Immune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model.

One of the major barriers that have restricted successful use of chimeric antigen receptor (CAR) T cells in the treatment of solid tumors is an unfavorable tumor microenvironment (TME). We engineered CAR-T cells targeting carbonic anhydrase IX (CAIX) to secrete anti-PD-L1 monoclonal antibody (mAb), termed immune-restoring (IR) CAR G36-PDL1. We tested CAR-T cells in a humanized clear cell renal cell carcinoma (ccRCC) orthotopic mouse model with reconstituted human leukocyte antigen (HLA) partially matched human leukocytes derived from fetal CD34

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W.A.M. has patents in the PD-1/PDL1 field. G.J.F. has patents/pending royalties on the PD-1/PD-L1 pathway from Roche, Merck MSD, Bristol-Myers-Squibb, Merck KGA, Boehringer-Ingelheim, AstraZeneca, Dako, Leica, Mayo Clinic, Eli Lilly, and Novartis. G.J.F. has served on advisory boards for Roche, Bristol-Myers-Squibb, Xios, Origimed, Triursus, iTeos, NextPoint, IgM, Jubilant, Trillium, IOME, GV20, Invaria, and Geode. G.J.F. has equity in NextPoint, Triursus, Xios, iTeos, IgM, GV20, Invaria, and Geode. M.H. is a co-founder of Neomer Diagnostics where he is also on the advisory board. K.W. received a sponsored-research agreement from Gilead Sciences. K.W. served as a consultant for Gilead Sciences and Horizon Therapeutics. D.A.B. reports nonfinancial support from Bristol Myers Squibb, honoraria from LM Education/Exchange Services, advisory board fees from Exelixis and AVEO, personal fees from Charles River Associates, Schlesinger Associates, Imprint Science, Insight Strategy, Trinity Group, Cancer Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Medical Network, Aptitude Health, ASCO Post/Harborside, Targeted Oncology, and AbbVie, and research support from Exelixis and AstraZeneca, outside of the submitted work. C.J.W. holds equity in BioNTech, Inc., and receives research funding from Pharmacyclics. S.S. reports receiving commercial research grants from Bristol-Myers Squibb, AstraZeneca, Exelixis, and Novartis; is a consultant/advisory board member for Merck, AstraZeneca, Bristol-Myers Squibb, CRISPR Therapeutics AG, AACR, and NCI; receives royalties from Biogenex; and mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. T.K.C. reports institutional and personal, paid and unpaid support for research, advisory boards, consultancy, and honoraria from AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers-Squibb, Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Nuscan, Novartis, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events (Peerview, OncLive, MJH, and others), outside the submitted work. T.K.C. has institutional patents filed on molecular alterations and immunotherapy response/toxicity, and ctDNA. T.K.C. has equity in Tempest, Pionyr, Osel, and Precede Bio. T.K.C. has served on committees for NCCN, GU Steering Committee, ASCO/ESMO, ACCRU, and KidneyCan. T.K.C. has medical writing and editorial assistance support may have been funded by Communications companies in part. T.K.C. has mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter.