Melan-A–specific Cytotoxic T Cells Are Associated with Tumor Regression and Autoimmunity Following Treatment with Anti-CTLA-4

Abstract

Purpose: Ipilimumab is a monoclonal antibody that blocks the immune-inhibitory interaction between CTL antigen 4 (CTLA-4) and its ligands onTcells. Clinical trials in cancer patients with ipilimumab have shown promising antitumor activity, particularly in patients with advanced melanoma. Often, tumor regressions in these patients are correlated with immune-related side effects such as dermatitis, enterocolitis, and hypophysitis. Although these reactions are believed to be immune-mediated, the antigenic targets for the cellular or humoral immune response are not known. Experimental Design: We enrolled patients with advanced melanoma in a phase II study with ipilimumab. One of these patients experienced a complete remission of his tumor. The specificity and functional properties of CD8-positiveTcells in his peripheral blood, in regressing tumor tissue, and at the site of an immune-mediated skin rash were investigated. Results: Regressing tumor tissue was infiltrated with CD8-positiveT cells, a high proportion of which were specific for Melan-A. The skin rash was similarly infiltrated with Melan-A^specific CD8-positive T cells, and a dramatic (>30-fold) increase in Melan-A^specific CD8-positive T cells was apparent in peripheral blood. These cells had an effector phenotype and lysed Melan-A^expressing tumor cells. Conclusions: Our results show that Melan-A may be a major target for both the autoimmune and antitumor reactions in patients treated with anti-CTLA-4, and describe for the first time the antigen specificity of CD8-positive T cells that mediate tumor rejection in a patient undergoing treatment with an anti-CTLA-4 antibody. These findings may allow a better integration of ipilimumab into other forms of immunotherapy.

Imaging of CTLA4 Blockade–Induced Cell Replication with 18F-FLT PET in Patients with Advanced Melanoma Treated with Tremelimumab

“…Overall, quantitative immune monitoring assays failed to detect expansions of antigenspecific T cells, either to tumor or to infectious disease antigens (16,18), although T-cell expansions to melanoma antigens can be detected in occasional patients (14,15). On the contrary, biopsies of regressing tumor lesions demonstrate that CD8 and CD4 T-cell proliferation is likely to have occurred, because regressing lesions after therapeutic CTLA4 blockade have dense intratumoral infiltrates by these 2 cell subsets; no such infiltrates were noted in biopsies of progressing tumors (19).…”

“…Most of the studies have focused on analyzing T-cell activation in peripheral blood. Despite occasional cases of expansion of melanoma-specific T cells (14,15), the bulk of the data suggest that there is no detectable expansion of tumor antigen-specific lymphocytes, in particular when focusing on CD81 T-cell responses. The most consistent effects in peripheral blood cells after administering anti-CTLA4 antibodies have been limited to marginal increases in the surface expression of nonspecific activation markers predominantly on CD41 T lymphocytes (16)(17)(18).…”

Immunosuppressive Tumor Microenvironment in Cervical Cancer Patients

“…Since these antibodies affect all T cells regardless of specificity, side effects of these antibodies include mild to severe autoimmunity [168,169]. Early promising clinical trials show enhanced anti-tumor T-cell responses upon treatment with anti-CTLA4 antibodies [170][171][172]. A recent phase III trial showed increased survival in melanoma patients after ipilimumab treatment [173].…”

Immunological correlates of treatment and response in stage IV malignant melanoma patients treated with Ipilimumab

“…10 The exact mechanism by which anti-CTLA-4 antibodies promotes this immune mediated tumor-killing is still not completely understood. Some studies have pointed toward an induction of tumor specific CD8 C T cells, 11,12 while other authors have speculated that effect might be conveyed though inhibition of regulatory T cells. 13 In addition to that, levels of circulating MDSC have recently been reported to be reduced by Ipilimumab treatment, a phenomenon which reportedly is augmented in clinical responders.…”