Abstract
Human telomerase reverse transcriptase (hTERT) is highly expressed in >85% of human tumors and is thus considered as a good tumor-associated antigen candidate for vaccine development. We conducted a phase I study to investigate the safety, tolerability, clinical response, and immunogenicity of INVAC-1, a DNA plasmid encoding a modified hTERT protein in patients with relapsed or refractory solid tumors. INVAC-1 was either administered by intradermal route followed by electroporation or by Tropis, a needle-free injection system. Safety and tolerability were monitored by clinical and laboratory assessments. Progression-free survival and overall survival were reported using Kaplan-Meier survival analysis. Immunogenicity was studied by ELISpot, Luminex, and Flow Cytometry. Twenty-six patients were treated with INVAC-1 administered at three dose levels (100, 400, and 800 μg). Vaccination was well tolerated and no dose-limiting toxicity was reported. One treatment-related grade 3 SAE was reported. Fifty-eight percent of patients experienced disease stabilization. PFS was 2.7 months, median OS was 15 months, and 1-year survival was reached for 65% of patients. INVAC-1 vaccination stimulated specific anti-hTERT CD4 T-cell response as well as cytotoxic CD8 T-cell response. No evidence of peripheral vaccine-induced immunosuppression was observed. INVAC-1 vaccination was safe, well tolerated, and immunogenic when administered intradermally at the three tested doses in patients with relapsed or refractory cancers. Disease stabilization was observed for the majority of patients (58%) during the treatment period and beyond.See related commentary by Slingluff Jr, p. 529.
Highlights
Human telomerase reverse transcriptase, the catalytic subunit of the telomerase complex, is highly expressed in more than 85% of human tumors from diverse phenotypes and associated with poor prognosis [1,2,3,4,5,6], with little or no expression in normal somatic cells [7]. hTERT expression and activity are associated with maintenance of telomere length and play a role in the unlimited proliferative capacity of cancer cells
We demonstrated that INVAC-1 was able to induce hTERT-specific cellular immune responses with CD4þ Th1 effector and memory CD8þ T cells
Three patients were treated with INVAC-1/EP at each dose level of the escalation phase (100, 400, and 800 mg) and 11 patients were treated in the 800 mg EP extension cohort (Supplementary Fig. S1)
Summary
Human telomerase reverse transcriptase (hTERT), the catalytic subunit of the telomerase complex, is highly expressed in more than 85% of human tumors from diverse phenotypes and associated with poor prognosis [1,2,3,4,5,6], with little or no expression in normal somatic cells [7]. hTERT expression and activity are associated with maintenance of telomere length and play a role in the unlimited proliferative capacity of cancer cells. Human telomerase reverse transcriptase (hTERT), the catalytic subunit of the telomerase complex, is highly expressed in more than 85% of human tumors from diverse phenotypes and associated with poor prognosis [1,2,3,4,5,6], with little or no expression in normal somatic cells [7]. HTERT expression and activity are associated with maintenance of telomere length and play a role in the unlimited proliferative capacity of cancer cells. Telomerase overexpression in tumor cells results from promotor mutations, chromosomal. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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