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Journal of Clinical Oncology, Vol 24, No 15 (May 20), 2006: pp. 2230-2232 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.6952
Is Tumor Immunity the Same Thing As Autoimmunity? Implications for Cancer ImmunotherapyColumbia University and Memorial Sloan-Kettering Cancer Center, New York, NY The immune system is capable of inducing tumor regression in selected patients, and the mechanisms regulating this process are becoming better understood.1 Therapeutic responses are generally attributed to the activation of tumor-specific T cells, both CD4+ and CD8+, and there is evidence that the presence of tumor-infiltrating T cells is associated with a favorable prognosis in many types of cancer.2 The activation of T cells is a highly regulated process designed to promote protective immunity against pathogenic organisms and neoplastic cell growth, while preventing emergence of autoreactive T cells. The molecular basis for controlling T-cell activation and tolerance is encoded in a family of costimulatory molecules that deliver stimulatory and inhibitory signals through a series of ligands expressed by responding T cells. The B7 family of costimulatory molecules is among the best described and nicely illustrates the general paradigm for T-cell regulation. T cells recognize peptides presented by major histocompatibility complexes on antigen-presenting cells through their T-cell receptors. The ligation of the costimulatory molecule B7 on antigen-presenting cells with CD28 on the surface of T cells initiates a signal cascade resulting in T-cell activation and proliferation through secretion of interleukin-2 (IL-2) and upregulation of the IL-2 receptor.3 Shortly after activation, a protein known as cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4) is recruited to the cell surface where it binds B7 molecules with greater affinity than CD28, thereby preventing costimulation. This leads to decreased proliferation and IL-2 release by the T cell. The importance of CTLA-4 signaling is evident in CTLA-4–deficient mice that are characterized by uncontrolled T-cell proliferation, marked lymphadenopathy, and T-cell–mediated tissue destruction.4 Four distinct single nucleotide CTLA-4 polymorphisms have been described, and these polymorphisms seem to impart an increased susceptibility to autoimmune disease.5 The recognition that T-cell responses are regulated by both stimulatory and inhibitory signals has led to a variety of approaches aimed at targeting these pathways as a general strategy for manipulating immune responses in cancer, autoimmune diseases, infectious diseases, and organ transplantation. Thus, activation of T cells for tumor immunotherapy can be achieved by targeting stimulatory pathways or by blocking inhibitory pathways. Direct delivery of the B7 costimulatory molecule encoded by a vaccinia virus into melanoma lesions induced objective clinical responses in two patients and was associated with vitiligo in three patients.6 Checkpoint blockade using a monoclonal antibody that blocks CTLA-4 induced three objective clinical responses when administered in combination with a peptide vaccine in patients with melanoma.7 In this trial, 43% of the treated patients experienced significant grade 3 or 4 immune-mediated toxicities, including dermatitis, enterocolitis, hypophysitis, uveitis, and hepatitis. The emergence of these unusual autoimmune phenomena in patients exposed to B7/CD28 signaling or anti–CTLA-4 antibodies suggests that there is a direct association between antitumor immunity and autoimmunity. In this issue, Beck et al8 report on 198 melanoma and renal cell carcinoma patients who were treated intravenously with a human anti–CTLA-4 monoclonal antibody, MDX-010 (ipilimumab) over a 3-year period. Patients received doses ranging from 1 to 9 mg/kg, and some also received peptide vaccines depending on individual protocols. They report an overall objective response rate of 14%, and the most frequent immune breakthrough event was enterocolitis, which occurred in 21% of their population. A highly significant improvement in objective clinical responses was seen in patients with enterocolitis compared with patients without enterocolitis in both melanoma patients (36% v 11%, respectively; P = .0065) and renal cell carcinoma patients (35% v 2%, respectively; P = .0016). These data raise several intriguing questions that have important implications for the future of tumor immunotherapy with agents that target T-cell costimulatory pathways. IS EFFECTIVE TUMOR IMMUNITY NECESSARILY COUPLED TO AUTOIMMUNITY? Although there seems to be a strong association between therapeutic responses and immunologic toxicities in cancer patients treated with anti–CTLA-4, it is not yet clear that the two events are causally related. A pointed example may be found in animal studies where passive administration of a monoclonal antibody directed against tyrosinase-related protein-1 to mice mediated regression of established B16 melanoma tumors and also caused autoimmune hypopigmentation. In this model, effective tumor immunity required Fc receptors, implicating the involvement of macrophages or natural killer cells, but no such requirement was noted for hypopigmentation.9 In other vaccine studies, mice vaccinated with a vaccinia virus expressing tyrosinase-related protein-2 induced rejection of established B16 melanoma tumors but did not induce vitiligo, again suggesting that tumor immunity could be uncoupled from hypopigmentation.10 However, subsequent studies have shown that, when CTLA-4 blockade is combined with xenogeneic DNA vaccines or granulocyte-macrophage colony-stimulating hormone–secreting irradiated whole-cell vaccines, increased rejection of established B16 tumors occurs and is associated with hypopigmentation.11,12 Knowledge of the effects of CTLA-4 blockade in other tumor systems and with other vaccine regimens would be helpful to better understand the relationship between tumor rejection and autoimmunity. The results of murine studies must also be interpreted cautiously when considering the cancer patient because the effector mechanisms may be different. WHAT ARE THE CELLULAR AND MOLECULAR MEDIATORS OF AUTOIMMUNITY IN PATIENTS RECEIVING ANTI–CTLA-4 MONOCLONAL ANTIBODIES? The specific mediators of the autoimmune effects would be important to identify to understand the relationship of autoimmunity and tumor rejection. In the article by Beck et al,8 the authors obtained biopsy material in 39 patients and reported a predominant neutrophilic infiltrate in 46%, a lymphocytic infiltrate in 15%, and a combined neutrophilic and lymphocytic infiltrate in 38% of the patients. This is quite unexpected and suggests that the enterocolitis may not be entirely a result of the activation of T cells. The effect of CTLA-4 blockade on neutrophils has not been evaluated in great detail, but there is at least one report using a CTLA-4 immunoglobulin fusion protein in patients with psoriasis, which is a disease characterized by the presence of highly activated T cells in skin lesions. In this trial, neutrophils were eliminated more rapidly than T lymphocytes from psoriatic lesions, suggesting that neutrophils may be regulated by CTLA-4.13 T cells can also mediate intestinal inflammation, and in transgenic mice expressing high levels of the suppressor of cytokine signaling 1 in lymphocytes, spontaneous colitis occurred at a young age. Characterization of these mice demonstrated significantly decreased CTLA-4 protein levels, suggesting that control of intestinal T-cell activation was mediated through CTLA-4.14 Thus, there may be subtle differences in the enterocolitis induced by CTLA-4 blockade, and this may be important in the clinical management of this complication. The acute effects would be expected to be mediated by neutrophils; however, the relationship between the occurrence of the acute inflammation and T-cell checkpoint blockade remains to be elucidated. Perhaps cytokine and chemokine induction by a small number of activated T cells serves to recruit neutrophils. Further investigation into the pathophysiology of the enterocolitis and its response to treatment will be an important goal for future clinical trials. HOW CAN AUTOIMMUNITY BE CONTROLLED IN TUMOR IMMUNOTHERAPY PATIENTS? The control of enterocolitis is important because five patients in the article by Beck et al8 developed intestinal perforation or required colectomy. They used a rapid-taper, high-dose corticosteroid regimen that did control symptoms in most patients and, interestingly, did not seem to adversely influence the antitumor response. Again, this reinforces the laboratory findings described earlier showing that tumor immunity and autoimmunity may be uncoupled. In four patients with corticosteroid-refractory disease, all patients responded promptly to blockade of tumor necrosis factor alpha using infliximab. Whether nonsteroidal anti-inflammatory agents can prevent the development or control the progression of enterocolitis in patients treated with CTLA-4 blockade might warrant evaluation in future trials. The occurrence of colitis in this setting also suggests that the colon may be a relatively common site for autoimmune toxicity as a result of toll-like receptor stimulation and high antigenic load resulting from the high level of endogenous flora. Investigation of pretreatment antibiotic decontamination has been suggested to address this observation. The recognition that T cells are tightly regulated by stimulatory and inhibitory costimulatory pathways has led to a variety of new targets to augment tumor-specific T-cell immunity. The potent therapeutic responses observed with CTLA-4 blockade with or without vaccination have been especially promising in early clinical trials. However, these trials have also reported the appearance of unexpected immunologic adverse events, with enterocolitis being the most common. Careful monitoring of patients selected for participation in such trials must now include attention to these disorders. Nonetheless, it is intriguing that enterocolitis is associated with a much higher frequency of antitumor response. A better understanding of the cellular and molecular basis of this enterocolitis and its relationship to tumor-specific T-cell responses will be an important goal for murine models and clinical investigation. Renewed dialogue between tumor immunologists and rheumatologists would be useful to compare and contrast current models to delineate the similarities and differences between tumor rejection and autoimmunity. Agents such as ipilimumab represent a significant step forward in the quest to bring the enhanced understanding of basic immunology into the therapeutic arena. As more costimulatory pathways become targets for drug development, it will be of the utmost importance to understand how to control the immune response to achieve therapeutic goals without inducing unintended pathology. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. Author Contributions
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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