Dr Leidner on the Investigation of TCR-Engineered T-Cell Immunotherapy in Solid Tumors

Rom S. Leidner, MD, medical oncologist, Providence Cancer Institute Franz Clinic; member, Earle A. Chiles Research Institute, Providence Health, discusses the rationale for assessing neoantigen-targeted, T-cell receptor (TCR)–engineered T-cell immunotherapy in select patients with solid tumors, as presented at the Frontiers in Cancer Immunotherapy 2024 Symposium.

In 2016, 2 key TCRs were identified from a patient with colon adenocarcinoma and lung metastases who had received standard tumor-infiltrating lymphocyte therapy and remained alive, demonstrating a significant clinical response. This patient had TCRs specific to the KRAS G12D driver mutation. One TCR targeted a 9-mer peptide overlapping with G12D, and the other targeted a 10-mer peptide. Notably, the 9-mer peptide was CD8 co-receptor–independent, allowing it to be transduced into both CD4-positive and CD8-positive T cells for potential use in other patients. Conversely, the 10-mer peptide was CD8 co-receptor–dependent, necessitating sorting for CD8-positive T cells only.

This clinical success served as proof of concept that targeting a driver mutation in cancer could eradicate the tumor. Building on this success, researchers then explored whether the KRAS G12D mutation, which is common across various cancers and crucial for cancer cell growth and persistence, could be targeted in other tumors. This approach involved retrovirally transducing the identified TCR into T cells from other cancer patients. However, a key caveat for this process was that patients were required to share the HLA-C*08:02 type, which restricts the targeted KRAS G12D mutation.

At the Frontiers in Cancer Immunotherapy 2024 Symposium, Leidner presented 2 case studies from patients with pancreatic cancer who were treated with these TCRs. Both patients had TCRs retrovirally transduced into their own T cells that were obtained through leukapheresis. Out of the 2 patients, 1 responded to the treatment. The presentation focused on comparing and contrasting the characteristics and responses of these 2 patients, offering insights into the factors influencing the effectiveness of TCR therapy targeting KRAS G12D mutations in this tumor type.