title: The oncolytic peptide LTX-315 overcomes resistance of cancers to immunotherapy with CTLA4 checkpoint blockade.
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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1015, Equipe Labellisée Ligue Nationale Contre le Cancer, Gustave Roussy Cancer Campus, Villejuif, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Université Paris Sud, Paris Saclay, Le Kremlin-Bicêtre, France.
authors.forename: T
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1015, Equipe Labellisée Ligue Nationale Contre le Cancer, Gustave Roussy Cancer Campus, Villejuif, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Université Paris Sud, Paris Saclay, Le Kremlin-Bicêtre, France.
authors.forename: J M
authors.initials: JM
authors.lastname: Pitt
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1015, Equipe Labellisée Ligue Nationale Contre le Cancer, Gustave Roussy Cancer Campus, Villejuif, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Université Paris Sud, Paris Saclay, Le Kremlin-Bicêtre, France.
authors.forename: M
authors.initials: M
authors.lastname: Vétizou
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1015, Equipe Labellisée Ligue Nationale Contre le Cancer, Gustave Roussy Cancer Campus, Villejuif, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Marabelle
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1015, Equipe Labellisée Ligue Nationale Contre le Cancer, Gustave Roussy Cancer Campus, Villejuif, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Université Paris Sud, Paris Saclay, Le Kremlin-Bicêtre, France.
authors.forename: C
authors.initials: C
authors.lastname: Flores
authors.affiliation: University of Tromsø, Tromsø, Norway.|Lytix Biopharma AS, Tromsø, Norway.
authors.forename: Ø
authors.initials: Ø
authors.lastname: Rekdal
authors.affiliation: Université Paris Sud, Paris Saclay, Le Kremlin-Bicêtre, France.|Equipe 11 Labellisée par la Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.|Cell Biology and Metabolomics platforms, Gustave Roussy Comprehensive Cancer Center, Villejuif, France.|INSERM, U1138, Paris, France.|Université Pierre et Marie Curie, Paris, France.|Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.|Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.|Center of Clinical Investigations in Biotherapies of Cancer (CICBT1428), Villejuif, France.
authors.forename: G
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1015, Equipe Labellisée Ligue Nationale Contre le Cancer, Gustave Roussy Cancer Campus, Villejuif, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Université Paris Sud, Paris Saclay, Le Kremlin-Bicêtre, France.|Université Pierre et Marie Curie, Paris, France.|Center of Clinical Investigations in Biotherapies of Cancer (CICBT1428), Villejuif, France.
authors.forename: L
authors.initials: L
authors.lastname: Zitvogel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D054357:Chemokine CXCL10 / Q000032:analysis; D016207:Cytokines / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D024243:HMGB1 Protein / Q000032:analysis; D053646:Interleukin-2 Receptor beta Subunit / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000628:therapy; D009842:Oligopeptides / Q000627:therapeutic use*; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; D054357:Chemokine CXCL10; D016207:Cytokines; D024243:HMGB1 Protein; C508032:Ifnar1 protein, mouse; D053646:Interleukin-2 Receptor beta Subunit; C000609766:LTX-315; D009842:Oligopeptides; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D053633:Receptor, Interferon alpha-beta