Adoptive Cell Therapy for Patients With Metastatic Melanoma: Evaluation of Intensive Myeloablative Chemoradiation Preparative Regimens

TLDR

Metastatic melanoma treatment with IL‑2 or dacarbazine yields objective response rates of 12–15%. The study updates previous work to evaluate the safety and efficacy of two intensified myeloablative lymphodepleting regimens. Two sequential ACT trials with autologous tumor‑infiltrating lymphocytes were conducted, using cyclophosphamide and fludarabine plus either 2 Gy or 12 Gy total‑body irradiation for lymphodepletion before cell transfer, and responses were assessed by RECIST. The intensified regimens achieved objective response rates of 52 % with 2 Gy TBI and 72 % with 12 Gy TBI, with responses in all visceral sites including brain, one treatment‑related death, and correlations between response and IL‑7/IL‑15 levels and telomere length, yielding overall 50–70 % response rates in refractory metastatic melanoma.

Abstract

The two approved treatments for patients with metastatic melanoma, interleukin (IL)-2 and dacarbazine, mediate objective response rates of 12% to 15%. We previously reported that adoptive cell therapy (ACT) with autologous antitumor lymphocytes in lymphodepleted hosts mediated objective responses in 51% of 35 patients. Here, we update that study and evaluate the safety and efficacy of two increased-intensity myeloablative lymphodepleting regimens.We performed two additional sequential trials of ACT with autologous tumor-infiltrating lymphocytes (TIL) in patients with metastatic melanoma. Increasing intensity of host preparative lymphodepletion consisting of cyclophosphamide and fludarabine with either 2 (25 patients) or 12 Gy (25 patients) of total-body irradiation (TBI) was administered before cell transfer. Objective response rates by Response Evaluation Criteria in Solid Tumors (RECIST) and survival were evaluated. Immunologic correlates of effective treatment were studied.Although nonmyeloablative chemotherapy alone showed an objective response rate of 49%, when 2 or 12 Gy of TBI was added, the response rates were 52% and 72% respectively. Responses were seen in all visceral sites including brain. There was one treatment-related death in the 93 patients. Host lymphodepletion was associated with increased serum levels of the lymphocyte homeostatic cytokines IL-7 and IL-15. Objective responses were correlated with the telomere length of the transferred cells.Host lymphodepletion followed by autologous TIL transfer and IL-2 results in objective response rates of 50% to 70% in patients with metastatic melanoma refractory to standard therapies.