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Editorial |
Norris Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, California 90033
Correspondence: Address correspondence and reprint requests to: Jeffrey S. Weber, MD, PhD; E-mail: jweber{at}usc.edu.
Progress in cancer immunotherapy has been modest in the last two decades since interleukin (IL)-2 was shown to induce long-term sustained responses in a proportion of patients with melanoma and renal cell cancer.1,2 That cytokine was approved in the late 1990s by the US Food and Drug Administration for the treatment of stage IV renal cell cancer and melanoma. The exact mechanism of action by which IL-2 mediates regression of melanoma is unknown. Various empiric combinations of agents active in melanoma have been tested with IL-2, including chemotherapy agents and other cytokines,3,4 without a clear benefit in overall survival. The article by Maker et al.5 in this issue of Annals of Surgical Oncology describes a study of immunotherapy with high-dose IL-2 combined with a novel antibody that abrogates the effects of cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) in patients with stage IV melanoma.6 The CTLA-4 molecule is expressed on activated T cells and competes with coactivator CD28 for binding of B7.1 and B7.2 on antigen-presenting cells, thus causing a downmodulation of T-cell activation. Its abrogation with an antibody would be expected to achieve immune activation and proliferation by elimination of downregulatory influences—particularly T-regulatory cells. The antibody has been tested alone in small pilot trials and combined with a peptide vaccine regimen or dacarbazine; it was found to have clinical activity and to induce a spectrum of autoimmune and other side effects that are unique and characteristic.7–9 These side effects are often associated with response and clinical benefit and consist of colitis, rashes, hypophysitis, hepatitis, uveitis, and nephritis; they are believed to have an autoimmune basis. These side effects have been predicted on the basis of murine CTLA-4 gene knock-out models in which mice rapidly develop lymphoproliferative disease with multiorgan lymphocytic infiltration and tissue destruction, with particularly severe myocarditis and pancreatitis, and die by 3 to 4 weeks of age.10
The rationale for combining the two agents is clear, because the authors hypothesized that CTLA-4 antibody inhibits T-regulatory cells that are known to express CTLA-4, and the subsequent addition of IL-2 should allow for antitumor T-cell proliferation and activation unfettered by T-regulatory cells.11 This hypothesis was not tested directly by the authors, and the proper choices on dosing and scheduling for the combination are hard to assess given that the mechanism of action of IL-2 remains obscure. To add even more uncertainty, the mechanism of CTLA-4 antibody likely is via abrogation of its inhibitory activity on T-regulatory cells, but the mechanism of tumor regression and the mechanism by which the antibody is associated with autoimmunity are unclear. Nonetheless, the authors added escalating doses of CTLA-4 antibody administered up to a tolerable 3 mg/kg every 3 weeks to their standard high-dose IL-2 regimen for two cycles. Three doses of the antibody were given (two doses 3 weeks apart just before starting the high-dose IL-2), and two cycles of high-dose bolus IL-2 were administered with a third dose of the antibody just before the second cycle of IL-2. The toxicity of the regimen seemed somewhat greater than with IL-2 alone, because five patients had autoimmune breakthrough events typically observed with CTLA-4 antibody but not generally seen with IL-2 alone, including four episodes of colitis. There were no treatment-related deaths. Only 11 doses of IL-2 were administered for an average course, and this is less than that achieved by the authors in previously published studies. Was the ability to administer more IL-2 diminished by the administration of the antibody? The objective response rate in the 36 patients treated was 22%, with regression in 8 patients of lesions seen in soft tissue and nodal and lung, but evidently not liver, bone, or other visceral, locations. Five (21%) of 24 responded at the highest antibody dose of 3 mg/kg. The authors correctly suggested that synergy between the two agents was unlikely, although no mechanism by which synergy would be achieved was postulated. The response rate may be additive as a result of independent contributions of the two agents, although statistically one could not be sure that the responses were simply due to IL-2 alone. Most responses were sustained, with six of eight responses ongoing from 11 to 19 months as of the time of this writing.
The trial and the article describing it are worthwhile and important for several reasons. The results suggest that the CTLA-4 antibody, a promising prototype of a new class of immunostimulatory drugs, could be safely and successfully combined with other immune modulators that have clinical activity. Although the authors may have underdosed their patients with the antibody and did not demonstrate that they reached dose-limiting autoimmune toxicity, with only 20% autoimmune dose-limiting events, significant levels of autoimmune toxicity were observed in the trial. The data also raise the possibility that clinical response and survival are not associated with autoimmune side effects, as has been postulated for several other trials,6–8 because only two of the eight responders had autoimmune breakthrough events and because of the five patients with grade 3 or 4 autoimmunity, only two had a response. Of interest is that six of the responders have had sustained responses, even with the administration of steroids for autoimmunity, which seems to be a hallmark of this interesting antibody.
As in many interesting clinical trials, more questions are raised than are answered. Was the dose of antibody chosen too low? Is the dose of IL-2 optimal? Did the cytokines work at cross purposes? Is there really evidence that T-regulatory activity was suppressed or eliminated? Were the autoimmune side effects blunted with IL-2 compared with the authors’ prior experience with that same dose of antibody with a peptide vaccine? Did that diminish the clinical benefit? If the authors preserved peripheral blood cells from patients on the IL-2 with CTLA-4 antibody trial and are addressing some of these questions in the laboratory, I would be interested in seeing the results, because these experiments should provide the field of immunotherapy with important information on the mechanism of antitumor action of this novel drug.
New murine models in which the gene for human CTLA-4 is knocked in and expressed on murine T cells may help to answer some of these questions by providing insights into the optimal dosing, scheduling, and combination of agents to use with CTLA-4 antibody.12 Animal models may provide guidance, but ultimately an extensive series of dose-ranging and phase II clinical trials must be conducted to determine the optimal manner in which to examine this promising CTLA-4–abrogating agent with other immune modulators. The article by Maker et al.5 is only the first step in that direction.
Received for publication August 5, 2005. Accepted for publication August 25, 2005.
REFERENCES
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