Abstract / Summary
Abstract Effective therapies remain limited for neurofibromatosis type 1 (NF1)- and schwannomatosis (SWN)-related nerve sheath tumors, particularly for malignant peripheral nerve sheath tumors (MPNSTs). Although tumor-infiltrating lymphocyte (TIL) therapy induces durable responses in multiple solid tumors, its feasibility and optimized manufacturing workflows have not been established for these hereditary neoplasms. Herein, we evaluated T cell infiltration in 109 clinical specimens and detected moderate-to-high CD3⁺ T cell infiltration in most neurofibromas (84.0%), schwannomas (98.3%), and MPNSTs (75.0%), supporting the biological prerequisite for TIL intervention in this disease. We established OM-400, a pre-rapid expansion (pre-REP) protocol utilizing CD3/CD28-bead co-stimulation plus low-dose IL-2 (400 IU/mL) for NF1/SWN-related nerve sheath tumor-derived TILs. Compared with the traditional high-dose-IL-2 method, OM-400 achieved 100% expansion success, shortened culture duration, enriched CD8⁺ effector T cells, showed preliminary evidence of better preservation of original TCR repertoires based on analysis of one representative specimen, and enhanced autologous tumor-reactive cytotoxicity and IFN-γ secretion. Exploratory subgroup analysis across 15 independent patient samples covering NF1, SWN, and NF1-related MPNST revealed no statistically significant differences in TIL performance among subtypes. However, the study was not powered to establish equivalence, and larger cohorts are needed to definitively assess the impact of tumor subtype. Using autologous MPNST patient-derived xenograft models, we confirmed that OM-400-expanded TILs infiltrated tumor tissue and significantly suppressed in vivo tumor growth. In summary, this work provides first preclinical proof of concept for TIL-based immunotherapy against NF1/SWN-related nerve sheath tumors and establishes a reproducible manufacturing platform to facilitate future clinical translation.