, Livingston P, eds. Specific immunotherapy of cancer with vaccines. Ann NY Acad Sci 1993; 690. Boon T. Tumor antigens recognized by cytolytic T lymphocytes: present perspectives for specific immunotherapy. Int J Cancer 1993; 54: 177-80. Chen L, Ashe S, Brady WA, et al. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell 1992; 71: 1093-102. Dranoff G, Jaffee E, Lazenby A, et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA 1993; 90: 3539-43. Welt S, Divgi CR, Real FX, et al. Quantitative analysis of antibody localisation in human metastatic colon cancer: a phase I study of monoclonal antibody A33. J Clin Oncol 1990; 8: 1894-906. Amlot PL, Stone MJ, Cunningham D, et al. A phase I study of an antiCD22-deglycosylated ricin A chain immunotoxin in the treatment of B-cell lymphomas resistant to conventional therapy. Blood 1993; 9: 2624-33. Schlimok G, Funke I, Bock B, et al. Epithelial tumor cells in the bone marrow of patients with colorectal cancer: immunocytochemical

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detection, phenotypic characterization and prognosis significance. J Clin Oncol 1990; 8: 831-37. Pantel K, Schlimok G, Braun S, et al. Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cells. J Natl Cancer Inst 1993; 85: 1419-24. Hardingham JE, Kotasek D, Farmer B, et al. Immunobead-PCR: A technique for the detection of circulating tumor cells using immunomagnetic beads and the polymerase chain reaction. Cancer Res 1993; 53: 3455-58.

Tumour pharmacokinetics?—we do need to know See page 1184

Years of effort and millions of pounds are invested in the development of new anticancer drugs but disappointingly few have made it into clinical practice and even fewer have improved cancer mortality. Specific searches are underway for new molecular targets for therapy; old drugs are being looked at afresh coupled with ingenious modifications;’ and novel routes of administration and scheduling are being explored. But do we know to what extent anticancer drugs reach and interact with tumours in vivo? As more tumour targeting approaches are being explored-for example, gene therapy2-quantification of drug delivery to tumour tissue itself may become mandatory. Until now, we have had only crude tools to investigate drug uptake in vivo into tumours-indirect measures of exposure to drugs such as plasma pharmacokinetics and normal tissue toxicity, and surrogate endpoints including clinical tumour regression and patient survival. The report by Presant et al in this issue indicates the way forward-investigation of in-vivo tumour

pharmacokinetics.

The initial observation that the cytotoxic agent fluorouracil (5FU) could be detected in vivo is now about 10 years old.3 Presant’s group has studied the clearance of 5FU in human tumours in vivo by use of magnetic resonance spectroscopy. By adapting a magnetic resonance imaging (MRI) machine and placing a spectroscopy coil over the tumour site, fluorine signals from 5FU can be detected and their half-life within the tumour estimated. If the signal half-life is longer than the plasma half-life, the tumour is judged to have "trapped" the 5FU. Importantly Presant’s paper shows a relation between such trapping of 5FU and tumour response. The implications are considerable: changes in 5FU tumour uptake can now be directly quantified after different routes of admini-stration and novel scheduling and the in vivo mechanism of biochemical modulation can be

investigated. 5FU is the most active and commonly used anticancer drug in the treatment of colorectal cancer, and therapeutic advances are being made in both the metastatic and adjuvant settings by better use of the drug. The potential number of patients who might benefit is huge and the resource implications are immense. While randomised trials are underway to try and tease out the optimum use of 5FU, detailed studies of 5FU tumour dosimetry in vivo would greatly complement our understanding of clinical effects. The method used by Presant et al could be duplicated in many of the two thousand 1-55 tesla MRI machines now in service in hospitals throughout the world, although some specialised 19F magnetic resonance spectroscopy (MRS) hardware and software would be required. The researchers estimate that 40% of tumours can be

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present, enough to make a larger trial possible but perhaps too few for routine clinical use. They estimate, however, that 80% of tumours would be accessible if whole-body 19F coils could be developed. Moreover, Presant et al use a bolus protocol but investigation of other scheduling is possible; Findlay et aP reported similar preliminary results by use of an infusional protocol. One fundamental problem with MRS, however, is its low sensitivity-only drugs given in very high doses are accessible. A new generation of higher field MR instruments is being introduced for research purposes, and 3 tesla or 4 tesla magnets are available; these give sensitivity gains of 2-fold or 2’6-fold. Presant et al suggest that this technology can be exploited to individualise cancer chemotherapy, but extended clinical trials would be needed to establish the cost-benefit analysis in this disease because 5FU is used in a palliative setting, and no good second line treatment is currently available. There is of course a danger that such developments can go badly wrong. The technique still needs much work, and cannot be seen simply as a "coin in the slot" method-like chemosensitivity testing, it might promise too much too soon. We have to consider whether our aim is to individualise treatment by predicting 5FU response in each patient or whether this technique should be used at an earlier stage in drug development as a research tool. Technical problems and signal interpretation are outstanding considerations, and we need to establish whether the 5FU is in fact taken up into the tumour cells themselves. Possible approaches for this purpose include modelling the MRS signal or devising strategies to extracellular from intracellular distinguish use of compartmentalisation-eg, DTPA-gadolinium contrast agent to enhance the signal of extracellular 5FU.6 Clearly, for such an innovative technique as MR spectroscopy to have an impact on drug development in general, it needs to be applicable to drugs that do not contain the paramagnetic fluorine atom. Despite the poor sensitivity of MRS for other nuclei, recent laboratory studies have shown that a drug labelled with the "C nucleus can be detected in vivo, as can a phosphoruscontaining drug, and that it is also possible to detect drugs that contain the ubiquitous hydrogen atom (J R Griffiths and J D Glickson, unpublished). Why have such innovative, direct approaches to facilitate our understanding of anticancer therapy not been demanded by clinicians and the drug industry before? As clinicians and scientists we have a fundamental need to make sure anticancer drugs get into human tumours in sufficient concentration, and industry is forever seeking ways to streamline and rationalise its drug development programmes.’ Such innovations as represented by this paper are difficult to develop, require long-term investment by cohesive multidisciplinary teams, but should be embraced by academia and industry. What is the way forward to maximise such potential? MRS methodological developments need to continue and the few international groups with sufficient critical mass and skills need to be encouraged as central resources examined

at

and international investigation and experimentation. The complementary functional imaging tool of positron emission tomography (PET) needs to

for

national