Identifying Tumor-Reactive CD8 TIL in Patients with Solid Malignancies: Clinical Implications

Recently, there have been major advances in defining tumor-reactive T cells within human maligancies. Our group has published that the tumor-reactive CD8 T cells are highly enriched in the CD39/CD103 double positive (DP) fraction of cells. These cells are found in most solid malignancies that we have explored thus far, including melanoma, lung cancer, renal cancer, breast cancer, head and neck cancer, colon cancer, ovarian cancer, and pancreatic cancer. Interestingly, some cancers show a much higher frequency of these CD39/103 DP CD8 TIL (e.g., melanoma and lung cancer 30-80%), while other tumor types have a much lower frequency of these cells (e.g., pancreatic and colorectal liver metastases 2-15%). The CD39/103 DP CD8 TIL have a resident memory phenotype, and are highly enriched within tumor site when compared to peripheral blood. These cells are enriched for cells reactive to tumor-mutated Ags and viral-associated tumor Ags (HPV cancers). They express high levels of exhaustion markers: PD-1, CTLA-4, TIM-3, Lag-3; but also are enriched for activation and proliferation markers (e.g., 4-1BB, Granzyme B, and Ki-67). More recently, we have found a way to grow these cells in culture with the ultimate goal of delivering a TIL population that is highly enriched for tumor reactivity. To this end, we have found that we can sort and culture as few as 2000-10,000 DP CD8 TIL and grow them to billions in a 5-week span. We plan to perform a Phase I clinical trial with the expanded DP CD8 TIL population within the coming year