Report on the First in Human Experience Using a Highly Purified CD34-Tagged CD19-Targeting CAR T Cell in Patients with Aggressive B-Cell Malignancies

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Background Chimeric Antigen Receptor T cell (CAR-T) therapy has increased long term disease control, with 3 FDA approved CAR products now available DLBCL but only 40% of patients have a durable response and there are significant side effects, including Cytokine Release Syndrome (CRS), Immune effector Cell-associated Neurotoxicity Syndrome (ICANS) and prolonged cytopenias .We designed a CD19 CAR with a CD28 costimulatory domain and a modified CD34 tag (CD34t) and launched a Phase I clinical trial (NCT04214886) of our CD19-CD34t CAR T-cell to evaluate manufacturing feasibility, safety and efficacy in B-cell malignancies . Methods Patients were eligible if they had relapsed or refractory aggressive B-cell malignancies progressing after two or more lines of standard therapy, including stem cell transplant . Other eligibility/ineligibility criteria were similar to previously published CAR-T clinical trials. . Trial design was a standard 3+3 dose escalation design with the intent to evaluate 3 doses levels (DL): DL-1: 1 × 10 6 transduced T cells/kg; DL-2: 1.5 x 10 6 transduced T cells/kg, DL-3: 2 × 10 6 transduced T cells/kg. Results We enrolled 6 heavily pretreated refractory DLBCL patients (average of 3.5 prior lines of therapy), four with previous autologous stem cell transplant ; 3 treated on DL-1 and 3 on DL-2. All had CAR-T product successful made (mean vein-to-vein time: 12 days) and the % CAR-T cells in the infusion product increased from average of 8.6% to 99.5% after CD34 selection. Rate of CRS 33.3% (no grade III or IV CRS) and for ICAN was 16.7% (no grade III or IV ICANS). All patients had count recovery (ANC>100, Plt>50 and Hgb>8) within 28 days of infusion. No patients required tocilizumab but the patient with ICANS (maximum grade 2) received short course of steroids. Three (50%) patients achieved a complete remission (CR) (1 in DL1, 2 in DL2), 1 patient had a partial response (PR) (DL1), one had stable disease (SD) and one had progressive disease (PD). All patients who achieved a CR at Day 28 have continued to be in a remission with ongoing follow up (range 27-54 months). Our CAR T tracking analysis did not show a persistent T-cell phenotype in complete responders versus non-complete responders. We documented a peak CAR-T expansion at D+7 post infusion and for many of the patients, a low level of circulating CAR + T-cells persisting for at least 1-year post-infusion. Conclusions Our 6 patient experience demonstrates that utilizing a CD34t modified CD19 CAR with CD28 costimulatory domain, we successfully produced a CAR with potentially reduced toxicity compared to previously published CD28 costimulatory CARs and with improved persistence. Ongoing and future studies utilizing our platform will provide further insights into the impact purification has on overall CAR efficacy and toxicity.

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