P1451: preliminary results from the flu/cy/alemtuzumab arm of the phase i balli-01 trial of ucart22, an anti-cd22 allogeneic car-t cell product, in patients with relapsed/refractory (r/r) cd22+ b-cell all

Background: UCART22 is a genetically modified allogeneic T-cell product manufactured from non-HLA matched healthy donor cells. Donor-derived T-cells are transduced with a lentiviral vector to express the anti-CD22 chimeric antigen receptor (CAR; anti-CD22 scFv-41BB-CD3ζ) and are modified using Cellectis’ TALEN® technology to disrupt the T-cell receptor α constant (TRAC) and CD52 genes to minimize risk of graft-vs-host disease (GvHD) and allow use of anti-CD52 drugs for lymphodepletion (LD). Preliminary results from the phase 1, open-label, dose-escalation BALLI-01 study (NCT04150497) in patients (pts) with R/R B-ALL showed that UCART22 is tolerable and shows anti-leukemic activity after LD with fludarabine and cyclophosphamide (FC) (Jain, ASH 2020). Host T-cell recovery was observed in all pts (days 7-28). Aims: Subsequent UCART22 dose-finding cohorts utilized a new LD regimen that included addition of alemtuzumab to FC (“FCA”), which could deepen and sustain host T-cell depletion and promote CART-cell expansion and persistence. Methods: After informed consent, eligibility criteria include age 15‒70 yrs, adequate organ function, ECOG PS ≤ 1, B-ALL blast CD22 expression ≥ 70% by flow cytometry. Pts must have received ≥ 2 Tx regimens. After LD with FCA (F=30 mg/m2 × 3d, C=0.5 g/m2 × 3d, A=20 mg/d × 3d), pts received one infusion of UCART22 at 1 ×106 cells/kg (FCA-DL2) or 2.5 ×106 cells/kg (FCA-DL2i). DLTs are assessed over a 28d observation period after UCART22 infusion. The primary endpoint is the safety, tolerability, and MTD of UCART22. Additional endpoints are anti-leukemic activity (investigator assessed), and expansion, trafficking, persistence of UCART22 in peripheral blood [PB] and bone marrow [BM] assessed by flow cytometry and vector copy number [VCN] and immune reconstitution assessed by flow cytometry. Results: As of October 1, 2021, 12 pts received LD; 11 were administered UCART22, of which 6 received UCART22 after FCA. Enrollment in FC-DL1/DL2 (n=5), FCA-DL2 (n=3), and FCA-DL2i (n=3) was complete. Median age was 30 yrs (20-61) and 7/11 (58%) had B-ALL with recurrent genetic abnormalities (WHO classification). Pts were heavily pretreated, having received a median of 3 (2–6) prior Tx including blinatumomab 8/11 (73%); inotuzumab 5/11 (45%); CD19 CAR-T therapy 3/11 (27%); and HSCT 3/11 (25%). Median BM blast % prior to LD was 60 (3.5-97). UCART22 at DL2 and DL2i administered after FCA LD regimen was well tolerated. No DLTs nor ICANS were observed. Three patients experienced CRS (grade [G]1, n=2; G2, n=1). Two patients experienced G ≥3 infections that were not related to UCART22. One serious AESI of G2 GvHD limited to the skin was reported in the setting of reactivation of prior allogeneic transplant donor stem cells. Anti-leukemic activity (blasts < 5% by day 28) was observed in 2 pts in the FCA cohort; 1 in DL2 and 1 in DL2i. Host lymphocytes on average remained suppressed throughout the 28-day DLT observation period for all pts in the FCA cohorts, correlating with UCART22 proliferation and increases in inflammatory cytokines. Summary/Conclusion: UCART22 after FCA LD was well tolerated and associated with improved host lymphocyte suppression and UCART22 expansion. UCART22 expansion correlated with antileukemic activity with changes in relevant inflammatory markers. Overall, the data support the safety and antileukemic activity of UCART22 after FCA LD in pts with R/R B-ALL. The study is enrolling pts at FCA-DL3 (5 × 106 UCART22 cells/kg).