TSC-100 and TSC-101, TCR-T Cell Therapies That Target Residual Recipient Cells after Reduced Intensity Conditioning Transplantation, Induce Complete Donor Chimerism with Favorable Prognosis: Early Results of a Phase 1 Trial

Disease relapse after allogeneic hematopoietic cell transplantation (HCT) affects ∼40% of patients and has high mortality. A potential solution is to target antigens mismatched between transplant recipients and donors. TSC-100 and TSC-101 are allogeneic donor derived T-cell receptor-engineered T cells that target HA-1 and HA-2 hematopoietic cell antigens respectively, both presented on HLA-A*02:01. By choosing donors who are either HLA-A*02:01 or HA-1 negative, TSC-100 or TSC-101 selectively eliminate all residual patient hematopoietic cells post-HCT and prevent relapse (figure 1). TSCAN-001 (NCT05473910) is a multi-center, multi-arm, controlled Phase 1 study evaluating TSC-100 and TSC-101 in adult AML, MDS or ALL eligible for reduced intensity conditioning-based haploidentical donor transplantation. HLA-A*02:01 and HA-1 or HA-2-positive patients receive either TSC-100 or TSC-101 after HCT. HLA-A*02:01-negative control arm patients receive HCT alone. Upon count recovery after HCT, treatment arm patients receive single or repeated doses of TSC-100 or TSC-101. At submission, 11 patients were enrolled, 7 in treatment arms (4 TSC-101, 3 TSC-100) and 4 in the control arm, with a median follow-up of 162 days post-HCT (range 2-339 days). No DLTs occurred, and patients were enrolled at Dose Level 3 in both TSC-100 and TSC-101 arms. Safety was similar in treatment and control arms with expected post-HCT adverse events. Graft-versus-host disease (GvHD) was similar in control (3 events) and treatment arms (4 events) and serious adverse events of GvHD or infections were observed in all arms. No cytokine release syndrome or neurotoxicity occurred after TSC-100/101 with minimal increases in CRP/ ferritin. No clinical relapses or deaths occurred to date. Translational analysis found peak TSC-100/101 expansion and activation 7-14 days post dosing, with ongoing persistence at longest follow-up of 203 days. Chimerism analysis of 8 patients with >100 days follow-up (figure 2) using a high-sensitivity NGS-based AlloHeme assay in whole blood, CD33+ or CD3+ cells found complete donor chimerism (>99.87%) after Day 42 in all cells in all 5 out of 5 TSC-100/101 patients (100%) compared with 1 out of 3 control patients (33%). A control patient required early withdrawal of immunosuppression for increasing mixed chimerism. Post-HCT MRD by NGS (LOD <0.05%) was detected in 1 control and none of the treatment arm patients. The prognostic value of complete donor chimerism by AlloHeme was evaluated in the ACROBAT study (NCT04635384) in which 73 patients achieved >99.9% chimerism in CD33+ cells and, after median follow-up of 9 months/ 270 days (range 72-608 days), 3 relapsed (4%), comparing favorably with 18-20% 6-month relapse rates in CIBMTR data. In summary, TSC-100 and TSC-101 post-HCT induce MRD negativity and complete donor chimerism which may be associated with substantially reduced relapse rates.