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Originally published as JCO Early Release 10.1200/JCO.2004.06.939 on October 13 2004 © 2004 American Society of Clinical Oncology.
T-Cell Chauvinists Versus Antibody Advocates—Can't We All Just Get Along?Memorial Sloan-Kettering Cancer Center, New York, NY The modern era of targeted therapy for cancer dates back to 1975 with the production of monoclonal antibodies (MAbs). Investigators soon began producing MAbs against cancer cells; among the nonhematologic tumor targets, melanoma took the lead. This was largely due to the fact that melanoma is more easily grown in tissue culture than most other nonhematologic tumors, and multiple melanoma cell lines were available to define MAb specificity. One of the first murine MAbs raised against melanoma was R24, a MAb initially identified for its potent ability to fix human complement and to mediate antibody-dependent cellular cytotoxicity. Specificity studies showed that R24 bound to GD3, which like GD2 and GM2 is a ganglioside expressed on melanoma and other tumors of neuroectoderm origin but on few normal tissues. This was the first indication that gangliosides were attractive targets for immunotherapy. R24 was first tested clinically 20 years ago. Despite the fact that R24 is a mouse MAb, such that only a few treatments could be given before neutralizing antimouse antibodies developed, partial responses were seen in three of the first 12 patients.1 Since then, many trials with R24 have been conducted in centers around the world resulting in a consistent 10% response rate,2 making R24 one of the most active MAbs in nonhematologic tumors. GD2, another ganglioside expressed by melanoma—although at levels eight to 10 times lower than GD3—has also been targeted in melanoma trials, including in the phase I trial by King et al3 in this issue of the Journal of Clinical Oncology. Most of the melanoma trials targeting GD2 have used one of two MAbs, 3F8 and 14.18, either alone4,5 or in combination with cytokines.6,7 Although occasional clinical responses have been seen, true phase II trials in melanoma have not been done with anti-GD2 MAb. However, in tumors expressing higher levels of GD2, such as neuroblastoma, complete responses in bone marrow have been seen in approximately 25% of patients8,9 Over the past decade, only a handful of investigators continued to explore antibody-based immunotherapy for melanoma, as most of the field has been dominated by investigators focusing solely on T-cell–based therapy, the so-called "T-cell chauvinists."10 In the meantime, MAb therapies have been successfully developed for other tumor types. US FDA-approved MAbs include trastuzumab (anti-HER2/neu for breast cancer), rituximab (anti-CD20 for B-cell lymphoma), cetuximab (anti-epidermal growth factor receptor for colon cancer), and bevacizumab (anti-vascular endothelial growth factor for colon cancer). What happened to MAb therapy of melanoma? Why have MAbs been commercialized for other tumor types even though MAb treatment started a decade earlier in melanoma? Perhaps melanoma has been a casualty by being the first. After the initial MAb trials in melanoma, there was overexuberance for immunotherapy in general, fed by the press and investors. After the initial MAb clinical trials in melanoma showed only partial responses in a minority of patients, there was a backlash leading to a general assumption that MAb therapy was ineffective. Funding, both public and private, became more scarce and biotechnology companies started to focus MAb therapies on more common epithelial cancers with larger market size. In the meantime, an astounding amount of new information regarding T-cell biology was becoming available. This included identification of melanoma antigens recognized by T cells, understanding of how these antigens are presented, the importance of costimulation and the nature of anergy. As a result, the MAb field has shifted away from melanoma while the melanoma field shifted towards T cells. New advances in the ability to measure specific T-cell responses have sparked clinical trials in melanoma using vaccine or adoptive transfer strategies. The field is moving quickly; as new information becomes available, clinical trials reflect this new information. However, there has yet to be an approved antigen-specific T-cell cancer therapy. This is partially related to the fact that the T-cell field is younger than the antibody field and it may be too soon to expect an effective product. Also, successful T-cell therapy for melanoma faces some unique barriers which include—but are not limited to—selection of appropriate antigens that can function as rejection antigens, loss of expression of either human leukocyte antigen or costimulatory molecules on the tumor cells, production of immunosuppressive substances by melanoma, and the difficulty in producing cell products for clinical trials. Although melanoma immunotherapy is currently dominated by T-cell chauvinists as opposed to "antibody advocates," it is likely that the most successful immunotherapy will involve cooperation between T cells and antibodies. There are multiple examples in preclinical models in which tumor rejection requires both an antibody response and cellular component. Mice immunized against tyrosinase-related protein-1 (TRP1/gp75) are protected from developing lung metastases from B16 melanoma. This protection requires both an antibody response and CD4+ T cells.11 Using HER-2/neu transgenic mice, Wolpoe et al12 showed that immunization against HER-2/neu combined with passive infusion of neu-specific MAb had significant antitumor effects that also required CD4+ and CD8+ T cells.
The importance of cellular immune mechanisms in the antitumor effects of MAb is further supported by observations that the antitumor effects of both trastuzumab and rituximab are dramatically reduced in mice lacking activating Fc It is in this context that we should view the paper by King et al.3 They report the phase I results in melanoma patients treated with a humanized anti-GD2 ganglioside 14.18 MAb linked to interleukin-2. This represents a strategy to target a ganglioside antigen with a MAb while at the same time trying to stimulate a coordinated cellular response that could mediate antibody-dependent cellular cytotoxicity against melanoma. Whether this chimeric MAb will prove to be effective must await the planned phase II trial, but this approach acknowledges the need to coordinate both T-cell and antibody responses against tumor cells. It is tempting to speculate whether the advantage of a coordinated immune response against cancer may also extend to T-cell–focused immunotherapy. Passive transfer of melanoma-specific T cells into patients has been largely ineffective, although transfer of polyclonal cultures of tumor-infiltrating lymphocytes into patients after nonmyeloablative chemotherapy has induced partial responses in approximately 50% of patients, with near-complete responses in two patients in whom the majority of circulating CD8+ T cells were from the infused tumor-infiltrating lymphocytes.17 This noteworthy result, achieved with no apparent contribution from antibodies, seems to support the T-cell chauvinist view that antibodies are not needed. On the other hand, antibody advocates might argue that only when virtually every circulating CD8+ T cell recognized the melanoma antigen were near-complete responses seen, suggesting that even massive T-cell responses are not adequate alone for complete tumor rejection. Additional studies will help to clarify this point, but just as successful chemotherapy strategies generally rely on combinations of active drugs, we should not ignore the possible value of combining cellular and humoral immune responses against melanoma. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES
1. Houghton AN, Mintzer D, Cordon-Cardo C, et al: Mouse monoclonal IgG3 antibody detecting GD3 ganglioside: A phase I trial in patients with malignant melanoma. Proc Natl Acad Sci U S A 82:1242-1246, 1985 2. Nasi M, Meyers M, Livingston P, et al: Anti-melanoma effects of R24, a monoclonal antibody against GD3. Melanoma Res 7:S155-S162, 1997 (suppl 2)
3. King DM, Albertini MR, Schalch H, et al: A phase I clinical trial of the immunocytokine EMD 273063 (hu. 14.19-IL2) in melanoma patients. J Clin Oncol 22:4463-4473, 2004
4. Cheung N, Lazarus H, Miraldi F, et al: Ganglioside GD2 specific monoclonal antibody 3F8: A phase I study in patients with neuroblastoma and malignant melanoma. J Clin Oncol 5:1430-1440, 1987 5. Saleh MN, Khazaeli MB, Wheeler RH, et al: Phase I trial of the chimeric anti-GD2 monoclonal antibody ch14.18 in patients with malignant melanoma. Hum Antibodies Hybridomas 3:19-23, 1992[Medline] 6. Murray JL, Kleinerman ES, Jia SF, et al: Phase Ia/Ib trial of anti-GD2 chimeric monoclonal antibody 14.18 (ch14.18) and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in metastatic melanoma. J Immunother Emphasis Tumor Immunol 19:206-217, 1996[Medline] 7. Albertini M, Hank J, Schiller J, et al: Phase Ib trial of chimeric antidisialoganglioside antibody plus interleukin 2 for melanoma patients. Clin Cancer Res 3:1277-1288, 1997[Abstract] 8. Cheung NK, Kushner BH, Yeh SD, et al: 3F8 monoclonal antibody treatment of patients with stage 4 neuroblastoma: A phase II study. Int J Oncol 12:1299-1306, 1998[Medline]
9. Cheung NV, Lazarus H, Miraldi FD, et al: Reassessment of patient response to monoclonal antibody 3F8. J Clin Oncol 10:671-672, 1992 10. Houghton AN, Lloyd KO: Stuck in the MUC on the long and winding road. Nat Med 4:270-271, 1998[CrossRef][Medline] 11. Weber LW, Bowne WB, Wolchok JD, et al: Tumor immunity and autoimmunity induced by immunization with homologous DNA. J Clin Invest 102:1258-1264, 1998[Medline]
12. Wolpoe ME, Lutz ER, Ercolini AM, et al: HER-2/neu-specific monoclonal antibodies collaborate with HER-2/neu-targeted granulocyte macrophage colony-stimulating factor secreting whole cell vaccination to augment CD8+ T cell effector function and tumor-free survival in Her-2/neu-transgenic mice. J Immunol 171:2161-2169, 2003 13. Clynes RA, Towers TL, Presta LG, et al: Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med 6:443-446, 2000[CrossRef][Medline]
14. Uchida J, Hamaguchi Y, Oliver JA, et al: The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy. J Exp Med 199:1659-1669, 2004
15. Weng WK, Levy R: Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 21:3940-3947, 2003
16. Cartron G, Dacheux L, Salles G, et al: Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 99:754-758, 2002
17. Dudley ME, Wunderlich JR, Robbins PF, et al: Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298:850-854, 2002
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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III receptors and are enhanced by blocking inhibitory FcII receptors.
