Telomerase Peptide Vaccination Combined with Temozolomide: A Clinical Trial in Stage IV Melanoma Patients

Abstract

Purpose: The study is a proof-of-principle trial evaluating toxicity, immune response, and clinical response in melanoma patients after combined therapy with temozolomide and the telomerase peptide vaccine GV1001. Our previous GV1001 trials showed immune responses in approximately 60% of lung or pancreatic cancer patients. Experimental Design: Twenty-five subjects with advanced stage IV melanoma (M1B or M1C) received concomitant temozolomide and GV1001. Temozolomide was administered 200 mg/m2 orally for 5 days every fourth week, and GV1001 as eight injections over 11 weeks. Immune response was evaluated by delayed type hypersensitivity, T-cell proliferation, and cytokine assays. The immunologic responders continued monthly vaccination. Results: The treatment was well tolerated. A GV1001-specific immune response was shown in 18 of 23 evaluated subjects (78%). Patients developing long-term T-cell memory survived more than those rapidly losing their responses. The immune response exhibited several characteristics of possible clinical significance including high IFNγ/IL-10 ratios, polyfunctional cytokine profiles, and recognition of naturally processed antigens. Survival compared favorably with matched controls from a benchmark meta-analysis (1 year: 44% vs. 24%, 2 years: 16% vs. 6.6%). The clinical responses developed gradually over years, contrary to what is expected from chemotherapy. Five patients developed partial tumor regression and six more recorded stable disease. One patient has no remaining disease on fluorodeoxyglucose positron emission tomography scans after 5 years. Conclusions: The immunologic response rate is considerable compared with previous GV1001 trials without concomitant chemotherapy, although low toxicity is retained. The results warrant further studies of GV1001/temozolomide treatment and support the general concept of combining cancer vaccination with chemotherapy. Clin Cancer Res; 17(13); 4568–80. ©2011 AACR.

Analysis of Spontaneous Tumor-Specific CD4 T-cell Immunity in Lung Cancer Using Promiscuous HLA-DR Telomerase-Derived Epitopes: Potential Synergistic Effect with Chemotherapy Response

“…Another promiscuous TERT-derived CD4 epitope called GV1001 was reported by Gaudernack and colleagues (48). This peptide has been used in clinical trials with encouraging results when combining to CT in melanoma and NSCLC (25,26). Nevertheless, the impact of spontaneous GV1001-specific immune response on vaccination efficiency and clinical outcome has not been investigated yet.…”

“…Therefore TERT activity has been observed in all studied cancer forms, including stem cell-like tumor cells (23) and is therefore a hallmark of cancer cells (24). Furthermore, recent clinical studies using a TERT-derived CD4 epitope vaccine called GV1001 was able to increase survival of cancer patients when combined with radio or CT (25,26). These results suggested the interplay between anti-TERT-CD4 T-cell immunity and conventional anticancer therapy.…”

T-helper cell receptors from long-term survivors after telomerase cancer vaccination for use in adoptive cell therapy

“…In our GV1001 vaccine trials, we have observed immune response rates ranging from 50% to 80%, combined with low toxicity. [1][2][3][4] None of the patients experienced serious adverse events. Interestingly, the GV1001 immune response was associated with improved survival in all trials.…”

“…This includes studies in melanoma, non-small cell lung cancer (NSCLC), and pancreatic cancer patients evaluating vaccination with the telomerase peptide GV1001. [1][2][3][4] Human telomerase reverse transcriptase (hTERT) is overexpressed in most human cancers and thus a widely applicable target for cancer therapy. 5,6 Because hTERT expression is important for tumor growth, the risk of tumor escape is presumably limited.…”

“…[1][2][3][4] This includes a series of T-cell clones from two long-term survivors, patients C and D, in the NSCLC trial CTN-2000. 2,29 Both patients developed a de novo GV1001-specific response after vaccination, associated with tumor regression and extended survival.…”