GEN-011: Advancing Neoantigen-Specific T Cell Therapy with ATLAS^TM Guidance Beyond TIL Strategies

In recent years, the FDA has granted approval to engineered autologous T cell therapies, which have shown significant effectiveness against blood cancers. The non-engineered TIL therapies have also demonstrated remarkable benefits in early clinical trials for solid tumors. However, TIL therapies have some drawbacks, such as the requirement for specialized surgery to acquire tumor tissue for T cell isolation, limited neoantigen diversity, and the risk of T cells being pro-tumor, exhausted, or non-specific to the tumor. These factors can limit the effectiveness and availability for some patients.

A new autologous, peripheral blood-derived non-engineered T cell therapy, GEN-011, has been developed to leverage the advantages of TIL while mitigating its limitations. It targets genuine tumor-specific neoantigens identified by the ATLAS bioassay and circumvents potentially pro-tumor Inhibigens. The process involves collecting peripheral blood mononuclear cells and a tumor biopsy from each participant, followed by whole exome sequencing (WES) of the tumor DNA. The ATLAS bioassay is then used to screen individual tumor mutations against the patient's T cells to pinpoint neoantigen targets that are responsive to pre-existing CD4+ and/or CD8+ T cells.

The manufacturing process, PLANET, expands the patient's peripheral blood T cells on stimulatory neoantigens identified by ATLAS. The outcome is GEN-011 drug products that contain billions of antigen-specific, cytolytic T cells. The development and engineering runs using peripheral blood T cells from both cancer patients and healthy donors have resulted in products with over 97% T cells, the majority of which are central and effector memory phenotypes. There is a median 534-fold increase in antigen-specific T cells in GEN-011 products compared to their initial frequency in peripheral blood, with up to 67% of cells activating upon antigen recognition. Additionally, the T cells in the products can secrete up to 50,000 pg/mL of IFN-gamma when stimulated by antigens.

In cancer patient samples, GEN-011 products respond to up to 89% of the intended neoantigen targets. GEN-011 offers several key advantages over TIL therapy. It covers an unparalleled breadth of neoantigens, targeting up to 30 relevant neoantigens with non-exhausted CD4+ and CD8+ memory T cells to counteract non-tumor specific 'passenger' T cells. It also avoids pro-tumor Inhibigens that could be harmful to clinical outcomes. Furthermore, GEN-011 does not necessitate additional surgery or viable tumor for production.

In summary, GEN-011 is a groundbreaking T cell therapy candidate that promises to enhance accessibility and efficacy for patients with solid tumors. All individuals who provided samples for this study gave their informed consent.