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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / therapeutic use
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / cytology
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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CTLA-4 Antigen / immunology
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CTLA-4 Antigen / metabolism*
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Cell Line, Tumor
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Chemokine CXCL10 / analysis
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Cytokines / metabolism
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Drug Resistance, Neoplasm
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HMGB1 Protein / analysis
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Interleukin-2 Receptor beta Subunit / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Neoplasms / drug therapy*
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Neoplasms / mortality
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Neoplasms / therapy
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Oligopeptides / therapeutic use*
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Programmed Cell Death 1 Receptor / metabolism
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Receptor, Interferon alpha-beta / deficiency
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Receptor, Interferon alpha-beta / genetics
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Toll-Like Receptor 4 / deficiency
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Toll-Like Receptor 4 / genetics
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Transplantation, Homologous
Substances
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Antibodies, Monoclonal
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CTLA-4 Antigen
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Chemokine CXCL10
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Cytokines
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HMGB1 Protein
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Ifnar1 protein, mouse
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Interleukin-2 Receptor beta Subunit
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LTX-315
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Oligopeptides
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Pdcd1 protein, mouse
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Programmed Cell Death 1 Receptor
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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Receptor, Interferon alpha-beta