Regulatable membrane-bound IL15 (mbIL15) engineered tumor infiltrating lymphocytes (OBX-115 TIL) generated from minimally invasive non-small cell lung (NSCLC) tissues show putative tumor reactive TIL enriched, stem-like phenotype and could potentially overcome MHC-loss driven immune evasion

Tumor infiltrating lymphocyte (TIL) therapy has generated promising results in melanoma and non-small cell lung cancer (NSCLC). However, several technical hurdles as well as resistance mechanisms still limit the application and efficacy of TIL therapy in NSCLC. First, the requirement of surgical tissue reduced the number of patients eligible for TIL therapy. Second, limited amount of putative tumor reactive (TR) cells infused, and the reduced persistence and exhaustion of this population has been linked with resistance to TIL therapy. Finally, another prominent resistance mechanism in this disease is the loss of antigen expression which could be driven by HLA allele loss and B2M loss. Here, we report the feasibility of manufacturing regulatable membrane bound IL-15 (mbIL15) engineered TIL (OBX-115 TIL) from minimally invasive core needle biopsies (CNB) from NSCLC. Using simulated core needle biopsies (sCNB), we were able to generate a TIL product similar to that generated from excisional tumors, with a CD39-CD69- “stem-like”, low PD-1 phenotype, distinct from TIL generated using a conventional, IL-2 based non-engineered TIL expansion process. Additionally, we demonstrated that OBX-115 TIL expanded by addition of a 41BB agonist in pre-Rapid Expansion Protocol (pre-REP) and mbIL21-41BBL engineered feeder cells in REP showed putative TR-TIL enrichment when compared to TIL generated using conventional process. Furthermore, we also demonstrated that OBX-115 TIL show MHC independent cytotoxicity through both direct killing via LTBR/NKG2D pathway and transactivation of autologous natural killer (NK) cells that is independent of exogenous IL-2. To conclude, our data suggests that OBX-115 cells could be manufactured robustly from CNB tissues which have the potential to overcome several key hurdles of TIL therapy in NSCLC.