CELL INTELLIGENCE · 肿瘤细胞治疗研究

BACKGROUND: Tumor-infiltrating lymphocyte (TIL) therapy entails isolating, activating, expanding, and reinfusing isolated lymphocytes from tumors, presumably representing a collection of high-affinity T cells that can recognize the melanoma tumor-specific peptides expressed on endogenous human leukocyte antigens. The US Food and Drug Administration (FDA) recently approved commercial TIL (lifileucel [Amtagvi]) for treatment of BRAF wild-type/resistant, checkpoint inhibitor failure, unresectable or metastatic melanoma based on a registrational trial showing an overall response rate of 31.5% in treated patients. Following FDA approval, patient outcomes beyond the originally selected clinical trial populations remain unknown. OBJECTIVE: We report initial real-world, single-institutional observations and outcomes for patients with melanoma referred for TIL therapy. METHODS: A retrospective analysis of the cell therapy database of outcomes in 45 patients with unresectable or metastatic melanoma referred for TIL therapy considerations is reported. RESULTS: The median age of the patients was 68 years (range, 27-83); 37 (82.2%) had stage IV and 38 (84.4%) had BRAF wild-type disease, and 15 (33.3%) had central nervous system disease. Twenty-three patients were male (51.1%); 28 (62.2%) patients completed surgical tumor harvest, 23 (51.1%) patients completed TIL infusion, and 1 patient was just starting lymphodepleting (LD) chemotherapy at the time of data analysis. Three patients died from disease progression, and 1 went on comfort care prior to starting LD chemotherapy. Eight (28.5%) TIL products were out of specification. Seventeen referred patients did not proceed to tumor resection: 8 (47.1%) were deemed ineligible owing to small tumor size (<1.5 cm), comorbidities, or nonresectable site/brain metastases; 3 had no definitive evidence of disease; 2 died due to rapid disease progression; and 3 deferred due to autoimmune colitis from prior checkpoint inhibitors and patient choice (n = 1). The median overall survival (mOS) for all patients who successfully pursued TIL therapy was not reached, with a 1-year OS of 79.2% (95% CI, 60.2%-100%) compared with patients who did not pursue TIL therapy, with a mOS of 10.15 months and a 1-year OS of 42% (95% CI, 23.4%-75.4%; P = 0.007; Figure 2). Workflow modifications were implemented as part of a quality improvement initiative after 6 months. Upon receipt of a TIL referral, consultation with the cellular therapy (CT) team was initiated, followed by an urgent referral to the surgical oncology team. A CT nurse served as the central point of contact, coordinating all subsequent encounters, including operating room scheduling, tumor collection, CT laboratory processing, and industry partner manufacturing slot allocation. Table 2 demonstrates a reduction in the average time interval between referral and CT consult (17.6 vs 10.7 days with the new workflow) and a time interval between initial referral and receiving actual TIL infusion (128 days vs 96.3 days). CONCLUSIONS: Our institutional real-world data show that only about half of TIL therapy referrals proceed with the actual TIL infusions. While TIL therapy seeks to achieve the approximately 32% response rate observed in the registrational trial, real-world outcomes in an intent-to-treat population are anticipated to be inferior. Advanced melanoma affords a narrow time window from referral to completion of TIL manufacturing and infusion, necessitating efficient workflows to enable early treatment and optimize patient outcomes.