CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma.

PURPOSE: Treatment with ipilimumab can cause objective tumor responses in patients with metastatic melanoma. We have treated 177 evaluable patients in three clinical trials and have long-term follow-up to evaluate the durability of responses. EXPERIMENTAL DESIGN: Patients with metastatic melanoma were treated in three trials from 2002 to 2005. In protocol 1, 56 patients received ipilimumab with gp100 peptides. In protocol 2, 36 patients received ipilimumab with interleukin-2. In protocol 3, 85 patients received ipilimumab with intrapatient dose-escalation and were randomized to receive gp100 peptides. We have analyzed their long-term follow-up and survival data. RESULTS: With median follow-up for protocols 1, 2, and 3 being 92, 84, and 71 months, median survival was 14, 16, and 13 months with 5-year survival rates being 13%, 25%, and 23%, respectively. Patients in protocol 2 had a 17% complete response (CR) rate, compared with 7% in protocol 1 and 6% in protocol 3. These CR rates are higher than previously reported for the same trials because some patients who eventually became complete responders had continual tumor regression months to years after therapy. All but one of the 15 complete responders are ongoing at 54+ to 99+ months. CONCLUSIONS: This report provides the longest follow-up of patients with melanoma treated with ipilimumab and shows that ipilimumab can induce durable, potentially curative tumor regression in a small percentage of patients with metastatic melanoma. The combination of ipilimumab and interleukin-2 seems to have an increased CR rate, but this needs to be tested in a randomized trial.

Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1.

PURPOSE: Adoptive immunotherapy using tumor-infiltrating lymphocytes represents an effective cancer treatment for patients with metastatic melanoma. The NY-ESO-1 cancer/testis antigen, which is expressed in 80% of patients with synovial cell sarcoma and approximately 25% of patients with melanoma and common epithelial tumors, represents an attractive target for immune-based therapies. The current trial was carried out to evaluate the ability of adoptively transferred autologous T cells transduced with a T-cell receptor (TCR) directed against NY-ESO-1 to mediate tumor regression in patients with metastatic melanoma and synovial cell sarcoma. PATIENTS AND METHODS: A clinical trial was performed in patients with metastatic melanoma or metastatic synovial cell sarcoma refractory to all standard treatments. Patients with NY-ESO-1-positive tumors were treated with autologous TCR-transduced T cells plus 720,000 iU/kg of interleukin-2 to tolerance after preparative chemotherapy. Objective clinical responses were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Objective clinical responses were observed in four of six patients with synovial cell sarcoma and five of 11 patients with melanoma bearing tumors expressing NY-ESO-1. Two of 11 patients with melanoma demonstrated complete regressions that persisted after 1 year. A partial response lasting 18 months was observed in one patient with synovial cell sarcoma. CONCLUSION: These observations indicate that TCR-based gene therapies directed against NY-ESO-1 represent a new and effective therapeutic approach for patients with melanoma and synovial cell sarcoma. To our knowledge, this represents the first demonstration of the successful treatment of a nonmelanoma tumor using TCR-transduced T cells.

Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vaccines.

PURPOSE: To identify prognostic factors associated with survival beyond 4 years and overall response in patients with metastatic melanoma treated with high-dose bolus i.v. interleukin-2 (IL-2) given either alone or in combination with a variety of melanoma vaccines. STUDY DESIGN: 684 consecutive patients with metastatic melanoma received high-dose bolus i.v. IL-2 either alone or in conjunction with a variety of melanoma vaccines. Treatments occurred between August 1, 1985 and January 1, 2006. RESULTS: The overall objective response rate was 13% for patients receiving IL-2 alone and 16% for patients who received IL-2 with vaccine. In patients treated with IL-2 alone (n=305) and IL-2 with vaccine (n=379), having an objective response was associated with survival beyond 4 years (P<0.0001). No pretreatment factors could be identified that were strongly associated with increased rate of objective response or long-term survival in patients receiving IL-2 alone. In patients receiving IL-2 with vaccines, there were increased response rates in patients with s.c. or cutaneous disease only and lower response rates with visceral disease only. Patients who received the gp100:209-217(210M) peptide plus IL-2 showed a strong trend to increased objective responses compared with IL-2 alone (22% versus 12.8%; P=0.01) and also compared with patients who received a variety of vaccines that did not include this immunogenic peptide (13.8%; P=0.009). CONCLUSION: IL-2 can produce a modest response rate in patients with metastatic melanoma including patients with durable complete responses. S.c. or cutaneous disease only and vaccination with gp100:209-217(210M) peptide was associated with significant increase in response rates.

Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade.

PURPOSE: CTL-associated antigen 4 (CTLA-4) can inhibit T-cell activation and helps maintain peripheral self-tolerance. Previously, we showed immune-related adverse events (IRAE) and objective, durable clinical responses in patients with metastatic melanoma treated with CTLA-4 blockade. We have now treated 139 patients in two trials and have sufficient follow-up to examine factors associated with clinical response. EXPERIMENTAL DESIGN: A total of 139 patients with metastatic melanoma were treated: 54 patients received ipilimumab in conjunction with peptide vaccinations and 85 patients were treated with intra-patient dose escalation of ipilimumab and randomized to receive peptides in accordance with HLA-A*0201 status. RESULTS: Three patients achieved complete responses (CR; ongoing at 29+, 52+, and 53+ months); an additional 20 patients achieved partial responses (PR) for an overall objective response rate of 17%. The majority of patients (62%, 86 of 139) developed some form of IRAE, which was associated with a greater probability of objective antitumor response (P = 0.0004); all patients with CR had more severe IRAEs. Prior therapy with IFNalpha-2b was a negative prognostic factor, whereas prior high-dose interleukin-2 did not significantly affect the probability of response. There were no significant differences in the rate of clinical response or development of IRAEs between the two trials. The duration of tumor response was not affected by the use of high-dose steroids for abrogation of treatment-related toxicities (P = 0.23). There were no treatment-related deaths. CONCLUSION: In patients with metastatic melanoma, ipilimumab can induce durable objective clinical responses, which are related to the induction of IRAEs.