P1364: PHARMACOKINETIC PROFILE OF VARNIMCABTAGENE AUTOLEUCEL (IMN-003A), FIRST-IN-INDIA INDUSTRY CD19-DIRECTED CAR-T CELL THERAPY FOR PATIENTS WITH RELAPSED/ REFRACTORY B CELL MALIGNANCIES (IMAGINE STUDY) (2023)

Topic: 24. Gene therapy, cellular immunotherapy and vaccination - Biology & Translational Research Background: Varnimcabtagene autoleucel (IMN-003A) is an autologous CD19 directed CAR-T cell product with a 4-1BB co-stimulatory domain and A3B1 binder, a non-FMC63 murine single chain variable fragment, manufactured in India and tested in the IMAGINE study (CTRI/2022/03/041162), a phase-2 clinical trial for patients (pts) with relapsed/ refractory B cell malignancies. A fractionated infusion of 1 x 106 CAR+ cells (IMN-003A)/kg for B-ALL cohort and 5 x 106 CAR+ cells (IMN-003A)/kg for B-NHL cohort was administered over 3 days as 10%, 30% and 60% fractions after Flu-Cy lymphodepletion regimen. Safety and efficacy results are submitted in a separate abstract. Here we present the IMN-003A pharmacokinetic data and correlation with disease response. Aims: Study the pharmacokinetic profile of varnimcabtagene autoleucel (IMN-003A) and correlation with disease response. Methods: Peripheral blood (PB) samples were obtained after consent at screening and as per patient schedule after infusion. Persistence of IMN-003A was evaluated in PB after infusion by ddPCR. Safety and efficacy data were collected for analysis. Bone marrow minimal residual disease (MRD) was performed by flowcytometry (FC) at 10-4 sensitivity at screening, D+28 and D+90 for efficacy. IMN-003A was manufactured using cGMP compliant closed system (CliniMACS Prodigy). The manufacturing data was analyzed, including % CAR transduction in the final product (FP) by FC. Apheresis, FP, and PB samples were analyzed for T-cell subpopulations and surface markers by FC. Results: Twenty-one pts underwent apheresis and selected T cells were transduced to achieve the FP with a median manufacturing time of 14d (range 10-27) with 100% success. Two pts underwent second apheresis. The mean % transduction of IMN-003A on autologous T cells was 33.59% (range 8.50 - 58.35) with median transgene copies/ genome of 2.27 (range 0.76 – 4.16). The mean CD4/CD8 ratio at apheresis and final product was 0.81 and 1.03 respectively. The mean proportion of CD4 and CD8 positive naïve cells (CCR7+ RA+) was above 35% in the final product (Figure 1A). Median Product Doubling time and Apheresis to Infusion time was 1.04d (range 0.83 – 4.20) and 22d (range 16 - 95) respectively. Post IMN-003A infusion, there was a trend towards reversal of CD4/CD8 ratio. IMN-003A CAR-T cells showed maximum PB expansion (Tmax) at median 10d (range 7 – 21) with median Cmax 135,693 CAR copies/ μg gDNA (range 24,624 – 413,968). CAR-T cell persistence in PB was 94% at D+28 and 36% at D+90 (range 21 - NR). All pts had B-cell aplasia concurring with CAR-T expansion (Figure 1B); median not reached (range 42 - NR), with no apparent association with response at D+28 and D+90. Hypogammaglobulinemia was noted in 14 of 19 evaluable pts and 9 pts received IVIg. Of evaluable patients, CD4+ T-cell count recovery (>200/μL) was seen at median of 12 days (range 2 - 42) after infusion. Overall response rate (ORR) was 88.2% at D+28 and 72.7% at D+90. Two pts relapsed by D+90. Of MRD-evaluable pts, response was 100% at day+28 (n=7) and 83.3% at D+90 (n=6). Updated results will be presented at the meeting. Summary/Conclusion: In this industry-led first-in-India phase-2 study, IMN-003A production in a cGMP closed system was 100% successful and rapid. The peak of CAR-T expansion occurs at median 10d of infusion. Responses at D+90 are sustained and deep.Keywords: Acute lymphoblastic leukemia, Non-Hodgkin’s lymphoma, CAR-T, Pharmacokinetic