(1) Aleynick M (2) Svensson-Arvelund J (3) Pantsulaia G (4) Kim K (5) Rose SA (6) Upadhyay R (7) Yellin M (8) Marsh H (9) Oreper D (10) Jhunjhunwala S (11) Moussion CC (12) Merad M (13) Brown BD (14) Brody JD

Journal for immunotherapy of cancer | Free PMC Article

Common pathogen vaccines activated Flt3L-mobilized APCs, supporting cross-presentation and T cell cytotoxicity. Different vaccines activated distinct TLR pathways, signaling molecules, and APC subsets, resulting in variable T cell responses, which did not always correlate with APC activation. Several vaccines enhanced immune responses over the synthetic adjuvant PolyI:C. Compared to a single-agent BCG vaccine, a combination of three mechanistically distinct vaccines (BCG, Rabies, and PedvaxHIB) improved APC antigen presentation, tumor T cell infiltration, and antitumor efficacy in the context of in situ vaccination (Flt3L plus radiotherapy).

Contributed by Alex Najibi

BACKGROUND: Cancer immunotherapies are generally effective in patients whose tumors contain a priori primed T-cells reactive to tumor antigens (TA). One approach to prime TA-reactive T-cells is to administer immunostimulatory molecules, cells, or pathogens directly to the tumor site, that is, in situ vaccination (ISV). We recently described an ISV using Flt3L to expand and recruit dendritic cells (DC), radiotherapy to load DC with TA, and pattern recognition receptor agonists (PRRa) to activate TA-loaded DC. While ISV trials using synthetic PRRa have yielded systemic tumor regressions, the optimal method to activate DCs is unknown. METHODS: To discover optimal DC activators and increase access to clinical grade reagents, we assessed whether viral or bacterial components found in common pathogen vaccines are an effective source of natural PRRa (naPRRa). Using deep profiling (155-metric) of naPRRa immunomodulatory effects and gene editing of specific PRR, we defined specific signatures and molecular mechanisms by which naPRRa potentiate T-cell priming. RESULTS: We observed that vaccine naPRRa can be even more potent in activating Flt3L-expanded murine and human DCs than synthetic PRRa, promoting cross-priming of TA-reactive T-cells. We developed a mechanistically diverse naPRRa combination (BCG, PedvaxHIB, Rabies) and noted more potent T-cell cross-priming than with any single naPRRa. The naPRRa triplet-as part of Flt3L-primed ISV-induced greater intratumoral CD8 T-cell infiltration, T-cells reactive to a newly defined tumorous neoantigen, durable tumor regressions. CONCLUSIONS: This work provides rationale for the translation of pathogen vaccines as FDA-approved clinical-grade DC activators which could be exploited as immune-stimulants for early phase trials.

Author Info: (1) Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn Sch

Author Info: (1) Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. (2) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. (3) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. (4) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. (5) Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. (6) Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. (7) Celldex Therapeutics Inc, Hampton, New Jersey, USA. (8) Celldex Therapeutics Inc, Hampton, New Jersey, USA. (9) Genentech Inc, South San Francisco, California, USA. (10) Genentech Inc, South San Francisco, California, USA. (11) Genentech Inc, South San Francisco, California, USA. (12) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. (13) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. (14) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA joshua.brody@mssm.edu. Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Citation: J Immunother Cancer 2023 Jul 11: Epub

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/37487664

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