Is Tumor Immunity the Same Thing As Autoimmunity? Implications for Cancer Immunotherapy

The immune system is capable of inducing tumor regression in selected patients, and the mechanisms regulating this process are becoming better understood. 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 tumorinfiltrating T cells is associated with a favorable prognosis in many types of cancer. 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. 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. Four distinct single nucleotide CTLA-4 polymorphisms have been described, and these polymorphisms seem to impart an increased susceptibility to autoimmune disease. 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. 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. 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 al 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.