MB-105

P1, N=54, Recruiting, Baylor College of Medicine | Trial primary completion date: Jan 2026 --> Jun 2028

P2, N=46, Recruiting, March Biosciences Inc | Not yet recruiting --> Recruiting

P2, N=46, Not yet recruiting, March Biosciences Inc

P1, N=42, Recruiting, Baylor College of Medicine | Trial primary completion date: Jan 2025 --> Jan 2026

P1, N=42, Recruiting, Baylor College of Medicine | Trial completion date: Sep 2039 --> Sep 2040 | Trial primary completion date: Jan 2024 --> Jan 2025

More patients and longer follow-up are needed for validation. NCT0308190.

In the ongoing clinical trial at Baylor College of Medicine (MAGENTA, NCT03081910) autologous CD5 CAR T-cells produced transient expansion in peripheral blood of patients with refractory or relapsed (r/r) T-ALL/T-LBL producing a short-lived remission in one patient out of eight (13%) across three dose levels ranging from 10e7 to 10e8 CAR T-cells per m2 body surface area. Our preclinical studies showed blocking tonic CAR signaling with tyrosine kinase inhibitors (TKI) ibrutinib and dasatinib during ex vivo expansion of CD5 CAR T-cells minimized the extent of CAR-induced T-cell differentiation and preserved minimally differentiated T-cells co-expressing CD62L and CCR7...Close EBV monitoring and prophylactic B-cell ablation with rituximab has been implemented to reduce the incidence of EBV reactivation post CD5 CAR-T infusion...Systemic ablation of T- and NK-cells was limited due to the repopulation with CD7-negative lymphocyte subsets mirroring the mechanism observed post CD5 CAR T-cell infusion. Similar outcomes have been observed in clinical trials outside the US using autologous and allogeneic CD7 CAR T-cells where fratricide was mitigated by CD7 genome editing or PEBL-mediated disruption of surface expression.6,7 Collectively these results illustrate feasibility, safety, and preliminary efficacy of CAR T-cells targeting pan-T cell antigens CD5 and CD7 for the therapy of treatment-refractory or relapsed T-ALL and LBL.

Despite both normal and malignant T-cells having similar kinetics of CD5 trans-downmodulation upon coculture with CD5 CAR T-cells, healthy peripheral blood T-cells were more resistant to CD5-directed cytotoxicity as a subset of normal T-cells survived a 36-hour coculture with autologous CD5 CAR T-cells while tumor cells were eliminated...These subsets were rapidly replaced with conventional CD5+ T-cells following contraction of CD5 CAR T-cells.Taken together, these results indicate CD5 CAR induces temporary internalization and degradation of CD5 antigen on target cells, but this mechanism provides only short-term protection for normal and malignant T-cells from cytotoxicity. Long-term resistance of normal T-cells in patients having received CD5 CAR T-cell therapy was associated with the emergence of CD5-negative T-cell subsets.

P1, N=42, Recruiting, Baylor College of Medicine | Active, not recruiting --> Recruiting

P1, N=42, Active, not recruiting, Baylor College of Medicine | Recruiting --> Active, not recruiting

Seven patients received a single dose of CD5.CAR T-cells following lymphodepleting chemotherapy (LDC) with cyclophosphamide and fludarabine, and two patients received an additional dose following initial disease evaluation. Shortened manufacturing resulted in an enrichment of minimally differentiated CCR7+ CD62L+ T-cells (27-fold mean increase in CD4+, 13-fold increase in CD8+; p=0.01) and a 3.5-fold increase in CD27+ CD8+ T-cells (p=0.04) suggesting minimizing duration of ex vivo expansion increases anti-tumor function of CD5.CAR T-cells. Overall, these results show that even in patients with multiply relapsed/resistant TCL, CD5.CAR T-cells can produce anti-tumor responses that are sufficiently durable to enable them to proceed with alloHSCT without inducing clinically significant T-cell aplasia.