Interleukin-2 based therapy

BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)

High-dose bolus interleukin 2 (HD IL-2) received FDA approval in 1998 for the treatment of patients with metastatic melanoma largely based on its ability to produce durable complete responses in 5–10% of patients. In a retrospective review of 270 patients treated on multiple Phase II studies, the objective response rate was 16%, with a median duration of 9 months (range 4 to 106 + months). Despite the low objective response rate, 59% of complete responders remained progression-free at 7 years and no patient responding for longer than 30 months had progressed, suggesting that some patients are “cured” [90]. Treatment, however, was associated with significant toxicity limiting its application to a select group of patients treated in specialized centers.

Efforts to improve upon the activity of IL-2 in patients with melanoma have included combinations with chemotherapy (biochemotherapy), vaccines and adoptive T cell therapy. Although several phase II trials, a small phase III trial and two meta-analyses suggested that combinations of IL-2 and cisplatin-based biochemotherapy offered benefit relative to either chemotherapy or IL-2 alone, several multiinstitutional phase III trials have failed to confirm this benefit [91, 92].

Another approach to improving the activity of HD IL-2 involved the addition of a gp100 peptide vaccine. A phase III trial randomly assigned 185 patients with metastatic melanoma to HD IL-2 given alone every 3 weeks or in combination with a gp100 peptide vaccine [93]. Because of the restriction properties of the vaccine, enrollment was limited to patients who were shown to be HLA type A201. The study reported an objective response rate of 16% for the combination compared with 6% for HD IL-2 alone. There were eight complete responses (9%) in the combination arm, but only one (1%) among those treated with IL-2 alone. There was a trend toward increased overall survival (median 17.8 versus 11.1 months, p = 0.06), although the trial was not adequately powered to assess this endpoint. The clinical significance of this finding is uncertain considering the relatively poor response rate in patients treated with HD IL-2 alone, the current lack of availability of the specific formulation of vaccine adjuvant used in this trial and the observations that this same vaccine did not improve the efficacy of ipilimumab in a phase III trial [94] (see below).

Others have explored the efficacy of HD IL-2 in combination with adoptive transfer of tumor derived tumor reactive T cells. These approaches have included preparative regimens involving myeloablative chemotherapy with or without total body irradiation (TBI) in order to delete host immune cells and promote engraftment of adoptively transferred tumor-reactive T cells [95]. Autologous hematopoietic progenitor cell support was used in patients who received TBI. The NCI Surgery Branch recently reported the combined results from 3 separate trials. There were 52 objective responses in 93 patients (56% response rate), including 20 (22%) complete responses. Complete responses were ongoing at 37–82 months in 19 of the 20 responders, and the threeand 5-year actuarial survival rates for patients achieving a complete response were 100 and 93%, respectively. Efforts to confirm these results at other centers as well as to develop a more practical treatment regimen are currently underway.

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