Adoptive cell therapy for the treatment of patients with metastatic melanoma

Abstract

Adoptive cell therapy (ACT) is the best available treatment for patients with metastatic melanoma. In a recent series of three consecutive clinical trials using increasing lymphodepletion before infusion of autologous tumor infiltrating lymphocytes (TIL), objective response rates between 49% and 72% were seen. Persistence of infused cells in the circulation at one month was highly correlated with anti-tumor response as was the mean telomere length of the cells infused and the number of CD8+ CD27+ cells infused. Responses occur at all sites and appear to be durable with many patients in ongoing response beyond three years. In the most recent trial of 25 patients receiving maximum lymphodepletion, seven of the 25 patients (28%) achieved a complete response. Of the 12 patients in the three trials who achieved a complete response all but one are ongoing between 18 and 75 months. We recently demonstrated that ACT using autologous lymphocytes genetically modified to express anti-tumor T cell receptors can mediate tumor regression and this approach is now being applied to patients with common epithelial cancers.

Figure 1

Schema of the lymphodepleting preparative regimens used in the adoptive cell transfer protocols in the Surgery Branch, NCI.

Figure 2

Objective clinical regressions in patients with metastatic melanoma treated with cell transfer therapy. A. Regression of melanoma metastases in the heart (upper), adrenal (middle) and peritoneal cavity (lower) now ongoing at 34 months in a 53 year old male. B. Regression of multiple liver metastases now ongoing at 60 months in a 45 year old male. C. Rapid regression of multiple subcutaneous and nodal metastases now ongoing at 35 months in a 29 year old male. D. Regression of a large fungating scalp mass now ongoing at 34 months in a 40 year old male.

Figure 2

Objective clinical regressions in patients with metastatic melanoma treated with cell transfer therapy. A. Regression of melanoma metastases in the heart (upper), adrenal (middle) and peritoneal cavity (lower) now ongoing at 34 months in a 53 year old male. B. Regression of multiple liver metastases now ongoing at 60 months in a 45 year old male. C. Rapid regression of multiple subcutaneous and nodal metastases now ongoing at 35 months in a 29 year old male. D. Regression of a large fungating scalp mass now ongoing at 34 months in a 40 year old male.

Figure 2

Objective clinical regressions in patients with metastatic melanoma treated with cell transfer therapy. A. Regression of melanoma metastases in the heart (upper), adrenal (middle) and peritoneal cavity (lower) now ongoing at 34 months in a 53 year old male. B. Regression of multiple liver metastases now ongoing at 60 months in a 45 year old male. C. Rapid regression of multiple subcutaneous and nodal metastases now ongoing at 35 months in a 29 year old male. D. Regression of a large fungating scalp mass now ongoing at 34 months in a 40 year old male.

Figure 2

Objective clinical regressions in patients with metastatic melanoma treated with cell transfer therapy. A. Regression of melanoma metastases in the heart (upper), adrenal (middle) and peritoneal cavity (lower) now ongoing at 34 months in a 53 year old male. B. Regression of multiple liver metastases now ongoing at 60 months in a 45 year old male. C. Rapid regression of multiple subcutaneous and nodal metastases now ongoing at 35 months in a 29 year old male. D. Regression of a large fungating scalp mass now ongoing at 34 months in a 40 year old male.

Figure 3

Survival of patients treated with cell transfer therapy in four consecutive clinical trials using increasing regimens of a lymphodepleting preparative regimen prior to adoptive cell transfer (NMA, non-myeloablative chemotherapy; TBI, total body irradiation). The number in parentheses is the number of patients in each trial.

Figure 4

Objective response rates using RECIST criteria in patients with metastatic melanoma treated in the Surgery Branch, NCI using different therapeutic strategies. Overall response rates in patients treated with vaccines is about 3% and with IL-2 or anti-CTLA4 is about 15%. With increasing levels of lymphodepletion, adding total body irradiation (TBI) and nonmyeloablative chemotherapy (NMA) to adoptive cell transfer (ACT) can achieve response rates as high as 72%.

Figure 5

Schematic diagrams of the structure of retroviruses encoding conventional T cell receptors and chimeric T cell receptors prepared for use in adoptive cell transfer trials.