Clinical Response and Pharmacodynamic Assessment of INVAC-1, a DNA Plasmid Encoding an Inactive Form of Human Telomerase Reverse Transcriptase (htert), on Immune Responses, Immune Tolerability, Tumor Burden and Circulating Tumor DNA (ctdna) in Patients with Advanced Solid Tumors.

Background: INVAC-1 is an optimized plasmid encoding an inactive form of hTERT, a tumor antigen expressed in most of human tumors with little or no expression in normal somatic cells. We report here clinical response and pharmacodynamics of INVAC-1. Methods: A two center Phase I trial evaluated INVAC-1 given monthly for 3 cycles using intra-dermal injection followed by electroporation. Immune monitoring comprised detection of autoantibodies, lymphocyte phenotyping, inflammatory cytokine levels in blood, and CD4 and CD8 anti-hTERT responses assessed by Elispot IFN-γ. Anti-tumor activity was evaluated through RECIST 1.1 adapted to immune response, and plasma ctDNA. Results: Twenty patients (pts) with refractory/progressive tumors were enrolled and treated at three escalating doses of 100 µg, 400 µg and 800 µg. 12 pts experienced stable disease according to RECIST. For 10 of them, the treatment was extended up to nine months. INVAC-1 was well tolerated with no dose-limiting toxicities. No significant biological signs of autoimmunity were observed. A majority of pts had high levels of inflammatory plasma cytokines at inclusion but no significant modification was observed after INVAC-1 administration. IFN-γ polarized anti-hTERT CD4/CD8 immune responses were detected in 55% of pts, following INVAC-1 injections. INVAC-1 triggered de novo antihTERT response or enhanced pre-existing natural anti-hTERT immunity. The majority of pts mounted anti-hTERT T cell responses following the second- or third vaccination. ctDNA was evaluated in 14 pts. The most frequent mutations were TP53, KRAS and PIK3CA. We observed a ctDNA decrease in 5 cases, a stable ctDNA level in 5 cases and an increase in 4 cases. Conclusions: Results indicate that INVAC-1 was well tolerated and immunogenic at the doses and schedule tested. Disease stabilization was obtained for the majority of pts, according to RECIST criteria or ctDNA levels. Phase II studies of INVAC-1 in solid tumors and hematologic malignancies, preferably in pts with early diseases and adequate immune functions, are starting. Clinical trial identification: NCT02301754. Legal entity responsible for the study: Invectys. Funding: Invectys. Disclosure: J. Medioni, L.O. Teixeira, L. Doucet, S. Oudard, S. Culine, O. Adotevi, M.-A. Dragon-Durey, P. Laurent-Puig: Study investigator. V. Doppler: Sponsor employee. B. Souttou: Sponsor employer. S. Wain-Hobson: Invectys co-founder. R. Defrance: Consultant for study sponsor. T. Huet: Sponsor employee. P. Langlade-Demoyen: Invectys co-founder and CEO. All other authors have declared no conflicts of interest.