Preliminary Results of Nathali-01: A First-in-Human Phase I/IIa Study of UCART20x22, a Dual Allogeneic CAR-T Cell Product Targeting CD20 and CD22, in Relapsed or Refractory (R/R) Non-Hodgkin Lymphoma (NHL)

Abramson, Jeremy

Oral and Poster Abstracts
704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Poster I

Research, clinical trials, Biological therapies, adult, Lymphomas, non-Hodgkin lymphoma, Clinical Research, B Cell lymphoma, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Diseases, Therapies, Lymphoid Malignancies, Study Population, Human

Jeremy S. Abramson, MD¹, Aravind Ramakrishnan, M.D.², Ana Alfonso Pierola, M.D., Ph.D.³^*, Ira Braunschweig, M.D.⁴^*, Guillaume Cartron, MD, Ph-D⁵^*, Catherine Thieblemont, MD⁶^*, Jose A. Pérez-Simón⁷, Pere Barba, MD⁸, Peter A. Riedell, MD⁹, Carlos Solano, MD, PhD¹⁰, Thomas Gastinne, MD¹¹^*, Alexandra LaCroce¹²^*, Denise Thomas, M.Sc.¹²^*, Camille Poirot, Pharm.D.¹²^*, Sarah Meadows, Ph.D.¹²^*, Kathryn J. Newhall, PhD¹²^*, Daniel J. Lee, MD¹², Mark G. Frattini, MD, PhD¹² and Emmanuel Bachy, MD, PhD¹³^*

¹Massachusetts General Hospital Cancer Center, Boston, MA
²Sarah Cannon Transplant and Cellular Therapy Program at St. David's South Austin Medical Center, Austin, TX
³Department of Oncology-Hematology, Centro de Investigación Médica Aplicada (CIMA). Navarra university-IDISNA. Centro de Investigación Biomédica en Red de Cáncer, CIBERONC. Clínica Universidad de Navarra, Pamplona, Spain
⁴Rutgers Cancer Institute of New Jersey, New Brunswick, NJ
⁵Centre Hospitalier Universitaire de Montpellier, Montpellier, France
⁶Hopital Saint-Louis, Paris, France
⁷Hospital Universitario Virgen del Rocío, Sevilla, Spain
⁸Deparment of Hematology, Vall Hebron Institute of Oncology (VHIO), Hospital Universitari Vall D'Hebron, La Garriga, Barcelona, Spain
⁹Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL
¹⁰Hematology Department, Hospital Clínico Universitario-INCLIVA, Valencia, Spain
¹¹CHU de Nantes, Nantes, France
¹²Cellectis, Inc., New York, NY
¹³Clinical Hematology, Hospices Civils de Lyon and Claude Bernard Lyon 1 University, Lyon, France

Background: UCART20x22 is a dual targeted allogeneic CAR T-cell product candidate generated from healthy donor T-cells. Donor-derived T-cells are transduced with a bicistronic lentiviral vector to express CARs targeting CD20 and CD22. TALEN^® gene editing technology is used to inactivate the TRAC and CD52 genes to minimize graft-versus-host disease (GvHD) and allow for the use of alemtuzumab (CLLS52, an anti-CD52 monoclonal antibody) in the lymphodepletion (LD) regimen, respectively. UCART20x22 previously demonstrated robust and sustained activity in vitro and in vivo (Aranda-Orgilles B, et al. Cancer Immunol Res 2023). Here we present the initial preliminary results from the NatHaLi-01 trial (NCT05607420), the first-in-human Phase 1/2a dose-finding and expansion study evaluating UCART20x22 in R/R B-cell NHL.

Methods: The primary endpoints are safety, tolerability, and determining the recommended phase 2 dose of UCART20x22. Additional endpoints include anti-lymphoma activity and cellular kinetics of UCART20x22. Key eligibility criteria are age 18-80y, lymphoma expression of CD20 and/or CD22 by local assessment, and ≥ 2 prior treatment regimens including autologous CD19 CAR T-cell therapy (CAR19), if eligible. After LD with FCA (fludarabine 30 mg/m² × 3d, cyclophosphamide 0.5g/m² × 3d, CLLS52 12 mg on D1, 24 mg on D2, D3), a single infusion of UCART20x22 is administered at a flat dose level ([DL1] 50 x 10⁶ cells; [DL2] 150 x 10⁶ cells; and [DL3] 450 x 10⁶ cells).

Results: As of 01 July 2023, 3 pts were enrolled and treated at DL1. Pt 1 is a 76yo female with double-expressor diffuse large B-cell lymphoma (DLBCL) relapsed after R-CHOP, radiation therapy, and polatuzumab vedotin with bendamustine/rituximab (BR) and was considered ineligible for CAR19 due to recent high dose bendamustine. Pt 2 is a 65yo female with R/R triple-hit lymphoma transformed from follicular lymphoma who was previously treated with radiation therapy, BR, dose-adjusted R-EPOCH, and two separate CAR19 treatments. Pt 3 is an 18yo female with R/R DLBCL transformed from marginal zone lymphoma who previously received chemoimmunotherapy, venetoclax, ibrutinib, BR, CAR19, obinutuzumab, glofitamab, tafasitamab, lenalidomide, and an experimental epigenetic modifier.

Cytokine release syndrome (CRS) occurred in all patients. Pt 1 had G1 CRS and received tocilizumab (toci) x3 and dexamethasone (dex) x1. Pt 2 had G2 CRS and received toci and dex x1. Pt 3 had G1 CRS and received toci x1. All pts’ CRS resolved with treatment. No immune effector cell associated neurotoxicity (ICANS) or GvHD was observed. There were no UCART20x22 dose limiting toxicities (DLTs), and there was 1 CLLS52 SAE and 1 DLT. The SAE was G3 CMV reactivation and was managed with IV antivirals. The DLT was in Pt 2, who entered the study with G1/2 cytopenias and a hypocellular bone marrow and had prolonged bone marrow aplasia after treatment thought to be due to cumulative chemotherapy exposure. This pt proceeded to allogeneic hematopoietic stem cell transplant (HSCT) from a matched donor while in complete remission from UCART20x22 treatment.

Responses were assessed per Lugano criteria beginning on D28. At D28, all 3 pts responded with 2 CRs and 1 PR.

Host lymphocytes remained suppressed through D28 for all pts. UCART20x22 expansion was observed by flow cytometry in 3/3 pts and was initially detected on D7 followed by peaks between D9-14. Peak expansion ranged from 16-682 cells/μL and was predominantly CD8 T-cells. Ferritin levels and increases in serum cytokines, including IFNγ, TNFα, IL-2, and IL-6, correlated closely with UCART20x22 expansion.

Summary: Treatment with UCART20x22 at DL1 has been safe and well-tolerated, with no UCART20x22 DLTs or ICANS, and CRS was <G3 in all pts. There was 1 DLT of prolonged bone marrow aplasia in a pt with impaired hematopoietic reserve at study entry. UCART20x22 was active at DL1, with all 3 pts responding, including 2 CRs in pts who had previously received CAR19. UCART20x22 expansion was observed in all pts. These initial data support the continued study of UCART20x22 in R/R NHL, and updated results will be presented.

Disclosures: Abramson: Bluebird Bio: Consultancy; Regeneron: Consultancy, Honoraria; Genmab: Consultancy; Mustang Bio: Consultancy, Research Funding; Ono Pharma: Consultancy; MorphoSys: Consultancy; Merck: Research Funding; Lilly: Consultancy; Kymera: Consultancy; Janssen: Consultancy, Honoraria; Interius: Consultancy; Incyte: Consultancy; Genentech: Consultancy; Epizyme: Consultancy; Century Therapeutics: Consultancy; EMD Serono: Consultancy; Novartis: Consultancy; Cellectar Biosciences: Consultancy; Kite Pharma: Consultancy; Seagen Inc.: Research Funding; Takeda: Consultancy; Caribou Biosciences: Consultancy; Celgene: Consultancy; Alimera Sciences: Consultancy; Karyopharm Therapeutics: Consultancy; C4 Therapeutics: Consultancy; BMS: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy; AI Therapeutics: Research Funding. Pierola: Astra Zeneca: Research Funding; Astellas: Consultancy; BMS: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau; Syros: Consultancy, Speakers Bureau; Jazz Pharma: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Cartron: Roche: Consultancy, Honoraria; MabQi, Ownards Therapeutics, Abbvie, Roche, Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; MedxCell, Ownards Therapeutics, MabQi, Emercell, F. Hoffmann-La Roche Ltd, BMS, Abbvie: Consultancy; Jansen, Gilead, Novartis, F. Hoffmann-La Roche Ltd, BMS, Abbvie: Honoraria; Ownards Therapeutics: Consultancy; MabQi: Consultancy; MedxCell: Consultancy; Novartis: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Emercell: Consultancy; BMS: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Thieblemont: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Paris University, Assistance Publique, hopitaux de Paris (APHP): Current Employment; Kyte, Gilead, Novartis, BMS, Abbvie, F. Hoffmann-La Roche Ltd, Amgen: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Hospira: Research Funding; Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Bayer: Honoraria; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Other: Travel Expenses. Barba: Allogene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceutical: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nektar: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pierre-Fabre: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Riedell: Nkarta: Research Funding; Roche: Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Consultancy; Fate Therapeutics: Research Funding; Calibr: Research Funding; Nurix Therapeutics: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sana Biotechnology: Consultancy; Nektar Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tessa Therapeutics: Research Funding; Pharmacyclics: Consultancy; Intellia Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; MorphoSys: Research Funding; Xencor: Research Funding; CRISPR Therapeutics: Research Funding; Janssen: Consultancy; Genmab: Membership on an entity's Board of Directors or advisory committees; CVS Caremark: Consultancy; Celgene/ Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. LaCroce: Cellectis, Inc.: Current Employment, Current equity holder in publicly-traded company. Thomas: Cellectis, Inc.: Current Employment, Current equity holder in publicly-traded company. Poirot: Cellectis, Inc.: Current Employment, Current equity holder in publicly-traded company. Meadows: Cellectis, Inc.: Current Employment, Current equity holder in publicly-traded company. Newhall: Cellectis, Inc.: Current Employment, Current equity holder in publicly-traded company. Lee: Cellectis, Inc.: Current Employment, Current equity holder in publicly-traded company. Frattini: Cellectis, Inc.: Current Employment, Current equity holder in publicly-traded company; Lin Biosciences: Consultancy. Bachy: Novartis: Honoraria, Other: Personal Fees; Bristol Myers Squibb: Honoraria, Other: Personal Fees, Research Funding; Hospices Civils de Lyon Claude Bernard Lyon 1 University: Current Employment; Takeda: Honoraria; Pfizer: Honoraria, Other: Personal Fees; Incyte: Honoraria; Amgen: Research Funding; Roche: Consultancy, Honoraria; Kite, a Gilead Company: Honoraria, Other: Personal Fees.

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2110 Preliminary Results of Nathali-01: A First-in-Human Phase I/IIa Study of UCART20x22, a Dual Allogeneic CAR-T Cell Product Targeting CD20 and CD22, in Relapsed or Refractory (R/R) Non-Hodgkin Lymphoma (NHL)