Phase 1 Study of CD37-Directed CAR T Cells in Patients with Relapsed or Refractory CD37+ Hematologic Malignancies

Autor: Kit L. Shaw, Irene Scarfò, Lu Huang, Thomas R. Spitzer, Areej El-Jawahri, Steven L. McAfee, Matthew J. Frigault, Frederic I. Preffer, Kathleen Gallagher, Heather Daley, Nora Horick, Myriam Armant, Marcela V. Maus, Jerome Ritz, Daniella Cook, Keagan S Casey, Sarah Nikiforow, Yi-Bin Chen, Marc Wehrli
Rok vydání: 2021
Předmět:
Zdroj: Blood. 138:653-653
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood-2021-146236
Popis: Background: CD37 is a tetraspanin molecule expressed in B-cell and some T-cell lymphomas. We designed a Chimeric Antigen Receptor (CAR) targeting CD37 and with 4-1BB and CD3z intracellular signaling domains (CART37). Preclinical studies indicated comparable anti-tumor activity to CD19-directed CAR-T cells against B-cell lymphomas, promising activity against CD37 + T-cell lymphomas, and no evidence of off-tumor activity (PMID: 30089630). The lentiviral vector used in the clinical study includes a truncated EGFR reporter gene. NCT04136275 is a Phase 1, single-site, open-label, dose-escalation trial enrolling subjects with lymphoma who have received ≥ 2 prior regimens, and whose tumor cells express CD37. Methods: We developed a clinical assay to assess CD37 expression on patient tumor samples using flow cytometry and IHC. Peripheral blood mononuclear cells are collected via leukapheresis and manufactured using the CliniMACS Prodigy®. Following release testing, fresh or cryopreserved cell product is infused. Subjects undergo lymphodepletion with fludarabine and cyclophosphamide, then receive CART37 as a single infusion. Planned starting dose was 100 x 10 6 CAR + T cells, with options to dose-escalate to 300 x 10 6 CAR + T cells or dose de-escalate to 30 x 10 6 CAR + T cells in the event of dose-limiting toxicities (DLT) using a 3+3 design. The primary outcome measure is incidence of adverse events (AEs), including DLTs. Additional outcome measures are clinical response, progression-free and overall survival; correlative studies focus on quantification and persistence of CAR + cells in blood, residual tumor, and cytokine modulation. Results: As of July 13, 2021, 4 subjects (ages 35-70 years) have received CART37. Subjects had a median of 5.5 prior lines of systemic therapy. Two subjects had primary refractory double-hit high-grade B cell lymphoma (HGBCL) that had relapsed after commercial CD19 CAR-T; one subject had cutaneous T cell lymphoma relapsed after extracorporeal photopheresis, alemtuzumab, total skin electron beam radiation, allogeneic hematopoietic stem cell transplant (HSCT), brentuximab, and donor lymphocyte infusion, and one subject had Hodgkin's lymphoma refractory to six prior regimens, including chemotherapy, brentuximab vedotin, nivolumab and everolimus. All subjects were infused in the DL1 cohort, but one subject (with cutaneous T cell lymphoma) received only 19 x 10 6 CAR + due to limited ex vivo expansion. Three subjects developed low-grade CRS and ICANS, and one subject developed refractory Grade 3 CRS and Grade 3 ICANS which resolved with medical management. One patient with HGBCL developed CD19 neg and CD37 neg progressive disease prior to the day 28 evaluation. The three other subjects demonstrated deep responses (2 CR, 1 PR that converted to CR) as best response. Two subjects are alive 208 and 272 days from CAR37 infusion. All subjects had detectable expansion of CART37 by flow cytometry and molecular assays. Two subjects (who received ≥ 100 x 10 6 CART37 had robust expansion and developed prolonged pancytopenia with marrow aplasia; cetuximab infusion decreased detection of truncated EGFR on circulating T cells but had no impact on vector copy number. Both subjects underwent allogeneic HSCT after conditioning with flu/cy/TBI(400) and post-transplant cyclophosphamide (PTCy) based GVHD prevention and successfully engrafted, and had no detectable CART37 after HSCT. Conclusions: In this initial cohort, CART37 infusion resulted in CRS or ICANs as is common for CAR T cell products. Bone marrow aplasia was unexpected and was observed in two subjects who received at least 100 x 10 6 CART37; this was successfully rescued with allogeneic HSCT. Three of four subjects had deep clinical responses in heavily pretreated, refractory disease of diverse lymphoma subtypes. The protocol is open to enrollment with dose de-escalation to 30 x10 6 CART37 and has been amended to require identification of a potential donor prior to treatment in the case that rescue allogeneic HSCT is needed. CART37 has a potential role in enabling allogeneic transplantation in patients with relapsed or refractory hematologic malignancies. Disclosures Frigault: Takeda: Consultancy; Editas: Consultancy; BMS: Consultancy; Novartis: Consultancy, Research Funding; Iovance: Consultancy; Arcellx: Consultancy; Kite: Consultancy, Research Funding. Chen: Gamida: Consultancy; Incyte: Consultancy. Wehrli: CSL Behring: Patents & Royalties; Nestle: Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company. Spitzer: Bluebird Bio: Consultancy; Jazz Pharmaceuticals: Consultancy; Qihan Bio: Consultancy; Syneos Health: Consultancy. Preffer: Cytek Biosciences: Other: Unspecified Relationship. Shaw: Orchard Therapeutics, Ltd: Current equity holder in publicly-traded company. Nikiforow: Kite/Gilead: Other: Ad hoc advisory boards; Novartis: Other: Ad hoc advisory boards; Iovance: Other: Ad hoc advisory boards; GlaxoSmithKline (GSK): Other: Ad hoc advisory boards. Ritz: Amgen: Research Funding; Equillium: Research Funding; Kite/Gilead: Research Funding; Avrobio: Membership on an entity's Board of Directors or advisory committees; Akron: Consultancy; Biotech: Consultancy; Blackstone Life Sciences Advisor: Consultancy; Clade Therapeutics, Garuda Therapeutics: Consultancy; Immunitas Therapeutic: Consultancy; LifeVault Bio: Consultancy; Novartis: Consultancy; Rheos Medicines: Consultancy; Talaris Therapeutics: Consultancy; TScan Therapeutics: Consultancy. Maus: Novartis: Consultancy; Micromedicine: Consultancy, Current holder of stock options in a privately-held company; Kite Pharma: Consultancy, Research Funding; GSK: Consultancy; Intellia: Consultancy; In8bio (SAB): Consultancy; CRISPR therapeutics: Consultancy; Cabaletta Bio (SAB): Consultancy; BMS: Consultancy; Bayer: Consultancy; Atara: Consultancy; AstraZeneca: Consultancy; Astellas: Consultancy; Arcellx: Consultancy; Agenus: Consultancy; Adaptimmune: Consultancy; WindMIL: Consultancy; Tmunity: Consultancy; Torque: Consultancy, Current holder of stock options in a privately-held company; tcr2: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; century: Current equity holder in publicly-traded company; ichnos biosciences: Consultancy, Current holder of stock options in a privately-held company.
Databáze: OpenAIRE
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