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• W4200444379 abstract "BackgroundImmune checkpoint blockade (ICB) induces peripheral CD8 T cell proliferation and facilitates mutation-derived neoantigen targets for CD8 T cell antitumor immunity but the kinetics of immune re-invigoration remain poorly understood. Adoptive Cell Therapy (ACT) by ex-vivo T cell expansion has proven effective in high-mutational cancers, yes approaches have largely been restricted to antigen-unspecific T cell expansion. Selective neoantigen-specific CD8 T cell (NART) expansion potentially warrants improved ACT prognosis.MethodsHere, we interrogated CD8+ T cell patient-specific neoepitope recognition using DNA barcode-labelled pMHC multimers and phenotypic characteristics in pre- and post-treatment PBMCs (n = 85 samples) in 24 patients (pts) with metastatic urothelial carcinoma (mUC) treated with PD-L1-blockade. To increase the number of NARTs, we then applied our synthetic neoantigen pMHC presenting and stimulatory (ImmPACT) scaffolds to direct neoantigen-specific proliferation of CD8 T cells from six pts.ResultsPredicted neoepitope libraries (n = 200-587 peptides per pt) were generated with 55% HLA-coverage (31 of 56 patient HLA types, mean = four HLAs per pt). Disease control pts (best RECIST 1.1 Stable Disease, Partial or Complete Response) experienced a significant increase in the number of NART responses from pre- to 3 weeks post-treatment while NARTs displayed a PD1+ Ki67+ effector phenotype 3 weeks post-treatment. Pre-, 3 weeks-, and 9 weeks post-treatment PBMCs were expanded towards neoantigens for which NARTs were detected, up to 8 neoantigen targets per pt using ImmPACT scaffolds. From 1.3 - 4.6 x 106 PBMCs, successful expansions (n = 13 of 16) yielded viable lymphocyte counts up to 3.2 x 107 cells, and up to 4.01 x 105 NARTs. Both previously un- and detected NART populations could be expanded, resulting in 100-1000-fold expansions.ConclusionsProviding novel insights into ICB-induced NART activation mechanistics this study suggests early-stage NART recognition is associated with response to ICB in mUC patients, while sub-detection level NART populations can be antigen-specifically expanded 1000-fold using ImmPACT scaffolds.Legal entity responsible for the studyThe authors.FundingThe research was funded in part by the Ludwig Center for Cancer Research; the NIH/NCI Cancer Center Support Grant P30 CA008748, the K12CA184746-01A1 (S.A.F.); Ludwig Collaborative and Swim Across America Laboratory (MSKCC, New York, NY 10065, USA); Parker Institute for Cancer Immunotherapy (MSKCC, New York, NY 10065, USA); Department of Medicine (MSKCC, New York, NY 10065, USA); Weill Cornel Medicine (MSKCC, New York, NY 10065, USA); and the Independent Research Fund Denmark.DisclosureJ. Sejerø Holm: Non-Financial Interests, Institutional, Full or part-time Employment: PokeAcell. S.A. Funt: Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Research Grant: Genetech/Roche; Non-Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Stocks/Shares: Urogen; Financial Interests, Personal, Stocks/Shares: Allogene Therapeutics; Financial Interests, Personal, Stocks/Shares: Neogene Therapeutics; Financial Interests, Personal, Stocks/Shares: Kronos Bio; Financial Interests, Personal, Stocks/Shares: Inconovir; Financial Interests, Personal, Research Grant, K12CA184746-01A1: NCI; Financial Interests, Personal, Research Grant: Bochner-Fleisher Research Scholar. D.F. Bajorin: Non-Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Non-Financial Interests, Personal, Advisory Board: Genentech-Roche; Non-Financial Interests, Personal, Advisory Board: AstraZeneca; Non-Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Funding: Merck; Financial Interests, Personal, Funding: Genentech-Roche; Financial Interests, Personal, Funding: AstraZeneca; Financial Interests, Personal, Funding: Novartis; Financial Interests, Personal, Funding: Bristol Myers Squibb. S. Reker Hadrup: Financial Interests, Personal, Ownership Interest: PokeAcell; Financial Interests, Personal, Other, Patent holder: Patent: EP2088/009356. All other authors have declared no conflicts of interest. BackgroundImmune checkpoint blockade (ICB) induces peripheral CD8 T cell proliferation and facilitates mutation-derived neoantigen targets for CD8 T cell antitumor immunity but the kinetics of immune re-invigoration remain poorly understood. Adoptive Cell Therapy (ACT) by ex-vivo T cell expansion has proven effective in high-mutational cancers, yes approaches have largely been restricted to antigen-unspecific T cell expansion. Selective neoantigen-specific CD8 T cell (NART) expansion potentially warrants improved ACT prognosis. Immune checkpoint blockade (ICB) induces peripheral CD8 T cell proliferation and facilitates mutation-derived neoantigen targets for CD8 T cell antitumor immunity but the kinetics of immune re-invigoration remain poorly understood. Adoptive Cell Therapy (ACT) by ex-vivo T cell expansion has proven effective in high-mutational cancers, yes approaches have largely been restricted to antigen-unspecific T cell expansion. Selective neoantigen-specific CD8 T cell (NART) expansion potentially warrants improved ACT prognosis. MethodsHere, we interrogated CD8+ T cell patient-specific neoepitope recognition using DNA barcode-labelled pMHC multimers and phenotypic characteristics in pre- and post-treatment PBMCs (n = 85 samples) in 24 patients (pts) with metastatic urothelial carcinoma (mUC) treated with PD-L1-blockade. To increase the number of NARTs, we then applied our synthetic neoantigen pMHC presenting and stimulatory (ImmPACT) scaffolds to direct neoantigen-specific proliferation of CD8 T cells from six pts. Here, we interrogated CD8+ T cell patient-specific neoepitope recognition using DNA barcode-labelled pMHC multimers and phenotypic characteristics in pre- and post-treatment PBMCs (n = 85 samples) in 24 patients (pts) with metastatic urothelial carcinoma (mUC) treated with PD-L1-blockade. To increase the number of NARTs, we then applied our synthetic neoantigen pMHC presenting and stimulatory (ImmPACT) scaffolds to direct neoantigen-specific proliferation of CD8 T cells from six pts. ResultsPredicted neoepitope libraries (n = 200-587 peptides per pt) were generated with 55% HLA-coverage (31 of 56 patient HLA types, mean = four HLAs per pt). Disease control pts (best RECIST 1.1 Stable Disease, Partial or Complete Response) experienced a significant increase in the number of NART responses from pre- to 3 weeks post-treatment while NARTs displayed a PD1+ Ki67+ effector phenotype 3 weeks post-treatment. Pre-, 3 weeks-, and 9 weeks post-treatment PBMCs were expanded towards neoantigens for which NARTs were detected, up to 8 neoantigen targets per pt using ImmPACT scaffolds. From 1.3 - 4.6 x 106 PBMCs, successful expansions (n = 13 of 16) yielded viable lymphocyte counts up to 3.2 x 107 cells, and up to 4.01 x 105 NARTs. Both previously un- and detected NART populations could be expanded, resulting in 100-1000-fold expansions. Predicted neoepitope libraries (n = 200-587 peptides per pt) were generated with 55% HLA-coverage (31 of 56 patient HLA types, mean = four HLAs per pt). Disease control pts (best RECIST 1.1 Stable Disease, Partial or Complete Response) experienced a significant increase in the number of NART responses from pre- to 3 weeks post-treatment while NARTs displayed a PD1+ Ki67+ effector phenotype 3 weeks post-treatment. Pre-, 3 weeks-, and 9 weeks post-treatment PBMCs were expanded towards neoantigens for which NARTs were detected, up to 8 neoantigen targets per pt using ImmPACT scaffolds. From 1.3 - 4.6 x 106 PBMCs, successful expansions (n = 13 of 16) yielded viable lymphocyte counts up to 3.2 x 107 cells, and up to 4.01 x 105 NARTs. Both previously un- and detected NART populations could be expanded, resulting in 100-1000-fold expansions. ConclusionsProviding novel insights into ICB-induced NART activation mechanistics this study suggests early-stage NART recognition is associated with response to ICB in mUC patients, while sub-detection level NART populations can be antigen-specifically expanded 1000-fold using ImmPACT scaffolds. Providing novel insights into ICB-induced NART activation mechanistics this study suggests early-stage NART recognition is associated with response to ICB in mUC patients, while sub-detection level NART populations can be antigen-specifically expanded 1000-fold using ImmPACT scaffolds." @default.
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• W4200444379 title "55P Neoantigen-reactive CD8 T-cells experience broadened and activated recognition profile following PD-L1 blockade and 1000-fold neoantigen-specific expansion using ImmPACT scaffolds" @default.
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