Safety and Efficacy of Tumor-Infiltrating Lymphocyte Therapy with Reduced-Dose Lymphodepleting Conditioning in High-Risk Metastatic Melanoma Patients

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Background Non-myeloablative lymphodepleting chemotherapy (LDC) is a crucial component of TIL therapy ensuring T cell engraftment and durable anti-tumor activity. High intensity preconditioning with cyclophosphamide (Cy 60 mg/kg daily for 2 days) and fludarabine (Flu 25 mg/m 2 daily for 5 days) dosing is typically used. Given 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. Methods Patients received reduced-dose LDC if they met ≥1 inclusion criteria: age ≥70 years, recently treated brain metastases (BM), bowel metastases, bleeding, need for continuous antiplatelet or anticoagulation use. LDC was given as Cy 30 mg/kg daily for 2 days, Flu 25 mg/ m 2 daily for 5 days followed by lifileucel infusion on Day 0 and IL-2 (max: 6 doses). Safety was evaluated using CTCAE v5 and efficacy was reported using RECIST v1.1. Results We treated 17 pts, 9 (53%) males, 8 females (47%) median age: 66 years (range: 36-78). Five had been treated for BM, 59% had LDH ≥ upper limit of normal (ULN), and 35% were BRAFv600 mutant. The median number of IL-2 doses administered was 5 (range: 1-6). IL-2 was discontinued due to hypotension requiring vasopressor (n=1), grade 4 hyponatremia (n=1), infection (n=1), atrial fibrillation (n=1), tachycardia (n=1), grade 3 transaminitis (n=2), combination of tachycardia and/or weight gain, hypoxia, rigors (n=3), and patient refusal (n=1). All patients achieved the grade 4 lymphopenia with a median nadir of absolute lymphocyte count of 0.005 k/µL. Most common 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 death occurred within 30 days of TIL infusion. Long term adverse events of grade 3 uveitis (n=1) and grade 3 hearing loss (n=1) developed >30 days after lifileucel. Among 16 evaluable patients, the best response was partial response in 7 patients (44%), stable disease in 3 patients (18%), and progressive disease in 6 patients (38%). Median follow-up was 10 months (95% CI: 8.7 – not reached [NR]), median duration of response was NR, median progression free survival was 5.1 months (95% CI: 4.3 – NR), and median overall survival was NR (95% CI: 10 - NR). Conclusions Reducing Cy allowed successful completion of TIL therapy among 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.

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