HLA-A*02

P=N/A, N=200, Recruiting, A2 Biotherapeutics Inc. | Trial primary completion date: Dec 2024 --> Dec 2025

P1, N=63, Recruiting, TScan Therapeutics, Inc. | Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Dec 2024 --> Dec 2025

Preclinical studies demonstrated that MDG1011 displayed key 3S attributes of high specificity, sensitivity, and safety required for regulatory approval of a first-in-human (FIH) clinical study of patients with myeloid malignancies (CD-TCR-001: ClinicalTrials.gov Identifier: NCT03503968). MDG1011 IMP manufacturing was successful at 92%, even including heavily pretreated elderly patients with very advanced disease. The IMPs applied in nine patients all displayed antigen-specific functionality. Elsewhere, clinical study results for MDG1011 showed no dose-limiting toxicity and signs of biological and/or clinical activity in several patients.

To our knowledge, this study is the first demonstrating the clinical promise of lete-cel in HLA-/NY-ESO-1-positive patients with advanced MRCLS.

Finally, we enumerated potential cross-reactivities between tumoral and viral epitopes and highlighted some challenges in their identification for therapeutic use. Moreover, the thousands of peptide-HLA complexes generated in our work constitute a valuable resource to study T-cell cross-reactivity.

Our findings highlight the potential of targeting the ATAD2 YSDDDVPSV immunopeptide for SCLC immunotherapy, thereby offering a promising avenue for the development of adoptive T cell therapies to effectively treat ASCL1-positive or NEUROD1-positive SCLC carrying HLA-A∗02:01.

P2, N=52, Active, not recruiting, Adaptimmune | Recruiting --> Active, not recruiting | N=120 --> 52

Examples are the tyrosine kinase inhibitors avapritinib and ripretinib in gastrointestinal stromal tumours (GIST), the immune check point inhibitor atezolizumab in alveolar soft part tissue sarcoma, the γ-secretase inhibitor nirogacestat in desmoid tumours, the NTRK inhibitors larotrectinib and entrectinib in tumours with NTRK fusions, the mTOR inhibitor nab-sirolimus in PEComa, and the EZH-2 inhibitor tazemetostat in epithelioid sarcoma...The challenges in drug development in soft tissue sarcoma are due to the rarity and the molecular heterogeneity of the disease and the fact that many subtypes are associated with complex karyotypes or non-targetable molecular alterations. We believe that progress maybe possible with a better understanding of the complex biology, the development of novel compounds for difficult targets such as proteolysis targeting chimeras (Protacs), the utilisation of modern clinical trial designs, and enhanced collaboration of academia with industry to develop treatments with a strong biologic rationale.

Our findings demonstrate that RVS treatment enhances T cell function against breast cancer cells by reducing PD-1 expression. These results suggest that components of RVS may serve as potential candidates for restoring exhausted T cells in cancer therapy.

TCR-ESO showed little cross-reactivity, in contrast to TCR 1G4-α95LY. Our data indicate that highly effective TCRs against NY-ESO-1 are likely deleted in humans due to tolerance mechanisms, and that the TCR gene loci transgenic mice represent a reliable source to isolate effective and highly-specific TCRs for adoptive T cell therapies.

P1, N=15, Completed, University Hospital Tuebingen | Recruiting --> Completed | Trial completion date: Aug 2025 --> Jul 2024

P1, N=162, Recruiting, AstraZeneca | Trial primary completion date: Aug 2026 --> Sep 2028