Periodic Reporting for period 1 - TTT-therapy (Targeting Acute Leukemia with TdT-TCR-T-cell therapy)
Periodo di rendicontazione: 2023-10-01 al 2025-03-31
Acute lymphoblastic leukaemia (ALL) is a devastating blood cancer that primarily affects children and adults, often leading to relapse despite intensive treatments. Current therapies can be highly toxic and are not always effective, leaving patients with few options and a poor prognosis. There is an urgent need for safer and more targeted treatments that can eliminate cancer cells without harming healthy tissues. A novel approach using T-cell receptors (TCRs) targeting the nuclear enzyme TdT (published by Ali et al in Nature Biotechnology 2022) offers new hope in this fight, called TdT TCR T-cell therapy – TTT-therapy. This therapy was developed in context of the ERC Consolidator Grant OUTSOURCE. The Main Objectives of the ERC-funded TTT-therapy project have been to 1) perform research to clarify the possibilities to expand the treatment indication for the novel T cell receptor-based (TCR) T cell therapy (TTT-therapy) developed in context of the ERC consolidator project, OUTSOURCE, and 2) to develop a commercialization strategy for this therapy. In OUTSOURCE, the preclinical validation of the TdT TCR was completed, demonstrating safety and efficacy in vitro and in vivo.
In Main Objective 1, we conducted research that has clarified that also a subgroup of patients with acute myeloid leukemia (AML) express TdT, providing a rationale for including also this patient group in a clinical trial. By screening biobanked cryopreserved samples from 239 AML patients with an extensive immunophenotyping panel, we showed that 22% expressed high levels of TdT. We demonstrated that TdT+ AML blasts were efficiently killed by TdT TCR T cells in vitro. AML patients have an overall 5-year survival of only 30% and hence a great medical need that potentially could be met by TTT-therapy.
In Main Objective 2, the Project Leader worked together with her strong team of advisers with expertise in business development, clinical development, IPR and financial aspects needed for commercialization. In-depth interviews with Key Opinion Leaders in acute myeloid leukemia treatment and drug development was performed, resulting in development of a Target Product Profile and drafted clinical strategy. Moreover, an IPR and business strategy was developed, and the PCT phase of the approved TdT TCR patent and platform technology patent was secured. A clinical trial application (CTA) for TTT-therapy was submitted to EMA in March 2025 for a phase I/IIa clinical in r/r ALL, and this trial can be amended if future experimental in vivo data provide additional support for therapeutic efficacy in AML. A process for manufacturing of cells (part of the CTA) has been developed and technology transfer successfully performed to an academic GMP facility that will manufacture the gene-modified T cells for the trial. Validation runs were completed.
In Main Objective 2, the Project Leader worked together with her strong team of advisers with expertise in business development, clinical development, IPR and financial aspects needed for commercialization. In-depth interviews with Key Opinion Leaders in acute myeloid leukemia treatment and drug development was performed, resulting in development of a Target Product Profile and drafted clinical strategy. Moreover, an IPR and business strategy was developed, and the PCT phase of the approved TdT TCR patent and platform technology patent was secured. A clinical trial application (CTA) for TTT-therapy was submitted to EMA in March 2025 for a phase I/IIa clinical in r/r ALL, and this trial can be amended if future experimental in vivo data provide additional support for therapeutic efficacy in AML. A process for manufacturing of cells (part of the CTA) has been developed and technology transfer successfully performed to an academic GMP facility that will manufacture the gene-modified T cells for the trial. Validation runs were completed.
Taken together, we have successfully completed all main deliverables described in the project. The described work has the potential to contribute to saving lives that would otherwise be lost to acute leukemia.
Overview of results:
• Demonstrated expression of TdT in a subgroup of AML patients of 22% and showed that TdT+ AML cells are efficiently killed by TdT TCR T cells.
• Performed in-depth interviews with Key Opinion Leaders in acute myeloid leukemia treatment and drug development, resulting in development of a Target Product Profile
• Developed IPR and business strategy
• Secured PCT phase of the TdT TCR patent and platform technology patent
• Developed manufacturing process for TdT TCR T cells
• Did successful technology transfer to manufacturing site
• Validation runs successfully completed
• Submitted Clinical Trial Application for TTT-therapy for phase I/Iia clinical trial in r/r ALL to EMA
Key needs to ensure future success: We next aim to investigate in vivo efficacy in patient-derived xenograft models of AML. If successfully demonstrated, our subsequent goal is to identify additional funding to amend the phase I/IIa clinical trial of TTT-therapy in r/r ALL to include adult patients with TdT+ AML. In parallel, we aim to further develop the commercialization strategy.
Overview of results:
• Demonstrated expression of TdT in a subgroup of AML patients of 22% and showed that TdT+ AML cells are efficiently killed by TdT TCR T cells.
• Performed in-depth interviews with Key Opinion Leaders in acute myeloid leukemia treatment and drug development, resulting in development of a Target Product Profile
• Developed IPR and business strategy
• Secured PCT phase of the TdT TCR patent and platform technology patent
• Developed manufacturing process for TdT TCR T cells
• Did successful technology transfer to manufacturing site
• Validation runs successfully completed
• Submitted Clinical Trial Application for TTT-therapy for phase I/Iia clinical trial in r/r ALL to EMA
Key needs to ensure future success: We next aim to investigate in vivo efficacy in patient-derived xenograft models of AML. If successfully demonstrated, our subsequent goal is to identify additional funding to amend the phase I/IIa clinical trial of TTT-therapy in r/r ALL to include adult patients with TdT+ AML. In parallel, we aim to further develop the commercialization strategy.