Allogeneic stem cell transplant (HSCT) for acute lymphoblastic leukaemia (ALL) using CD34 selected stem cells followed by prophylactic infusions of pathogen-specific and CD19 CAR T cells

Background \u0026 Aim Disease relapse, graft versus host disease (GVHD) and infection are responsible for the majority of deaths after HSCT. We assessed a cellular engineering approach to simultaneously reduce the incidence of these complications using CD34+ stem cell selection combined with post-transplant infusion of pathogen-specific and leukemia-specific T cells. Methods, Results \u0026 Conclusion METHODS We conducted a pilot study in which patients with ALL in remission were treated with a CD34-selected stem cell transplant followed by two planned prophylactic infusions of donor-derived T cells targeting opportunistic pathogens (CMV, EBV and Aspergillus), and leukaemia (CD19 CAR T cells). Cellular products were manufactured locally. Patients did not receive anti-thymocyte globulin or post-transplant GVHD prophylaxis. RESULTS We performed matched sibling donor transplants on two patients aged 45 and 27 years with ALL in morphological CR. Patient 1 had Ph1 positive ALL with detectable BCR-ABL at the time of transplant (0.001%). Patient 2 was Ph1 negative and had no detectable disease by flow cytometry pre-transplant. Conditioning was cyclophosphamide 120mg/kg and TBI 1200cGy. Patients received CD34 selected stem cells (total CD34+ doses 3.5 and 3.6 × 106/kg; total CD3+ cell doses 1.3 and 0.2 × 104/kg). Neutrophil engraftment (\u003e0.5) occurred on days 11 and 12, platelet engraftment (\u003e20) on days 8 and 13. Patients received infusions of pathogen specific T cells (day 21) and CD19 CAR T cells (days 27 and 21). CRS (grades 1 and 2) and neurotoxicity (grade 1) developed in both patients; treated with tocilizumab, patient 1 also received dexamethasone. CAR T cells proliferated in vivo despite low disease burden and persisted in blood for at least 6 weeks in both patients (Figure 1). Patient 1 received foscarnet for 9 days and a second pathogen-specific T cell infusion on day 47 post-transplant. Patient 2 developed asymptomatic reactivation of HHV6 and BK virus. At 364 and 350 days post-transplant, both patients are well, free of GVHD and remain in remission. CONCLUSION This is the first description of a strategy that combines prophylactic donor-derived CAR T cell and pathogen-specific T cell administration after HSCT in the context of CD34+ selection to minimise development of GVHD. Our results demonstrate absence of GVHD, minimal treatment for viral reactivation and remission at 12 months post-transplant suggesting that this approach has promise for improving GVHD relapse free survival following HSCT.