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The oncolytic peptide LTX-315 overcomes resistance of cancers to immunotherapy with CTLA4 checkpoint blockade.

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Yamazaki T, Pitt JM, Vétizou M, Marabelle A, Flores C, Rekdal Ø, Kroemer G, Zitvogel L,


Yamazaki T, Pitt JM, Vétizou M, Marabelle A, Flores C, Rekdal Ø, Kroemer G, Zitvogel L, (click to view)

Yamazaki T, Pitt JM, Vétizou M, Marabelle A, Flores C, Rekdal Ø, Kroemer G, Zitvogel L,

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Cell death and differentiation 2016 4 15() doi 10.1038/cdd.2016.35

Abstract

Intratumoral immunotherapies aim at reducing local immunosuppression, as well as reinstating and enhancing systemic anticancer T-cell functions, without inducing side effects. LTX-315 is a first-in-class oncolytic peptide-based local immunotherapy that meets these criteria by inducing a type of malignant cell death that elicits anticancer immune responses. Here, we show that LTX-315 rapidly reprograms the tumor microenvironment by decreasing the local abundance of immunosuppressive Tregs and myeloid-derived suppressor cells and by increasing the frequency of polyfunctional T helper type 1/type 1 cytotoxic T cells with a concomitant increase in cytotoxic T-lymphocyte antigen-4 (CTLA4) and drop in PD-1 expression levels. Logically, in tumors that were resistant to intratumoral or systemic CTLA4 blockade, subsequent local inoculation of LTX-315 cured the animals or caused tumor regressions with abscopal effects. This synergistic interaction between CTLA4 blockade and LTX-315 was reduced upon blockade of the β-chain of the interleukin-2 receptor (CD122). This preclinical study provides a strong rationale for administering the oncolytic peptide LTX-315 to patients who are receiving treatment with the CTLA4 blocking antibody ipilimumab.Cell Death and Differentiation advance online publication, 15 April 2016; doi:10.1038/cdd.2016.35.

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