11P Successful transfer and prolonged persistence of engineered lymphocytes with T-cell receptor targeting NY-ESO-1

T-cells engineered to express antigen-specific T-cell receptors (TCR) recognize neoantigens derived from intracellular proteins and act against tumors. NY-ESO-1 is a cancer-testis antigen, exclusively re-expressed in cancer cells. Case-series of metastatic cancer patients treated with TCRs targeting NY-ESO-1 show a response rate of 50%. Third generation TCRs have increased stability and affinity in pre-clinical models. We present the results of the first three patients treated with specificity-enhanced third generation TCRs targeting NY-ESO-1, in an initial dose of a phase I-II trial. We first demonstrated safety, persistence, and efficacy of the novel TCR in murine models. We then treated three patients: A 73-year-old male with choroidal melanoma (CM); A 43-year-old male with synovial sarcoma (SS); A 40-year-old female with triple-negative breast cancer (TNBC). Patients had suffered disease progression after resction of local disease and standard-of-care treatment for metastatic disease. Patients were ECOG 0-1, carriers of HLA-A*02:01 and had positive immunohistochemistry for NY-ESO-1 from tumor tissue. Between June and September 2022 patients underwent lympho-pheresis and T-cells were ex-vivo retrovirally-transduced to express HLA-A*02:01-restricted TCRs targeting NY-ESO-1. Patients underwent lympho-depletion (Cyclophosphamide 250mg/m2 and Fludarabine 25mg/m2 D1-3) and 5 days later received 1*109 engineered TCRs, followed by 3-days of continues IL-2 (18x106IU/24H). No severe adverse events were observed. Grade 1-2 fever and chills were resolved shortly after IL-2 cessation. At one week after administration, flow cytometry showed 5% to 44% of CD3+ positive lymphocytes in patients’ blood were engineered TCRs and remaining detectable at 30 to 160 days. Best response was stable disease lasting 3 months for the MC and SS patients and progressive disease for the TNBC patient. This is an initial dose of a first-in-human investigator-initiated trial, using a specificity-enhanced third generation TCR targeting NY-ESO-1. A durable persistence was shown for the modified lymphocytes associated with short-term stabilization of metastatic disease and with acceptable safety.