Session: 614. Acute Lymphoblastic Leukemia: Therapy, excluding Transplantation: Poster III
Hematology Disease Topics & Pathways:
Biological, ALL, Leukemia, Diseases, Therapies, CAR-Ts, Pediatric, Young Adult, Study Population, Lymphoid Malignancies
Methods: Eligible subjects for PLAT-03 (NCT03186118), a pilot study of CD19t T-APCs, must have previously enrolled on the phase 2 portion of PLAT-02 and have a stored apheresis product available. Cohorts include subjects that have an identified predictive factor to lose CAR T cell persistence early, or have already experienced early loss of CAR T cell persistence before 6 months and can receive a reinfusion of CD19 CAR T cells prior to planned T-APCs. Patient-derived T-APC products are manufactured with selected and cryopreserved CD4 and CD8 cells from the subject’s original apheresis product. The T cells are activated and transduced with a lentiviral vector to express the CD19t transgene. Transduced cells are expanded in culture for 10-14 days, cryopreserved and release-tested. Subjects <25kg receive 10x106 T-APCs/kg and those ≥25kg receive a flat dose of 5x108 T-APCs. Subjects receive at least one, and up to six total doses of T-APCs at monthly intervals.
Results: Seven subjects (ages 9-23 years) have enrolled on PLAT-03; 5 enrolled based on low CD19 antigen burden at the time of lymphodepletion, and 2 based on rapid CAR T cell contraction between Days 10 and 14. T-APC products were successfully manufactured in 5/5 subjects, with two products pending manufacture. One of 5 subjects was unable to receive his planned T-APCs, as he lost CAR T cell persistence prior to T-APC infusion and failed to engraft a second infusion of CD19 CAR T cells. Of the 4 subjects that have received at least one dose of T-APCs, there have been no related adverse events (AEs) > grade 2, and no fever or cytokine release syndrome (CRS) has been observed. Grade 1-2 AEs that are at least possibly related to T-APCs have included hypogammaglobulinemia, nausea, vomiting and headache. Two subjects have completed T-APC treatment; one received all 5 available T-APC doses (subject S001), and one experienced loss of CAR T cell persistence after two T-APC doses and therefore was not eligible for further doses. Data is shown for subject S001, a 20 year old man with multiply relapsed B-ALL. He enrolled on PLAT-03 due to a low CD19 antigen burden of 4.79% by flow cytometry (inclusive of both normal and malignant CD19+ cells) just prior to lymphodepletion. He had minimal toxicity (grade 1 CRS) following CD19 CAR T cell infusion, and subsequently received 5 monthly doses of T-APCs. An increase in the quantity of detectable CAR T cells (EGFRt+ cells) was observed following T-APCs as shown below, and the subject has ongoing CAR T cell persistence at 8 months, as evidenced by B cell aplasia.
Conclusion: The first-in-human, pilot study PLAT-03 introduces CD19t T-APCs in an attempt to enhance durable CAR T cell persistence and leukemia remission following CD19 CAR T cell immunotherapy. T-APCs have been successfully manufactured from stored apheresis products collected for CAR T cell production. Four subjects have been successfully treated with at least one T-APC infusion to date, without any significant toxicity and with early evidence of efficacy. Accrual of subjects is ongoing to further assess the safety and feasibility of administering CD19t T-APCs, and to examine the impact of T-APCs on CD19 CAR T cell efficacy.
Disclosures: Park: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Jensen: Juno Therapeutics, Inc.: Consultancy, Patents & Royalties, Research Funding.
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