Disease relapse is the leading cause of death after reduced-intensity conditioning (RIC)-based allogeneic hematopoietic cell transplantation (HCT). TSC-101 is a donor-derived, T-cell receptor engineered T-cell (TCR-T) therapy candidate designed to target residual diseased recipient cells post-HCT by recognizing the HA-2 antigen, presented only on HLA-A*02:01 (HLA-A2)-positive hematopoietic cells. By selecting HLA-A*02:01-positive patients with HLA-A*02-negative donors, TSC-101 can selectively eliminate residual recipient cells post-HCT while sparing healthy donor-derived cells and thus prevent relapse.

The ALLOHA™ Trial (TSCAN-001, NCT05473910) is a multi-center, biologically controlled, Phase 1 study evaluating TSC-101 in HLA-A*02:01-positive adults with AML, ALL or MDS undergoing RIC-HCT from an HLA-A*02-negative haploidentical or mismatched unrelated donor. TSC-101 cells are infused after engraftment (~Day 21 post-HCT) with a second infusion planned approximately 40 days later. Control subjects receive RIC-HCT alone. Endpoints include dose limiting toxicities (DLTs), safety, and efficacy; exploratory endpoints include chimerism, minimal residual disease (MRD), and TCR-T kinetics.

As of 18 Jul 2025, endpoints were evaluated in the safety analysis set, including 17 subjects who received ≥1 infusion of TSC-101 and 14 who reached Day 21 on the control arm. Median follow-up (range) was 9.6 (2-29) months (m) in the TSC group and 11.9m (1-33m) in controls. Baseline prognostic features were similar, including age (65y vs 68y), mutated TP53 (mTP53) status in 4/17 (24%) TSC and 2/14 (14%) control subjects, and pre-HCT MRD positivity by NGS in 10/15 (67%) evaluable TSC and 8/14 (57%) control subjects.

No DLTs have been reported. Safety was similar between groups and consistent with post-HCT adverse events. Acute graft-versus-host-disease (aGvHD) of any grade (G) occurred in 10/17 (59%) TSC and 7/14 (50%) control subjects, including GII-IV aGvHD in 5/17 (29%) vs 3/14 (21%) in TSC and control groups, respectively. Chronic GvHD occurred in 3 subjects [1 TSC subject (mild) and 2 controls (1 mild, 1 moderate)]. Following TSC-101, cytokine release syndrome occurred in 2/17 (12%) subjects (1 G1 and 1 G2) and neurotoxicity in 1 subject (G1). There were no TSC-related deaths or graft failures.

Preliminary efficacy analyses showed lower rates of relapse with TSC-101 [3/17 (18%)] vs. control [5/14 (36%)], with improved relapse-free survival (RFS) (hazard ratio (HR) 0.48), relapse probability (HR 0.43), event free survival (HR 0.41) and overall survival (HR 0.44) compared to the control group. Among subjects with mTP53, relapses occurred in 1/4 (25%) TSC subjects (relapsed subject had complex karyotype and biallelic TP53m AML) vs. 2/2 (100%) control. One TP53m TSC subject is disease-free >2 years post-HCT. Additional direct evidence of TSC-101's anti-tumor activity was identified after 1 AML subject who relapsed on D264 after 2 TSC-101 infusions was given a third infusion of remaining TSC-101 cells (3.7 x 108; <DL1), without lymphodepletion or any anti-leukemia therapy, and sustained a complete remission for 5 months.

Translational analysis with high-sensitivity NGS-based chimerism in whole blood, CD33+, or CD3+ cells showed complete donor chimerism (>99.8%) in all cells at ≥1 timepoint after TSC-101 in all 15/15 (100%) evaluable subjects (>60 days post HCT) supporting early elimination of recipient hematopoietic cells. In contrast, complete chimerism ≥1 timepoint after HCT without intervention occurred in 8/14 (57%) control subjects. Bone marrow biopsies after TSC-101 (~Day 60 post-HCT), showed that none (0%) were MRD+, including 3 subjects who converted from MRD+ to MRD-negative post-infusion. In contrast, 3/10 (30%) control subjects were MRD+ at ~Day 60 and of those 2 subsequently relapsed. Cellular kinetics revealed peak expansion of TCR-T cells 13-21d post infusion followed by prolonged persistence. TCR-T cells were detectable in all TSC subjects at last follow-up, including 3 subjects >2y and 4 subjects >1y post-infusion.

In summary, the safety of TSC-101 remains consistent with the expected events post-HCT and no new safety signals have been identified. Preliminary analyses continue to show early elimination of residual recipient cells in all evaluable subjects which further supports the potential of TSC-101 to reduce relapses and improve relapse-free survival in RIC-HCT patients. Updated data will be presented.

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2025
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