Tumor Regression and Autoimmunity in Patients Treated With Cytotoxic T Lymphocyte–Associated Antigen 4 Blockade and Interleukin 2: A Phase I/II Study

Abstract

Background-Cytotoxic T lymphocyte-associated antigen (CTLA)-4 can inhibit T-cell responses and is involved in tolerance against self antigens. We previously reported autoimmune manifestations and objective cancer regressions in patients with metastatic melanoma treated with CTLA-4 blockade. The possibility of activating tumor-reactive T cells while removing inhibitory activity with CTLA-4 blockade has stimulated interest in using anti-CTLA-4 antibodies in combination with other cancer immunotherapies to improve clinical outcomes. In this study, we assessed the antitumor activity and autoimmune toxicity of CTLA-4 blockade in combination with an immune-activating stimulus, interleukin (IL)-2, in patients with metastatic melanoma.

Immunological markers and clinical outcome of advanced melanoma patients receiving ipilimumab plus fotemustine in the NIBIT-M1 study

“…19,22,23,28,[30][31] The evidence that IPI treatment of MM patients can upregulate the frequency in the periphery of memory/activated T cell subsets was also observed in our study. [24][25][26][27][28] Taken together these observations corroborate the hypothesis that changes of the frequency of circulating T cell subsets from patients enrolled in the NIBIT-M1 study resulted from the activity of the checkpoint blockade agent and were not affected by chemotherapy.…”

“…Similar observations were previously reported for IPI treatment of MM patients, though no association with the patients' clinical outcome was found. [24][25][26][27][28] The detailed phenotypic analysis carried out in PBMCs of patients enrolled in the NIBIT-M1 study allowed to identify for the first time multiple circulating T cell subsets, including memory/activated and Th17 T cells, which frequency in the circulation either at baseline or at W12 post-treatment was associated with the clinical outcome of MM patients. The analysis of the frequency at W24 post-treatment of T cell subpopulations in PBMCs of MM patients was informative for the identification of T lymphocytes persisting in the circulation in the course of treatment.…”

“…22,23 Moreover, increased levels in the periphery of central memory or effector memory CD4 C and CD8 C T cells have been described in patients undergoing IPI treatment, although there was no correlation with the clinical outcome. [24][25][26][27][28] A novel multifaceted immunomonitoring has been set up in the context of the NIBIT-M1 study, with the aim to determine simultaneously phenotypic and functional changes in circulating T cells from MM patients treated with IPI plus FTM. The presence in the baseline serum of MM patients of soluble NKG2D ligands (sNKG2DLs), such as ULBP-1 and ULBP-2, that can play a negative regulatory activity on both T and NK cells, inversely correlated with patients' OS.…”

Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25

“…Indeed, one study performed in mice revealed an essential role of IL-2 in mediating the antitumor activity of CTLA-4 blockade [28]. Moreover, a clinical trial showed that the therapeutic effects of CTLA-4 blockade against melanoma were not improved by simultaneous treatment with recombinant IL-2 (rIL-2) [29], suggesting that both treatments may act through the same pathway. Our results here uncover a key role for IL-2 and several components of the IL-2R complex (CD25 and CD122) in the antitumor effects of anti-CTLA-4 antibodies in murine colon cancer and sarcoma models.…”

Enhancing efficacy of therapeutic vaccinations by combination with other modalities

“…In addition to a 14% response rate, numerous immune-mediated side effects were seen, including nephritis, hepatitis, uveitis, panhypophysitis, dermatitis, and enterocolitis. Clinical trials using ipilimumab combined with a peptide vaccine showed antitumor activity in patients with melanoma, though severe but reversible immune breakthrough events (IBE) were seen [62].…”