Abstract
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. 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. 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. 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.
Highlights
Cancer chemotherapy had been to a large extent ineffective until the development of broad regimes combining different agents
The clinical responses developed gradually over years, contrary to what is expected from chemotherapy
The immunologic response rate is considerable compared with previous GV1001 trials without concomitant chemotherapy, low toxicity is retained
Summary
Cancer chemotherapy had been to a large extent ineffective until the development of broad regimes combining different agents. Cancer vaccination offers a different angle of attack, as compared with. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Most chemotherapeutic agents are immunosuppressive, and it was long assumed that vaccines should not be combined with chemotherapy. More recent knowledge has challenged this conventional wisdom [1, 2]. It is discussed whether chemotherapy may be utilized to counter tumor protection from regulatory T cells (Tregs), while prevailing the immunocompetence necessary for vaccine response [3,4,5]
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