Abstract
Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) for metastatic melanoma can be highly effective, but attrition due to progression before TIL administration (32% in prior institutional experience) remains a limitation. We hypothesized that combining ACT with cytotoxic T lymphocyte-associated antigen 4 blockade would decrease attrition and allow more patients to receive TIL. Thirteen patients with metastatic melanoma were enrolled. Patients received four doses of ipilimumab (3 mg/kg) beginning 2 weeks prior to tumor resection for TIL generation, then 1 week after resection, and 2 and 5 weeks after preconditioning chemotherapy and TIL infusion followed by interleukin-2. The primary endpoint was safety and feasibility. Secondary endpoints included of clinical response at 12 weeks and at 1 year after TIL transfer, progression free survival (PFS), and overall survival (OS). All patients received at least two doses of ipilimumab, and 12 of the 13 (92%) received TIL. A median of 6.5 × 1010 (2.3 × 1010 to 1.0 × 1011) TIL were infused. At 12 weeks following infusion, there were five patients who experienced objective response (38.5%), four of whom continued in objective response at 1 year and one of which became a complete response at 52 months. Median progression-free survival was 7.3 months (95% CI 6.1-29.9 months). Grade ≥ 3 immune-related adverse events included hypothyroidism (3), hepatitis (2), uveitis (1), and colitis (1). Ipilimumab plus ACT for metastatic melanoma is feasible, well tolerated, and associated with a low rate of attrition due to progression during cell expansion. This combination approach serves as a model for future efforts to improve the efficacy of ACT.
Highlights
The treatment of metastatic melanoma has evolved greatly over the past decade
We describe the results of a trial designed to assess the safety and feasibility of the addition ipilimumab to adoptive cell therapy (ACT) for metastatic melanoma
The treatment schema (Figure 1) began with the first dose of ipilimumab (3 mg/kg) administered 2 weeks prior to harvest of tumor at least 1 cm3 to serve as the source of tumor-infiltrating lymphocytes (TIL)
Summary
The treatment of metastatic melanoma has evolved greatly over the past decade. The standard treatment in these patients includes agents that enhance the immune response to melanoma. The objective response rate for this adoptive cell therapy (ACT) at the National Cancer Institute (NCI) was 55% for those that received TIL, with up to 22% demonstrating a complete response [4]. Investigators at MD Anderson Cancer Center and Sheba Medical Center (Tel Aviv, Israel) reported objective response rates of 48% and 40%, respectively, for melanoma patients who received TIL [6, 7]. The only other center reporting data by intention to treat (Sheba Medical Center) reported a similar 29% response rate. At both centers, dropout due to progression during the time required for TIL production (generally 6 weeks) resulted in a significant percentage of patients—nearly one-third—not receiving the full treatment
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