Anti-CD137 agonist antibody-independent and clinically feasible preparation of tumor-infiltrating lymphocytes from soft tissue sarcoma and osteosarcoma 2023

Description Background Tumor infiltrating lymphocytes (TILs) therapy has been proved for treatment of melanoma and is under investigation for other types of tumors. However, these successes are threatened by discontinued supply of GMP-grade anti-CD137 agonist, a key TIL preparation reagent. Therefore, exploring a GMP-adherent method for expanding TILs without anti-CD137 is urgent. Toward this end, we aimed to establish an anti-CD137–independent and clinically feasible TIL expansion protocol to prepare TILs from sarcoma tumors. Methods We collected resected tumors from patients and cut tissues into fragments. We used IL-2 and T-cell activator anti-CD3/CD28 without anti-CD137 to expand TILs in 2-3 weeks, then rapidly expanded them over 2 weeks. Their phenotypes were characterized using flow cytometry. Antitumor activity was validated by measuring CD107a on the TILs, the viability of tumor cells and using an autologous patient-derived xenograft (PDX) tumor model. Results We successfully expanded TILs > 90% of collected samples. TILs generated preferentially increased CD8+ T cells but suppressed CD4+ T cells. A small portion of TILs were resident memory T cells. The expanded TILs reduced autologous tumor cells by 38% in 24 hours. Infusion of TILs in mice bearing PDX tumors strongly inhibited sarcoma growth. FDA has approved use of this GMP-feasible protocol (IND 30562). In conclusion, it is feasible to generate antitumor TILs using CD3/CD28 activator to replace the anti-CD137 agonist.