Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens

Abstract

Purpose: 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.

Patients and methods: 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.

Results: 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.

Conclusion: 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.

Figures

Fig A1.

Transient depression of hematopoietic cell counts resulting from lymphodepletion is rapidly reversed in patients on all three clinical protocols. Mean absolute counts were calculated based on daily CBCs for all patients who received lymphodepletion and tumor-infiltrating lymphocytes (TIL) therapy as their first lymphodepleting cell therapy. (A) Absolute neutrophil counts, (B) absolute lymphocyte counts, and (C) platelet counts. NMA, nonmyeloablative; TBI, total-body irradiation.

Fig 1.

(A) Schedule of treatments administered for three lymphodepleting cell transfer regimens. (B) Kaplan-Meier plot showing the duration of survival of patients treated on each lymphodepleting cell transfer protocol. Vertical tick marks indicate patients who are still alive and on study. Cy, cyclophosphamide; Flu, fludarabine; TBI, total-body irradiation; CD34+, hematopoietic stem cells; TIL, tumor-infiltrating lymphocytes; IL-, interleukin.

Fig 2.

Adoptive cell therapy after lymphodepletion. (A) Telomere length of infused tumor-infiltrating lymphocytes (TIL) correlates with clinical response. Flow-fluorescent in situ hybridization analysis was used to quantify the mean telomere length of infused TIL for patients on all three protocols. (B) Lymphodepleting conditioning markedly increases the levels of circulating homeostatic cytokines, interleukin (IL)-7 and IL-15. Serum samples were evaluated before therapy (Pre) and immediately before TIL administration (day 0). NMA, nonmyeloablative; TBI, total-body irradiation.