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

O Klein, LM Ebert, T Nicholaou, J Browning… - Clinical Cancer …, 2009 - AACR
O Klein, LM Ebert, T Nicholaou, J Browning, SE Russell, M Zuber, HM Jackson…
Clinical Cancer Research, 2009AACR
Purpose: Ipilimumab is a monoclonal antibody that blocks the immune-inhibitory interaction
between CTL antigen 4 (CTLA-4) and its ligands on T cells. 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 …
Abstract
Purpose: Ipilimumab is a monoclonal antibody that blocks the immune-inhibitory interaction between CTL antigen 4 (CTLA-4) and its ligands on T cells. 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-positive T cells 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-positive T 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.
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