Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell therapy using a genetically modified T-cell receptor (TCR) to improve recognition of cancer cells expressing NY-ESO-1/LAGE-1a. Next generation NY-ESO-1 TCR T-cell therapies, such as GSK3901961 and GSK3845097, integrate added genetic modifications to enhance anticancer activity. GSK3901961 co-expresses the CD8α chain to stabilize TCR-human leukocyte A (HLA) class I interactions on CD4+ T cells, improving T-cell persistence and helper functions such as Type 1 T-helper antitumor responses. GSK3845097 co-expresses a dominant negative transforming growth factor-β (TGF-β) type II receptor to reduce TGF-β pathway activation and maintain T-cell proliferation, cytokine production, and cytotoxicity in the tumor microenvironment. A first-time-in-human master protocol (NCT04526509) will evaluate safety, tolerability, and recommended phase 2 dose (RP2D) of these and possible subsequent therapies. Substudy 1 will assess GSK3901961 in patients (pts) with advanced non-small cell lung cancer (NSCLC) or synovial sarcoma (SS). Substudy 2 will assess GSK3845097 in pts with advanced SS. Methods: Each substudy includes a dose confirmation stage to assess RP2D and a dose expansion stage. Key inclusion criteria are age ≥18 y; measurable disease per RECIST v1.1; HLA-A*02:01, A*02:05, or A*02:06 positivity; NY-ESO-1/LAGE-1a tumor expression; advanced (metastatic/unresectable) SS with t(X;18) translocation and anthracycline-based therapy receipt/completion/intolerance (SS only); and Stage IV NSCLC, receipt of ≥1 prior line(s) of standard of care (SOC) therapy including programmed death receptor- or ligand-1 inhibitors, and SOC chemotherapy receipt/intolerance (Substudy 1 only). Key exclusion criteria are prior malignancy that is not in complete remission or clinically significant systemic illness; prior receipt of gene/NY-ESO-1–specific therapy or allogenic stem cell/solid organ transplant; central nervous system metastases (SS only); and actionable genetic aberration and receipt/failure of ≥3 systemic therapy lines (Substudy 1 only). Primary endpoints are safety (adverse events) and tolerability (dose-limiting toxicities). Secondary endpoints include investigator-assessed overall response rate, duration of response, and maximum expansion/persistence and phenotype of infiltrating transduced T cells. Exploratory endpoints include laboratory parameters, overall survival, and anti-GSK3901961 or -GSK3845097 titers as applicable. Analyses will be descriptive. The substudies are enrolling. Funding: GSK (209012; NCT04526509). Editorial support was provided by Eithne Maguire, PhD, of Fishawack Indicia, part of Fishawack Health; funded by GSK. Previously presented at AACR 2021 (CT219). Clinical trial information: NCT04526509