CD19.CAR T Cells(University Hospital Heidelberg)

We retrospectively evaluated the treatment outcomes of 47 adult patients with TP53‐mutated acute lymphoblastic leukaemia (ALL) treated with either blinatumomab, inotuzumab or/and CD19 CAR T‐cell therapy. The complete remission with or without count recovery (CR/CRi) (negative minimal residual disease (MRD−) rate) following treatment with blinatumomab (n = 46), inotuzumab (n = 26) and CD19 CAR T cells (n = 6) was 58.7% (96.3%), 61.5% (60%) and 66.7% (75%) respectively. The median OS was 13.6 months (95% CI: 9.6–17.2) for all patients, and it was not significantly different based on the individual novel salvage therapy (p = 0.40). The 12‐month leukaemia‐free survival (LFS) for responders to blinatumomab, InO and CAR T cells was 20%, 11% and 0% (p = 0.743) respectively. Patients who had undergone allogeneic haematopoietic stem cell transplantation (HSCT) post‐response had improved 12‐month LFS compared to those who did not (35% vs. 9%, p = 0.014). Among relapsed patients following blinatumomab, 11 (61%) presented with CD19‐negative disease. Hence, targeted and immune‐based therapies are effective in inducing high MRD‐negative remission rates in adults with B‐cell ALL harbouring TP53 mutations. Nonetheless, the durability of remission is short in the absence of allogeneic HCT consolidation and relapse frequently manifested as CD19‐negative disease following blinatumomab.

Off-the-shelf CAR T cells need to reliably escape allogeneic immune responses to become universal medicines. The primary T cell product SC291 was engineered with a CD19 CAR, T cell receptor alpha constant (TRAC) knockout, and the hypoimmune (HIP) edits of HLA depletion and CD47 overexpression. Here, we report exploratory immune analyses from the ARDENT (NCT05878184) and GLEAM (NCT06294236) trials with HIP-edited CD19 CAR T cells. Although there was an alloimmune response against HLA-replete subpopulations of SC291, we observed no de novo immune response against fully edited HIP CAR T cells in all patients, irrespective of the dose or the patient's disease. The lack of antibodies against the HLA-replete CAR T cells was identified as a marker for deep tissue CD19 cell depletion, and all patients without such antibodies for 60 days showed concomitant B cell depletion in peripheral blood. The immune data presented support the reliability of the HIP concept to evade allorejection.