First Results of IMPT-314, an Autologous Bispecific CD19/CD20 Chimeric Antigen Receptor (CAR) in Enriched Naive and Central Memory T Cells, for the Treatment of Large B Cell Lymphoma (LBCL)

Background: CD19-directed CAR T-cell therapies have revolutionized the treatment of B-cell lymphomas, though many patients do not respond or relapse. IMPT-314 (rondecabtagene autoleucel) is a CD19/CD20 autologous bispecific CAR T-cell product uniquely manufactured using CD62L selection to yield a product enriched for naive and central memory T-cells. IMPT-314 was designed to enhance cell persistence, reduce CAR T exhaustion, and limit CD19 or CD20 antigen escape. IMPT-314 incorporates the same CAR construct and similar manufacturing process as CART19/20, which has reported durable responses in a single-institution Phase 1 trial (NCT04007029) (Larson et al., 2023; Puliafito et al., 2023). Here we present the first results with a focus on safety, early anti-lymphoma activity, product characteristics and pharmacokinetics in relapsed or refractory (R/R), CAR T-naive LBCL patients in the dose escalation and expansion Phase 1/2 multi-center trial (NCT05826535).

Methods: Duali-T-1 is a multi-cohort, open-label, single-arm trial. Patients enrolled in the CAR T-naive cohort required 2 or more prior lines of therapy, measurable disease at baseline (re-confirmed after optional allowed bridging therapy), and no prior treatment with an approved or investigational CAR T-cell product. After standard lymphodepletion (Flu/Cy 30/500 mg/m² daily for three days) patients received a single dose of IMPT-314 at dose level 1 (DL1) of 100 million CAR+ cells or dose level 2 (DL2) of 300 million CAR+ cells. The primary objectives for Phase 1 are the evaluation of key treatment emergent adverse events (TEAEs) and rate of investigator assessed response, to inform the recommended Phase 2 dose.

Results: As of May 31, 2024, 12 patients with R/R, CAR T-naive LBCL received IMPT-314 (DL1 n=10, DL2 n=2). The median age was 65 years (range 21-83), 67% (8/12) had advanced stage disease, and 58% (7/12) had elevated lactate dehydrogenase (LDH) at baseline. Patients received a median of 2.5 prior lines of therapy (range 2-6), and 41.7% (5/12) of patients received bridging therapy. The efficacy evaluable population consisted of 11 patients. One patient received IMPT-314 less than 28 days prior to the data cutoff date, continues on study, and is included only in the safety-evaluable population. Product characteristics post manufacturing confirmed the intended product profile, with a predominantly naive/central memory phenotype (median total CD62L+ cells 90.0%; range 64.1-98.8%). Responses were rapid with 100% (11/11) objective response rate at Day 28, and 73% (8/11) of patients obtaining complete response by three months. With median follow up of 5.6 months (range 1.1-8.8), 8 of 11 (73%) patients were in response at last follow up. Among related TEAEs following treatment with IMPT-314 through day 84 assessment there were no observed infections. Low grade (Grade 1-2) cytokine release syndrome (CRS) was observed in 75% (9/12) of patients, and no high-grade CRS was observed. Immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in two patients including one case of Grade 3 ICANS in a patient treated at DL2, which resolved promptly with corticosteroids. There were no fatal adverse events. In 11 patients evaluable for pharmacokinetic analysis, median time of maximal expansion was 13 days (range 7-29), median Cmax was 96,633 copies/µg gDNA (range 14,365 – 1,724,520) and median AUC(0-28day) was 993,926 days x copies/µg gDNA (range 83,457 - 8,537,457). Transgene was detectable in 91% (10/11) patients at the last assessable timepoint. Enrollment is ongoing, including in a recently added second-line LBCL cohort.

Conclusions: Initial results of IMPT-314 suggest a manageable tolerability profile, robust expansion, cellular persistence, and high rates of complete response in R/R, CAR T-naive LBCL. Additional results will be presented at the meeting. (Funded by ImmPACT Bio USA ; Duali-T-1 ClinicalTrials.gov number, NCT05826535)