Leveraging genetic variants of T cells to improve cellular immunotherapies and overcome common mechanisms of resistance for patients with cancer

• Applicant: Dr. Clarissa Heck
• Subject Area: Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 554434293

Novel cellular immunotherapies comprising adoptive cell therapies (ACTs) such as tumor infiltrating lymphocyte (TIL) therapies, chimeric antigen receptor (CAR) and T cell receptor (TCR) modified T cell therapies are transforming outcomes for patients with cancer, however many patients still do not benefit. A known resistance mechanism across multiple entities is the cancer cell intrinsic loss of the costimulatory molecule CD58. Previous data suggests that engineering ACTs poses an effective lever to improve response and overcome resistance to existing therapies. The Izar Lab developed a CRISPR/Cas9 base-editor (BE) screen of >30,000 single nucleotide variants (SNVs) in >100 genes in T cells. They identified and validated SNVs enhancing anti-tumor immunity (e.g. PIK3CD) and persistence (e.g. PPP3CA and RAF1) of ACTs in vitro. The objective of this project is to rigorously test the functional impact of these SNVs associated with enhanced hallmarks of anti-tumor T cell immunity in preclinical models of ACTs. Firstly, the aim is to leverage PIK3CD variants to improve anti-tumor activity of the ACTs in vivo. The second aim is to determine potential synergy of genetic variants for immunotherapeutic efficacy. Using non-viral base editing, SNVs will be introduced into TCR-T cells against melanoma, CAR-T cells against leukemia and TILs against patient derived melanoma models and in vivo testing of anti-tumor hallmarks will be performed. The readout will include measurement of tumor growth as well as spectral flow cytometry measurement of intratumoral T cell infiltration, proliferation, activation, phenotype and persistence. We hypothesize that PIK3CD variants modulate T cell signaling, enhancing the activity of T cell-based therapies and compensating the need for co-stimulation and hence, overcoming resistance mediated by CD58 loss across cancers. By combinatorial base editing of PIK3CD and PPP3CA or RAF1 we anticipate to additionally promote long-term efficacy of cell therapies. The long-term objective is to provide a reliable model, leveraging genetic T cell variants to generate improved cellular immunotherapies for cancer patients.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Benjamin Izar