To address antigen escape and loss of T-cell functionality, we report a phase-1 clinical trial (NCT04007029) evaluating autologous naïve and memory T (TN/MEM) cells engineered to express a bispecific anti-CD19/CD20 CAR (CART19/20) for patients with relapsed/refractory NHL, with safety as the primary end point. Ten patients were treated with 36–165 × 106 CART19/20 cells. No patient experienced neurotoxicity of any grade, or over grade-1 cytokine release syndrome. One case of dose-limiting toxicity (persistent cytopenia) was observed. Nine of ten patients achieved objective response (90% ORR), with seven achieving complete remission (70% CR rate). One patient relapsed after 18 months in CR, but returned to CR after receiving a second dose of CART19/20 cells. Median progression-free survival and overall survival were not reached with a 17-month median follow-up. In conclusion, CART19/20 TN/MEM cells are safe and effective in patients with relapsed/refractory NHL, with durable responses achieved at low dosage levels.

Y.Y.C. is an inventor on a patent application for CART19/20 and holds several patent applications in the area of CAR-T cell therapy. Y.Y.C. is a founder of, holds equity in, and receives consulting fees from ImmPACT Bio. She is a member of the scientific advisory board of and holds equity in Catamaran Bio, Notch Therapeutics, Pluto Immunotherapeutics, Prime Medicine, Sonoma Biotherapeutics, and Waypoint Bio. She has consulted for Novartis and Gritstone Bio. S.M.L. holds equity in 1200 Pharma and TORL BioTherapeutics, and has received research funding from Abbvie, Bioline, Bristol Myers Squibb (BMS), Janssen, Novartis, Pfizer, and Sanofi. C.M.W. is a current employee of and holds equity in Orca Bio. J.T. is a current employee of and holds equity in ImmPACT Bio. M.R. is a current employee of and holds equity in Fate Therapeutics. G.J.S. holds equity in Amgen, BMS, and Johnson & Johnson; has consulted for or received honoraria from Kite, Astellas, AbbVie, Incyte, BMS, Stemline, Karyopharm, Agios, Amgen, AstraZenecca, Novartis, Ono Pharma, Celgene, and Jazz; and has received research funding from Actinium, Actuate, AbbVie, AltruBio, Arog, Astellas, AVM Biopharma, Cellectis, Celgene, Cellerant, Constellation, CTI, Forma, Cyclacel, Daiichi-Sankyo, Deciphera, Ifly, FujiFilm, Gamida, Gilead, Genetech/Roche, Geron, Glycomimetics, Incyte, Janssen, Karyopharm, Kite, Mateon, Medimmune, Millenium, Novartis, Onconova, Pfizer, PreCOG, Regimmune, Samus, Sellas, Sangamo, Semline, Takeda, Tolero, and Trovagene. A.R. has received honoraria from consulting with Cstone, Merck, and Vedanta, is or has been a member of the scientific advisory board and holds stock in Advaxis, Appia, Apricity, Arcus, Compugen, CytomX, Highlight, ImaginAb, ImmPact, ImmuneSensor, Inspirna, Isoplexis, Kite-Gilead, Lutris, MapKure, Merus, PACT, Pluto, RAPT, Synthekine and Tango, has received research funding from Agilent and from Bristol-Myers Squibb through Stand Up to Cancer (SU2C), and patent royalties from Arsenal Bio. The other authors declare no conflicts of interest.

NCT04007029

This work was supported by the Parker Institute for Cancer Immunotherapy (grant no. 20163828 to Y.Y.C) and Jean and Stephen Kaplan (gift to Y.Y.C.). This trial was additionally supported by the Aramont Clinical/Translational Research Program in Hematologic Malignancies and the Hornsey Foundation. A.R. is supported by NIH grants R35CA197633 and P30CA016042. J.M.T. is supported by the Jaime Erin Follicular Lymphoma Research Consortium.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Patient clinical data and all associated specimens were obtained via informed consent and approval from UCLA's Institutional Review Board, under the Office of the Human Research Protection Program, on May 31, 2019.

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All data produced in the present study that are legally eligible for release are available upon reasonable request to the authors.