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Somatic copy number gains are pervasive across cancer types, yet their roles in oncogenesis are insufficiently evaluated. This inadequacy is partly due to copy gains spanning large chromosomal regions, obscuring causal loci. Here, we employed organoid modeling to evaluate candidate oncogenic loci identified via integrative computational analysis of extreme copy gains overlapping with extreme expression dysregulation in The Cancer Genome Atlas. Subsets of "outlier" candidates were contextually screened as tissue-specific cDNA lentiviral libraries within cognate esophagus, oral cavity, colon, stomach, pancreas, and lung organoids bearing initial oncogenic mutations. Iterative analysis nominated the kinase DYRK2 at 12q15 as an amplified head and neck squamous carcinoma oncogene in p53 -/- oral mucosal organoids. Similarly, FGF3, amplified at 11q13 in 41% of esophageal squamous carcinomas, promoted p53 -/- esophageal organoid growth reversible by small molecule and soluble receptor antagonism of FGFRs. Our studies establish organoid-based contextual screening of candidate genomic drivers, enabling functional evaluation during early tumorigenesis., Competing Interests: Declaration of interests A.A.S. has served as a consultant for Boehringer Ingelheim and Pharmacosmos and is a former employee of Tempus Labs. C.J.K. is a scientific advisory board member for Surrozen, Inc., Mozart Therapeutics, and NextVivo. C.C. has served as a scientific advisory board member/consultant for Genentech, Grail, DeepCell, Nanostring, and Viosera. W.C.H. is a consultant for Thermo Fisher, Solasta Ventures, MPM Capital, KSQ Therapeutics, Tyra Biosciences, Frontier Medicine, Jubilant Therapeutics, RAPPTA Therapeutics, Hexagon Bio, Serinus Biosciences, Function Oncology, and Calyx., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches., Competing Interests: Declaration of interests B.J.S. reports consultancy for Foresight Diagnostics. D.M.K. reports consultancy for Roche, Adaptive Biotechnologies, and Genentech and equity ownership interest in Foresight Diagnostics S.K.A. reports speaker honoraria from Takeda. M.J.F. reports consultancy and research funding from Adaptive Biotechnologies, research funding from Kite/Gilead, stock options from Allogene Therapeutics, and equity in Roche/Genentech. M.S.E. reports consultancy for Foresight Diagnostics. J.H.B. reports research funding from Kite Pharma. S.B. reports employment and stock ownership at Kite-a Gilead company. J.W. has research funding from Kite/Gilead, BMS, Novartis, Genentech/Roche, Morphosys/Incyte, AstraZeneca, and ADC Therapeutics, and consulting funding for Kite/Gilead, BMS, Novartis, Genentech/Roche, Morphosys/Incyte, AstraZeneca, ADC Therapeutics, Merck, MonteRosa, Umoja, and Ikusda. M.S.K. reports research funding from CRISPR Therapeutics and Nutcracker Therapeutics, and advisory committee membership for Myeloid Therapeutics and Daiichi Sankyo. Y.N. reports consulting for Leica Biosystems and Roche, and research funding from Kite Pharma. C.L.M. holds several patents focused on CAR T cells therapies; is a co-founder and holds equity in Lyell Immunopharma, CARGO Therapeutics, and Link Cell Therapies, which are developing CAR-based therapies; and consults for Lyell, CARGO, Link, Apricity, Nektar, Immatics, Mammoth, and Ensoma. R.G.M. is a co-founder of and holds equity in Link Cell Therapies and Syncopation Life Sciences. R.G.M. is a consultant for Lyell Immunopharma, NKarta, Arovella Pharmaceuticals, Innervate Radiopharmaceuticals, GammaDelta Therapeutics, Aptorum Group, Zai Labs, ImmunAI, Gadeta, FATE Therapeutics (DSMB), and Waypoint Bio. M.D. reports research funding from AstraZeneca, Genentech, Varian Medical Systems, and Illumina; ownership interest in CiberMed and Foresight Diagnostics; and consultancy from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Gritstone Oncology, Illumina, Novartis, and Roche. D.B.M. holds a patent with Pharmacyclics supporting ibrutinib for chronic graft-versus-host disease and receives consulting or research fees or serves as an advisor for Pharmacyclics, Kite Pharma, Adaptive Biotechnologies, Novartis, BMS, Janssen Pharmaceuticals, Roche, Genentech, Precision Bioscience, Allogene, Miltenyi Biotec, Fate Therapeutics, 2Seventy, and Adicet. A.A.A. reports consultancy for Celgene, Chugai, Genentech, Gilead, Janssen, Pharmacyclics, and Roche; scientific advisory board membership in the Lymphoma Research Foundation; professional affiliations with the American Society of Hematology, American Society of Clinical Oncology, American Society of Clinical Investigation, and Leukemia & Lymphoma Society; research funding from the National Cancer Institute, National Heart, Lung, and Blood Institute, National Institutes of Health, Celgene, Bristol Myers Squibb, and Pfizer; patent filings, including patent issued, licensed, and with royalties paid from FortySeven, a patent pending and Licensed to Foresight, a patent pending relating to MARIA, a patent issued and licensed to CiberMed, a patent issued, a patent pending to CiberMed, a patent issued to Idio-type Vaccines, and a patent issued, licensed, and with royalties paid From Roche; and equity ownership interests in CiberMed Inc., Foresight Diagnostics, FortySeven Inc., and CARGO Therapeutics. B.J.S., D.M.K., M.S.E., M.D., and A.A.A. also report patent filings related to cancer biomarkers. The remaining authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)