Phase I Dose-Escalation Trial of CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) T-Cells for the Treatment of Relapsed or Refractory B-Cell Lymphomas and Chronic Lymphocytic Leukemia

Abstract

Background: Single-input anti-CD19 CAR T-cells have demonstrated clinical efficacy for relapsed or refractory (R/R) non-Hodgkin B-cell lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Despite excellent response rates, over 50% of CD19 CAR T-cell recipients relapse. Preclinical data show engineering of bispecific anti-CD19/CD20 CAR T-cells via lentiviral transduction effectively targets tumor cells and overcomes antigen escape (Zah E et al., Cancer Immunol Res, 2016). Based on these promising preclinical results and the limitations of single-input anti-CD19 CARs, we investigated the bispecific anti-CD19/CD20 CAR naïve/memory T-cells in a phase I dose-escalation clinical trial for patients with R/R NHL/CLL (NCT04007029). Methods: This trial includes patients who have measurable disease after 2 lines of therapy for diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL), and after 3 lines of therapy for mantle cell lymphoma (MCL), follicular lymphoma (FL), CLL and small lymphocytic leukemia (SLL). Eligible participants received lymphodepleting chemotherapy with fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 for three days, followed by anti-CD19/CD20 CAR T-cell infusion. The CAR T-cell infusion will be given with standard "3+3" dose escalation to determine the maximum tolerated dose (MTD), with a dose range of 5 x 107 to 6 x 108 CAR-positive cells per patient. Results: To date, three patients received treatment on cohort 1 with 5 x 107 CD19/CD20 CAR T-cells for R/R MCL, FL and PMBCL, with an average age of 49.3 (range, 29-60) and a mean of 3.7 prior regimens (range, 3-4). All 3 patients' lymphomas were CD19+/CD20+ on tissue biopsy prior to CAR infusion and all 3 received bridging chemotherapy. The infusion was well tolerated and no major infusion reactions occurred. Peak expansion was noted on day 14. No dose limiting toxicities were identified. The maximum grade CRS was 1 and there was no ICANS. At the 6.0-month cutoff date, 2 of the 3 patients remain in ongoing complete remission. Unfortunately, one patient developed progressive disease 0.5 months after CAR infusion, yet remains alive after treatment with immunotherapy. Both of the responders continue to demonstrate ongoing CAR T-cell persistence and B-cell aplasia by 3.0 and 6.0-month follow up, respectively. Conclusions: Here we demonstrate impressive responses in 2 of 3 patients at the 5 x 107 CD19/CD20 CAR T-cell dosages. Bispecific CD19/CD20 CAR T-cell therapy appears to be safe and effective in patients with R/R NHL and CLL and obviates the challenges with the single antigen directed CARs by decreasing risk of target antigen loss and expression downregulation. A longer follow up period is required to determine the impact of modifying naïve/memory T cells and the durability of response. The trial continues to enroll patients and additional clinical and translational data are being collected on the initial patient cohort. Disclosures Timmerman: Corvus: Current equity holder in publicly-traded company; Marker Therapeutics: Current equity holder in publicly-traded company; Bluebird Bio: Current equity holder in publicly-traded company; Immune Design: Honoraria; Celldex Therapeutics: Consultancy; Valor: Research Funding; Merck: Research Funding; Spectrum Pharmaceuticals: Research Funding; BMS: Other: Travel support, Research Funding; Kite, a Gilead Company: Consultancy, Other: Travel support, Research Funding; Genmab: Current equity holder in publicly-traded company. Chen:Kalthera Therapeutics: Other: Co-founder; Notch Therapeutics: Membership on an entity's Board of Directors or advisory committees; Gritstone Oncology: Membership on an entity's Board of Directors or advisory committees. Larson:BMS, Bioline, Celgene, Juno, Janssen: Research Funding; TORL Biotherapeutics: Current equity holder in private company.

Optimization of metabolism to improve efficacy during CAR-T cell manufacturing

“…Studies have shown that the composition of T cell subsets and their metabolic adaptability are closely related to their antitumor activity. CD19 CAR-T cells that were manufactured from purified CD4+ or CD8+ Tcm or Tn have been shown to have enhanced metabolic adaptability and long-term anti-tumor response [ 18 , 19 ]. CD19 CART derived from TSCM showed good long-term response as compared to CD19 CART standardly manufactured, however it is unclear whether just having more Tscm or the decreased glycolysis of the Tscm drives the long-term response [ 20 ].…”

Real-World Experience of Axicabtagene Ciloleucel and Tisagenlecleucel for Relapsed or Refractory Aggressive B-cell Lymphomas: A Single-Institution Experience

“…Our group recently reported promising early outcomes in a phase 1 dose-escalation study evaluating a novel bi-specific CAR-T construct targeting CD19 and CD20 in 3 heavily pre-treated patients with R/R B-cell NHL. No dose-limiting toxicities occurred and 2 patients remained in ongoing CR at 6-month data cut-off (NCT04007029) (25). Wei et al reported on a novel CAR-T construct targeting CD19 and CD22 in 12 R/R DHL patients and reported a median OS and PFS that were both NR (median follow-up, 12.1 months) (26).…”

“…Prior to FDA approval of CD19-directed chimeric antigen T-cell receptor (CAR-T) therapies, patients with chemo-refractory disease or those relapsing after high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT) had limited therapeutic options and poor outcomes. The SCHOLAR-1 study, published prior to the implementation of CAR-T therapy, showed that patients with refractory BCL to first-or second-line chemotherapy, or relapsing less than 12 months after ASCT had dismal outcomes, including an overall response rate (ORR) of 26% (95% CI [21][22][23][24][25][26][27][28][29][30][31] to subsequent standard therapy and a median overall survival (OS) of 6.3 months (95% CI 5.9-7.0) (2). Chemoresistance is more pronounced in DHL/THL with inferior complete response (CR) rates (3) and post-ASCT outcomes (4) compared to their non-DHL/THL counterparts.…”