14 patients with B cell cancers and 1 with autoimmune disease were treated with allogeneic anti-CD19 CAR T cells edited for immune evasion (TRAC/B2M/CIITA KD + CD47 overexpression), following lymphodepletion. The drug product was heterogeneous; fully edited CAR T (40.9% of cells) did not induce an immune response on-study, but incomplete editing resulted in T/NK cell cytotoxicity against CAR T cells, and donor-specific antibodies (DSA) that mediated cytotoxicity. Durable B cell depletion was observed in 6 patients, and was associated with increasing CAR T dose and DSA absence. 3 non-responding patients had pre-existing DSA, suggesting a potential biomarker.
Contributed by Alex Najibi
ABSTRACT: 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.
Author Info: (1) Sana Biotechnology Inc., 1 Tower Place, South San Francisco, CA, USA. (2) Sana Biotechnology Inc., 1 Tower Place, South San Francisco, CA, USA. (3) Sana Biotechnology Inc., 1 T
Author Info: (1) Sana Biotechnology Inc., 1 Tower Place, South San Francisco, CA, USA. (2) Sana Biotechnology Inc., 1 Tower Place, South San Francisco, CA, USA. (3) Sana Biotechnology Inc., 1 Tower Place, South San Francisco, CA, USA. (4) Sana Biotechnology Inc., 1 Tower Place, South San Francisco, CA, USA. (5) Sana Biotechnology Inc., 1 Tower Place, South San Francisco, CA, USA. (6) Sana Biotechnology Inc., 1 Tower Place, South San Francisco, CA, USA. Electronic address: sonja.schrepfer@sana.com.
