Maximizing cancer therapy via complementary mechanisms of immune activation: PD-1 blockade, neoantigen vaccination, and Tregs depletion
| Autor: | Deborah H. Charych, Elena Di Matteo, Anna Morena D'Alise, Gabriella Cotugno, Maria De Lucia, Veronica Bignone, Fabio Giovanni Tucci, Guido Leoni, Rosa Bartolomeo, Elisa Scarselli, Elisa Micarelli, Jonathan Zalevsky, Alfredo Nicosia, Linda Nocchi, Francesca Langone, Rosa Maria Vitale, Fulvia Troise, Irene Garzia, Armin Lahm |
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| Přispěvatelé: | D'Alise, A. M., Leoni, G., de Lucia, M., Langone, F., Nocchi, L., Tucci, F. G., Micarelli, E., Cotugno, G., Troise, F., Garzia, I., Vitale, R., Bignone, V., Matteo, E. D., Bartolomeo, R., Charych, D. H., Lahm, A., Zalevsky, J., Nicosia, A., Scarselli, E. |
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
combined modality therapy medicine.medical_treatment T cell Programmed Cell Death 1 Receptor Immunology Gene Expression chemical and pharmacologic phenomena Cancer Vaccines T-Lymphocytes Regulatory Mice Immune system medicine Animals Humans tumor microenvironment Immunology and Allergy RC254-282 Pharmacology Tumor microenvironment Animal business.industry Neoplasms. Tumors. Oncology. Including cancer and carcinogens Cancer Basic Tumor Immunology adaptive immunity Immunotherapy vaccination medicine.disease Acquired immune system Vaccination medicine.anatomical_structure Oncology Cancer cell Cancer research Molecular Medicine Female business Cancer Vaccine Human |
| Zdroj: | Journal for ImmunoTherapy of Cancer, Vol 9, Iss 11 (2021) Journal for Immunotherapy of Cancer |
| ISSN: | 2051-1426 |
| Popis: | BackgroundA number of different immune pathways are involved in the effective killing of cancer cells, collectively named as the ‘Cancer Immunity Cycle’. Anti-PD-1 checkpoint blockade (CPB) therapy is active on one of these pathways and reinvigorates anticancer T cell immunity, leading to long-term responses in a limited fraction of patients with cancer. We have previously shown that neoantigens-based adenovirus vectored vaccine in combination with anti-PD-1 further expands pre-existing anticancer immunity and elicits novel neoantigen-specific T cells thereby increasing efficacy to 50% of tumor clearance in mice. Here we added a third component to the CPB plus vaccine combination, which is able to modify the suppressive tumor microenvironment by reducing the number of tumor-infiltrating regulatory T cells (Tregs), as strategy for improving the therapeutic efficacy and overcoming resistance.MethodsThe antitumor efficacy of anti-PD-1, neoantigen vaccine and Treg modulating agents, either Bempegaldesleukin (BEMPEG: NKTR-214) or an anti-CTLA-4 mAb with Treg-depleting activity, was investigated in murine tumor models. We evaluated tumor growth in treated animals, neoantigen-specific T cells in tumors, tumor-infiltrating lymphocytes (TILs) and intratumoral Tregs.ResultsThe addition of BEMPEG or anti-CTLA-4 to the combination of vaccine and anti-PD-1 led to complete eradication of large tumors in nearby 100% of treated animals, in association with expansion and activation of cancer neoantigen-specific T cells and reduction of tumor-infiltrating Tregs.ConclusionThese data support the notion that the integrated regulation of three steps of the cancer immunity cycle, including expansion of neoantigen-specific T cells, reversal of the exhausted T cell phenotype together with the reduction of intratumoral Tregs may represent a novel rationally designed drug combination approach to achieve higher cure rates. |
| Databáze: | OpenAIRE |
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