Nathali‐01: a phase 1/2a trial of ucart20x22, an allogeneic dual car t‐cell therapy for patients with relapsed/refractory b‐cell non‐hodgkin lymphoma (nhl)

Introduction: Autologous CAR T-cell therapies have been transformative in the treatment of selected blood cancers. Despite this remarkable success, long term studies on patients treated with CD19 or CD22 CAR T-cells revealed the emergence of relapses often due to antigen loss. The therapeutic options after CAR T-cell relapses are limited, underscoring the urgent need to develop novel therapies to improve current survival rates. In addition, there is a need to develop allogeneic “off-the-shelf” therapies that are readily available at the time of treatment decision and that overcome the development limitations of current autologous approaches. To address these challenges, UCART20x22, the first allogeneic dual CAR T-cell product candidate targeting two well-validated antigens in B-cell malignancies, CD20 and CD22, was generated from normal healthy donor T cells using a bicistronic lentiviral construct to express both CARs. TALEN® gene editing technology was used to inactivate the TRAC and CD52 genes to both minimize Graft-vs-Host Disease and allow for the use of alemtuzumab (an anti-CD52 monoclonal antibody) in the lymphodepleting regimen. UCART20x22 displays strong activity against tumor cell lines with diverse CD20/CD22 antigen combinations, as well as increased activity against cells presenting both targets simultaneously using in vitro cytotoxic and proliferation assays. The activity of UCART20x22 cells persists against tumor cells expressing both antigens (CD20, CD22) or only one. In a pre-clinical in vivo model carrying subcutaneous lymphoma tumors expressing different antigen combinations in a single mouse, UCART20x22 cells provide efficient in vivo clearance of tumor cells expressing one or two antigens in a dose dependent manner. Furthermore, in primary NHL patient samples expressing diverse CD22 and CD20 antigen levels, UCART20x22 displays robust and specific cytotoxic activity and IFN-γ release in all tested combinations. Methods: NatHaLi-01 (NCT05607420) is a Phase1/2a open-label dose-finding and dose-expansion study to evaluate the safety, expansion, persistence, and clinical activity of UCART20x22 in subjects with relapsed or refractory B-Cell NHL. Primary endpoints are safety, tolerability, and determining the MTD/RP2D of UCART20x22. Additional endpoints are anti-lymphoma activity and describing the expansion and trafficking of UCART20x22. Eligibility criteria include age 18‒80y, lymphoma cell expression of either or both CD20 and CD22, and ≥ 2 prior treatment regimens including autologous CD19 CAR T-cell therapy if eligible. After lymphodepletion with FCA (fludarabine 30 mg/m2 × 3d, cyclophosphamide 0.5g/m2 × 3d, alemtuzumab 12 mg on D1, 24 mg on D2, D3), patients will receive a single infusion of UCART20x22 at a flat dose level ([DL]; DL1-50 × 106 cells, DL2-150 × 106 cells, and DL3-450x106 cells). The trial is currently open for enrollment. The research was funded by: Cellectis, S.A. Keywords: aggressive B-cell non-Hodgkin lymphoma, cellular therapies, ongoing trials Conflicts of interests pertinent to the abstract. E. Bachy Honoraria: Roche, Takeda, Kite/Gilead, BMS, Novartis, Pfizer, Incyte, ADC Therapeutics Research funding: Amgen, BMS Other remuneration: Kite/Gilead, BMS, Novartis, Pfizer A. Ramakrishnan Consultant or advisory role Novartis, AztraZeneca, Genmab, Janssen A. Alfonso Consultant or advisory role BMS, Syros, Jazz Pharma, Astellas Honoraria: Novartis, BMS, Abbvie, Jazz Pharma, Janssen Research funding: Astra Zeneca P. A. Riedell Consultant or advisory role AbbVie, Genmab, ADC Therapeutics, Pharmacyclics, Novartis, BMS, Kite/Gilead, Nurix Therapeutics, Nektar Therapeutics, Takeda, Intellia Therapeutics, Sana Biotechnology, BeiGene, Janssen, and CVS Caremark Honoraria: Novartis Research funding: BMS, Kite/Gilead, Novartis, MorphoSys, CRISPR Therapeutics, Calibr, Xencor, Fate Therapeutics, Roche, and Tessa Therapeutics Other remuneration: Kite Pharma G. Cartron Consultant or advisory role Roche, BMS, Abbvie, Onwards therapeutics, MedXcell, MabQi Honoraria: Roche, BMS, Jansen, Gilead, Novartis, Abbvie Educational grants: Roche P. Barba Honoraria: Allogene, Amgen, BMS, Kit/Gilead, Incyte, Jazz Pharmaceuticals, Miltenyi Biomedicine, Nektar Novartis and Pierre Fabre S. Meadows Employment or leadership position: Cellectis, Inc. Stock ownership: Cellectis, Inc. A. LaCroce Employment or leadership position: Cellectis, Inc. Stock ownership: Cellectis, Inc. D. Thomas Employment or leadership position: Cellectis, Inc. Stock ownership: Cellectis, Inc. C. Poirot Employment or leadership position: Cellectis, S.A. Stock ownership: Cellectis, S.A. K. J. Newhall Employment or leadership position: Cellectis, Inc. Stock ownership: Cellectis, Inc. D. J. Lee Employment or leadership position: Cellectis, Inc. Stock ownership: Cellectis, Inc. M. G. Frattini Employment or leadership position: Cellectis, Inc. Stock ownership: Cellectis, Inc. J. Abramson Consultant or advisory role AbbVie, Astra-Zeneca, BeiGene, BMS, Caribou Biosciences, Cellectar, Century Therapeutics, Epizyme, Genentech, Genmab, Incyte, Interius, Janssen, Kite Pharma, Kymera, Lilly, Morphosys, Mustang Bio, Ono Pharma, Regeneron, Takeda