T-Cell Chauvinists Versus Antibody Advocates—Can't We All Just Get Along? (2004)

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. Since then, many trials with R24 have been conducted in centers around the world resulting in a consistent 10% response rate, 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 al 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 alone or in combination with cytokines. 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 patients 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.” In the meantime, MAb therapies have been successfully developed for other tumor types. US FDA-approved MAbs include trastuzumab (antiHER2/neu for breast cancer), rituximab (anti-CD20 for B-cell lymphoma), cetuximab (anti-epidermal growth factor receptor for colon cancer), and bevacizumab (antivascular 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 JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 22 NOVEMBER 15 2004