Safe and Effective Combination of Donor-Derived, Allogeneic CD19/CD22-CAR T Cells with Myeloablative Graft-Engineered Allo-HCT for High-Risk B-ALL

• Published in: Blood 2024-11, Vol.144 (Supplement 1), p.679-679
• Main Authors: Muffly, Lori, Ananth, Snegha, Danley, Lindsay, Wagner, Caroline, Kordek, Diana, DeNoble, Kimi, Fraser, Ayesha, Egeler, Emily, Molina, Alfonso, Ehlinger, Zachary, Desai, Moksha, Daghagh, Hossein, Tunuguntla, Ramya, Brown, Annie K., Ibañez, Raquel, Kramer, Anne Marijn, Good, Zinaida, Arai, Sally, Johnston, Laura, Lowsky, Robert, Rezvani, Andrew R., Shizuru, Judith, Mikkilineni, Lekha, Shiraz, Parveen, Sidana, Surbhi, Weng, Wen-Kai, Kennedy, Vanessa E., Bharadwaj, Sushma, Dahiya, Saurabh, Frank, Matthew J., Meyer, Everett H., Negrin, Robert S., Feldman, Steven A., Mackall, Crystal L., Sahaf, Bita, Miklos, David B., Smith, Melody
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2024-211959

Background: High-risk B-cell acute lymphoblastic leukemia (B-ALL) remains incurable for many patients despite treatment with autologous CAR T cells or allogeneic hematopoietic cell transplant (allo-HCT). We previously demonstrated that CAR T cells can be safely administered following allo-HCT without causing graft-versus-host disease (GVHD) in a preclinical murine model (Ghosh A, Smith M et al. Nat Med 2017). Hence, we hypothesized that adding allogeneic CD19/CD22-CAR T cells to a myeloablative allo-HCT containing donor T regulatory (Treg) cells (Orca-T) would augment graft versus leukemia without increasing acute GVHD or graft failure. We administered a CD19/CD22-CAR that was previously administered as an autologous CAR (NCT03233854) to patients with B-ALL where it demonstrated a high objective overall response but limited durable remission (Spiegel, J et. al. Nat Med 2021). Here, we report clinical outcomes of the initial dose escalation of donor-derived, allogeneic CD19/CD22-CAR T cells with Orca-T in our novel clinical trial design (NCT05507827). Methods: This is a single-center, phase 1, dose escalation and expansion trial of allogeneic CD19/CD22-CAR T cells in adults with high-risk B-ALL. Myeloablative conditioning with cyclophosphamide and total body irradiation precede infusion of investigational Orca-T, which consists of infusions of HSPCs and Tregs on Day 0 and an infusion of T conventional (Tcon) cells on Day 2. Allogeneic CD19/CD22-CAR-T cells are also infused on Day 2. Single agent pharmacologic GVHD prophylaxis with tacrolimus starts on Day 3. Three dose levels (DL) of allogeneic CD19/CD22-CAR T cells are being studied: DL1 (1x106), DL2 (2x106) and DL3 (3x106) CAR+ cells/kg. The primary objective is to evaluate safety and feasibility of administering allogeneic CD19/CD22-CAR T cells in combination with Orca-T. The primary endpoint is the incidence of engraftment without Grade III to IV acute GVHD at Day 42. Key secondary objectives include efficacy outcomes, CAR persistence, and immune reconstitution. Results: To date, eight patients have been enrolled and treated: 3 on DL1, 3 on DL2, and 2 on DL3 of the dose escalation phase. The median age is 28 (range, 21-52); six (75%) patients are Hispanic. Regarding high-risk disease features, 2 patients had Ph-like ALL, 1 had TP53-mutated ALL, 7 were MRD+ post-induction, and 1 had relapsed disease. At enrollment, 3 (37%) were in an MRD- CR, 4 (50%) were in an MRD+ CR, and 1 (13%) had active disease. Se