CELL INTELLIGENCE · 肿瘤细胞治疗研究

Nonmyeloablative lymphodepleting chemotherapy (LDC) is a crucial component of tumor-infiltrating lymphocyte (TIL) therapy ensuring T cell engraftment and durable antitumor activity. High-intensity preconditioning with cyclophosphamide (Cy; 60 mg/kg/day for 2 days) and fludarabine (Flu; 25 mg/m 2 /day for 5 days) dosing is typically used. Given the toxicity related to LDC, we investigated the safety and efficacy of reduced-dose LDC followed by standard of care lifileucel and high-dose interleukin-2 (IL-2) in a select cohort of melanoma patients. Patients received reduced-dose LDC if they met one or more of the following inclusion criteria: age 70 years, recently treated brain metastases, bowel metastases, bleeding, or need for continuous antiplatelet or anticoagulation use. LDC was given as Cy 30 mg/kg/day for 2 days and Flu 25 mg/ m 2 /day for 5 days, followed by a lifileucel infusion on day 0 and IL-2 (maximum 6 doses). Safety was evaluated using CTCAE v5, and efficacy was reported using RECIST v1.1. We treated 17 patients, including 9 males (53%) and 8 females (47%) The median patient age was 66 years (range, 36 to 78 years). Five had been treated for brain metastases, 59% had a lactate dehydrogenase level upper limit of normal, and 35% had a BRAFv600 mutation. The median number of IL-2 doses administered was 5 (range, 1 to 6). IL-2 was discontinued owing to patient refusal (n = 1), hypotension requiring vasopressor therapy (n = 1), grade 4 hyponatremia (n = 1), infection (n = 1), atrial fibrillation (n = 1), tachycardia (n = 1), grade 3 transaminitis (n = 2), and a combination of tachycardia and/or weight gain, hypoxia, and rigors (n = 3). All patients achieved grade 4 lymphopenia with a median absolute lymphocyte count nadir of 0.005 k/ L. The most frequent grade 3 treatment-related adverse events were anemia (n = 12; 71%), thrombocytopenia (n = 8; 47%), and febrile neutropenia (n = 10; 59%), with a median absolute neutrophil count recovery of 7 days. No deaths occurred within 30 days of TIL infusion. Among 16 evaluable patients, the best response was partial response in 7 patients (44%), stable disease in 3 (18%), and progressive disease in 6 (38%). The median follow-up was 10 months (95% confidence interval [CI], 8.7 months to not reached [NR]), the median duration of response was NR, the median progression-free survival was 5.1 months (95% CI, 4.3 to NR), and the median overall survival was NR (95% CI, 10 months to NR). Our data indicate that reducing Cy allowed successful completion of TIL therapy in high-risk metastatic melanoma patients without an obvious detrimental effect on response rate. This is the first report demonstrating the safety and feasibility of using real-world objective risk stratification to deliver reduced-dose lymphodepletion prior to lifileucel infusion in high-risk patients with metastatic melanoma. These findings warrant further investigation in a prospective trial of high-risk patients with metastatic melanoma.