CART19/20 was developed by engineering autologous naïve/memory T (T N/MEM) cells with a bispecific anti-CD19/CD20 chimeric antigen receptor (CAR) with the goal of mitigating antigen escape and lack of CAR T-cell persistence. We report an update of an ongoing first-in-human phase 1 clinical trial of CART19/20 for patients with relapsed/refractory non-Hodgkin lymphoma (R/R NHL) (NCT04007029).

Eligible patients were ≥18 years old with R/R diffuse large B-cell lymphoma (DLBCL) or primary mediastinal B-cell lymphoma (PMBCL) after ≥2 prior lines of therapy, or with mantle-cell lymphoma (MCL), follicular lymphoma (FL), or CLL/SLL after ≥3 prior lines of therapy. Autologous leukocytes were obtained by leukapheresis and sorted for CD14-/CD25-/CD62L+ T N/MEM cells, followed by lentiviral transduction of the bispecific CD19/CD20 CAR. Lymphodepletion chemotherapy with fludarabine 30 mg/m 2/day and cyclophosphamide 500 mg/m 2/day was administered on Days −5 to −3 prior to CAR T-cell infusion. The primary endpoint was assessment of safety. Secondary endpoints were overall response rate (ORR), progression free survival (PFS), overall survival (OS), and CART19/20 transgene persistence.

As of data cutoff on July 21, 2023, 11 patients had received CART19/20 cells (6 DLBCL, including 4 transformed FL; 3 primary FL; 1 PMBCL; 1 MCL). Patients were treated at two dose levels, either 50 x 10 6 ± 30% CAR+ cells (8 patients) or 200 x 10 6 ± 30% CAR+ cells (3 patients). The median age was 58 (range: 34 to 70). Patients had received a median of 3 prior lines of therapy (range: 2 - 4). None of the treated patients had received prior CAR-T cell therapy; one patient had received a prior CD19-directed therapy. All patients had stage IV disease and 9 of 11 patients received bridging therapy. The engineered CART19/20 cells were enriched with central-memory T cells (T CM: CD45RA-/CD45RO+/CD62L+) which composed a median of 30.8% (range: 5.3 - 80.1%) of the CAR+ T-cells in the infused products.

There were no occurrences of CRS grade ≥ 2 or neurotoxicity of any grade. Six patients had grade 1 cytokine release syndrome (CRS) with a median onset of 8 days from infusion (range: 5 - 11 days). One patient met criteria for dose-limiting toxicity with persistent thrombocytopenia after Day+120. Ten of the 11 patients achieved an objective response (91% ORR), with 8 patients (73%) achieving complete response (CR). One patient with FL, who progressed 18 months after receiving CART19/20, received a second infusion of CART19/20 cells and achieved a second CR for 14.9 months. With a median follow-up of 32.3 months (range: 5.1 - 44.0 months), the median PFS (95% CI 2.6 months - not estimable) and median OS (95% CI 5.7 months - not estimable) have not been reached.

Overall, CART19/20 demonstrated a favorable safety profile with no severe CRS or neurotoxicity of any grade. Moreover, CART19/20 showed robust activity in patients with R/R NHL with durable responses seen. By utilizing a bispecific CAR and enriching for T N/MEM cells, this phase 1 trial of CART19/20 demonstrates the possibility of improving outcomes through targeting common mechanisms of CAR-T cell resistance.

Walthers:Orca Bio: Current Employment, Current holder of stock options in a privately-held company. Ji:CART19/20 patent: Patents & Royalties: CART19/20 patent; ImmPACT Bio: Ended employment in the past 24 months. Roshandell:Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Schweppe:Link Immunotherapeutics: Current Employment. Berent-Maoz:Kite Pharma: Current Employment. de Vos:BeiGene: Consultancy. Oliai:Seagen: Research Funding; Arog: Research Funding; Jazz Pharmaceuticals: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Orca Bio: Research Funding. Schiller:Sangamo Bioscience: Research Funding; Actinium Pharmaceuticals: Research Funding; Karyopharm Therapeutics: Research Funding, Speakers Bureau; Astellas Pharma: Consultancy, Research Funding, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Celator: Research Funding; Stemline Therapeutics: Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; Gamida Cell: Research Funding; FORMA Therapeutics: Research Funding; Stemline Therapeutics: Research Funding; Samus Therapeutics: Research Funding; Kite: Research Funding, Speakers Bureau; Sellas Life Sciences: Research Funding; Fujifilm: Research Funding; Genentech/Roche: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Trovagene: Research Funding; ElevateBio: Research Funding; Tolero Pharmaceuticals: Research Funding; Agios: Research Funding; Novartis: Consultancy, Research Funding; Kronos Bio: Research Funding; AbbVie: Consultancy, Research Funding, Speakers Bureau; Arog: Research Funding; Actuate Therapeutics: Research Funding; REGiMMUNE: Research Funding; Precog: Research Funding; Daiichi Sankyo: Research Funding; Deciphera: Research Funding; Delta-Fly Pharma: Research Funding; Mateon Therapeutics: Research Funding; Geron: Research Funding; Onconova Therapeutics: Research Funding; Ono Pharmaceutical: Research Funding; AVM Biotechnology: Research Funding; Syros Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Agios: Consultancy; Ono Pharmaceutical: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company, Research Funding; Bristol Myers Squibb: Current equity holder in publicly-traded company, Research Funding, Speakers Bureau. Timmerman:Merck & Co., Inc.: Research Funding; BMS: Other: Travel/Accommodations/Expenses, Research Funding; Oncovalent Therapeutics: Consultancy; DAVA Oncology: Consultancy; Kite/Gilead: Consultancy, Honoraria, Research Funding. Ribas:Cstone: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Vedanta: Consultancy, Honoraria; Advaxis: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Appia Bio: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Apricity: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Arcus: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Compugen: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; CytomX: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Highlight: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; ImaginAb: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; ImmPACT: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; ImmuneSensor: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Inspirna: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Isoplexis: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Lutris: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; MapKure: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Merus: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; PACT: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Pluto: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; RAPT: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Synthekine: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Tango: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Agilent: Research Funding; Bristol-Myers Squibb: Research Funding; Arsenal Bio: Patents & Royalties. Chen:Novartis: Consultancy; Waypoint Bio: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Sonoma Biotherapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Prime Medicine: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Pluto Immunotherapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Notch Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Catamaran Bio: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; ImmPACT Bio: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; CART19/20 Patent: Patents & Royalties. Larson:TORL Biotherapeutics: Current equity holder in private company; Bristol Myers Squibb: Research Funding; Bioline: Research Funding; 1200 Pharma: Current equity holder in private company; Pfizer: Research Funding; ImmPACT Bio: Research Funding; Novartis: Research Funding; Janssen: Research Funding; AbbVie: Research Funding; Allogene: Research Funding; Ionis: Research Funding.

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2023
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