Efficacy of LCMV-based cancer immunotherapies is unleashed by intratumoral injections of polyI:C
Background Lymphocytic choriomeningitis virus (LCMV) belongs to the Arenavirus family known for inducing strong cytotoxic T-cell responses in both mice and humans. LCMV has been engineered for the development of cancer immunotherapies, currently undergoing evaluation in phase I/II clinical trials. I...
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| Language: | English |
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BMJ Publishing Group
2024-04-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/4/e008287.full |
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| author | Pedro Berraondo Ignacio Melero Marisol Quintero Fernando Aranda Maite Alvarez Henning Lauterbach Myriam Fernandez-Sendin Claudia Augusta Di Trani Nuria Ardaiz Celia Gomar Angela Bella Jose Gonzalez-Gomariz Leire Arrizabalaga Joan Salvador Russo-Cabrera Timo Schippers Klaus K Orlinger |
| author_facet | Pedro Berraondo Ignacio Melero Marisol Quintero Fernando Aranda Maite Alvarez Henning Lauterbach Myriam Fernandez-Sendin Claudia Augusta Di Trani Nuria Ardaiz Celia Gomar Angela Bella Jose Gonzalez-Gomariz Leire Arrizabalaga Joan Salvador Russo-Cabrera Timo Schippers Klaus K Orlinger |
| author_sort | Pedro Berraondo |
| collection | DOAJ |
| description | Background Lymphocytic choriomeningitis virus (LCMV) belongs to the Arenavirus family known for inducing strong cytotoxic T-cell responses in both mice and humans. LCMV has been engineered for the development of cancer immunotherapies, currently undergoing evaluation in phase I/II clinical trials. Initial findings have demonstrated safety and an exceptional ability to activate and expand tumor-specific T lymphocytes. Combination strategies to maximize the antitumor effectiveness of LCMV-based immunotherapies are being explored.Methods We assessed the antitumor therapeutic effects of intratumoral administration of polyinosinic:polycytidylic acid (poly(I:C)) and systemic vaccination using an LCMV-vector expressing non-oncogenic versions of the E6 and E7 antigens of human papillomavirus 16 (artLCMV-E7E6) in a bilateral model engrafting TC-1/A9 cells. This cell line, derived from the parental TC-1, exhibits low MHC class I expression and is highly immune-resistant. The mechanisms underlying the combination’s efficacy were investigated through bulk RNA-seq, flow cytometry analyses of the tumor microenvironment, selective depletions using antibodies and clodronate liposomes, Batf3 deficient mice, and in vivo bioluminescence experiments. Finally, we assessed the antitumor effectiveness of the combination of artLCMV-E7E6 with BO-112, a GMP-grade poly(I:C) formulated in polyethyleneimine, currently under evaluation in clinical trials.Results Intratumoral injection of poly(I:C) enhanced the antitumor efficacy of artLCMV-E7E6 in both injected and non-injected tumor lesions. The combined treatment resulted in a significant delay in tumor growth and often complete eradication of several tumor lesions, leading to significantly improved survival compared with monotherapies. While intratumoral administration of poly(I:C) did not impact LCMV vector biodistribution or transgene expression, it significantly modified leucocyte infiltrates within the tumor microenvironment and amplified systemic efficacy through proinflammatory cytokines/chemokines such as CCL3, CCL5, CXCL10, TNF, IFNα, and IL12p70. Upregulation of MHC on tumor cells and a reconfiguration of the gene expression programs related to tumor vasculature, leucocyte migration, and the activation profile of tumor-infiltrating CD8+ T lymphocytes were observed. Indeed, the antitumor effect relied on the functions of CD8+ T lymphocytes and macrophages. The synergistic efficacy of the combination was further confirmed when BO-112 was included.Conclusion Intratumoral injection of poly(I:C) sensitizes MHClow tumors to the antitumor effects of artLCMV-E7E6, resulting in a potent therapeutic synergy. |
| format | Article |
| id | doaj-art-4dfa0ffddcda4cb18561d27f12fde8c9 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-04-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-4dfa0ffddcda4cb18561d27f12fde8c92024-11-14T04:30:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-04-0112410.1136/jitc-2023-008287Efficacy of LCMV-based cancer immunotherapies is unleashed by intratumoral injections of polyI:CPedro Berraondo0Ignacio Melero1Marisol Quintero2Fernando Aranda3Maite Alvarez4Henning Lauterbach5Myriam Fernandez-Sendin6Claudia Augusta Di Trani7Nuria Ardaiz8Celia Gomar9Angela Bella10Jose Gonzalez-Gomariz11Leire Arrizabalaga12Joan Salvador Russo-Cabrera13Timo Schippers14Klaus K Orlinger15Program of Immunology and Immunotherapy, CIMA-University of Navarra, Pamplona, SpainCentro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, SpainHighlight Therapeutics, Valencia, SpainProgram of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, SpainProgram of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, SpainHookipa Pharma Inc, New York, NY, USAProgram of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, SpainProgram of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, SpainProgram of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, SpainProgram of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, SpainProgram of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, SpainProgram of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, SpainProgram of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, SpainProgram of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, SpainHookipa Pharma Inc, New York, NY, USAHookipa Pharma Inc, New York, New York, USABackground Lymphocytic choriomeningitis virus (LCMV) belongs to the Arenavirus family known for inducing strong cytotoxic T-cell responses in both mice and humans. LCMV has been engineered for the development of cancer immunotherapies, currently undergoing evaluation in phase I/II clinical trials. Initial findings have demonstrated safety and an exceptional ability to activate and expand tumor-specific T lymphocytes. Combination strategies to maximize the antitumor effectiveness of LCMV-based immunotherapies are being explored.Methods We assessed the antitumor therapeutic effects of intratumoral administration of polyinosinic:polycytidylic acid (poly(I:C)) and systemic vaccination using an LCMV-vector expressing non-oncogenic versions of the E6 and E7 antigens of human papillomavirus 16 (artLCMV-E7E6) in a bilateral model engrafting TC-1/A9 cells. This cell line, derived from the parental TC-1, exhibits low MHC class I expression and is highly immune-resistant. The mechanisms underlying the combination’s efficacy were investigated through bulk RNA-seq, flow cytometry analyses of the tumor microenvironment, selective depletions using antibodies and clodronate liposomes, Batf3 deficient mice, and in vivo bioluminescence experiments. Finally, we assessed the antitumor effectiveness of the combination of artLCMV-E7E6 with BO-112, a GMP-grade poly(I:C) formulated in polyethyleneimine, currently under evaluation in clinical trials.Results Intratumoral injection of poly(I:C) enhanced the antitumor efficacy of artLCMV-E7E6 in both injected and non-injected tumor lesions. The combined treatment resulted in a significant delay in tumor growth and often complete eradication of several tumor lesions, leading to significantly improved survival compared with monotherapies. While intratumoral administration of poly(I:C) did not impact LCMV vector biodistribution or transgene expression, it significantly modified leucocyte infiltrates within the tumor microenvironment and amplified systemic efficacy through proinflammatory cytokines/chemokines such as CCL3, CCL5, CXCL10, TNF, IFNα, and IL12p70. Upregulation of MHC on tumor cells and a reconfiguration of the gene expression programs related to tumor vasculature, leucocyte migration, and the activation profile of tumor-infiltrating CD8+ T lymphocytes were observed. Indeed, the antitumor effect relied on the functions of CD8+ T lymphocytes and macrophages. The synergistic efficacy of the combination was further confirmed when BO-112 was included.Conclusion Intratumoral injection of poly(I:C) sensitizes MHClow tumors to the antitumor effects of artLCMV-E7E6, resulting in a potent therapeutic synergy.https://jitc.bmj.com/content/12/4/e008287.full |
| spellingShingle | Pedro Berraondo Ignacio Melero Marisol Quintero Fernando Aranda Maite Alvarez Henning Lauterbach Myriam Fernandez-Sendin Claudia Augusta Di Trani Nuria Ardaiz Celia Gomar Angela Bella Jose Gonzalez-Gomariz Leire Arrizabalaga Joan Salvador Russo-Cabrera Timo Schippers Klaus K Orlinger Efficacy of LCMV-based cancer immunotherapies is unleashed by intratumoral injections of polyI:C Journal for ImmunoTherapy of Cancer |
| title | Efficacy of LCMV-based cancer immunotherapies is unleashed by intratumoral injections of polyI:C |
| title_full | Efficacy of LCMV-based cancer immunotherapies is unleashed by intratumoral injections of polyI:C |
| title_fullStr | Efficacy of LCMV-based cancer immunotherapies is unleashed by intratumoral injections of polyI:C |
| title_full_unstemmed | Efficacy of LCMV-based cancer immunotherapies is unleashed by intratumoral injections of polyI:C |
| title_short | Efficacy of LCMV-based cancer immunotherapies is unleashed by intratumoral injections of polyI:C |
| title_sort | efficacy of lcmv based cancer immunotherapies is unleashed by intratumoral injections of polyi c |
| url | https://jitc.bmj.com/content/12/4/e008287.full |
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