TSC-100 and TSC-101 Demonstrate the Potential to Reduce Relapse Rates and Increase Relapse-Free Survival in Patients with AML, ALL, or MDS Undergoing Allogeneic HCT with Reduced Intensity Conditioning (RIC): Preliminary Results from the Phase 1 Alloha Trial

Disease relapse is the leading cause of death in patients undergoing RIC allo-HCT, affecting up to 40% of patients. TSC-100 and TSC-1001 are donor-derived T-cell receptor engineered T-cells designed to selectively eliminate residual disease cells post-HCT by targeting HA-1 and HA-2 antigens, respectively, which are only expressed on hematopoietic cells of HLA-A*02:01-positive patients. By choosing donors who are negative for either HLA-A*02:01 or HA-1/HA-2, TSC-100 and TSC-101 can eliminate residual patient hematopoietic cells post-HCT while sparing donor-derived cells, thereby preventing relapse.

The ALLOHA Study (TSCAN-001, NCT05473910) is a multi-center, biologically controlled, Phase 1 study evaluating TSC-100 and TSC-101 in adults with AML, ALL or MDS undergoing RIC HCT with a haploidentical donor. HLA-A*02:01-positive subjects receive either one or two infusions of TSC-100 or TSC-101 after count recovery, ~days 21 and 61 post HCT. Control subjects receive RIC HCT as per standard of care. Endpoints include dose limiting toxicities, safety, efficacy and exploratory biomarkers including chimerism and minimal residual disease (MRD).

As of a 08 Jul 2024 data cut, 27 subjects enrolled and underwent HCT: 16 in the treatment arm [TSC-101 (8), TSC-100 (8)] and 11 in the control arm. Three subjects had ALL (all TSC), 9 had MDS (4 TSC, 5 controls) and 15 had AML (9 TSC, 6 controls). Median age was 69 yrs in the TSC arm and 70 in controls. Most subjects had high-risk molecular or cytogenetic abnormalities, including 4 with mTP53 (2 TSC, 2 controls). Median follow-up was 5.8 months (TSC) vs 5.3 months (control).

No DLTs occurred following TSC-100/TSC-101 infusions. Safety was similar in the treatment and control arms with expected post-HCT adverse events. Grade 2-4 acute graft-versus-host disease (GvHD) was similar in treatment (2 G2 events) and control arms (1 G2, 1 G3). Similarly, one mild chronic GVHD event occurred in the treatment arm and one in the control arm. No cytokine release syndrome or neurotoxicity occurred after TSC-100/TSC-101 infusions and no TSC-100/TSC-101-related deaths occurred. Two non-relapse deaths occurred in the treatment arm: one prior to any TSC infusion and related to an adenoviral infection, and another 15 months post-HCT from a wound infection. Three deaths occurred in the control arm: one non-relapse (septic shock) and two relapse-related.

No relapses have occurred in the treatment arm vs three in the control. Median time to relapse is not evaluable in TSC-treated subjects, where no relapses occurred, vs 159 days in control arm subjects. Additionally, there was a higher probability of being relapse free at 1 year post HCT in treatment arm vs control arm subjects (p=0.047). A hazard ratio 0.09 for EFS (p=0.025) was observed at 1 year and was associated with a significantly shorter time to death or relapse event in the control arm (p=0.0049).

Translational analysis was performed in 18 subjects (11 TSC, 7 controls) with >60-days post HCT follow-up. Peak TSC expansion occurred 7-14 days post dosing, with persistence >360 days in all 5 subjects with >1-year data. The highest dose level (DL3) had substantially higher blood TSC levels. High-sensitivity chimerism analysis with NGS in whole blood, CD33+, or CD3+ cells showed complete donor chimerism (>99.8%) at Day 42 in all cells in all 11 TSCs subjects (100%) compared with 2 of 7 control subjects (29%). Post-HCT MRD by NGS (LOD <0.1% in myeloid, <0.01% in lymphoid cancers) was negative in all TSC subjects post-TSC infusion, and positive in 2 control subjects post HCT. Five TSC subjects reached 1-year follow-up with no relapse, no detectable MRD and complete donor chimerism in the malignant lineage, including a subject with mTP53/del5q MDS and other subjects with high-risk genetics/cytogenetics.

In summary, no DLTs were identified after TSC-100/TSC-101 infusions of with post-infusion safety generally consistent with HCT. All TSC subjects remained relapse free, MRD negative, with full donor chimerism in the malignant lineage, consistent with effective elimination of residual diseased cells post-HCT. The data support the safety and potential of TSC-100/TSC-101 to reduce relapses and increase event-free and relapse-free survival in RIC HCT patients. Enrollment continues and updated data will be presented.