Final analysis of a phase I/IIa study with CV9103, an intradermally administered prostate cancer immunotherapy based on self-adjuvanted mRNA.

Abstract

4535 Background: CV9103 is a prostate cancer (PCA) vaccine that contains the four antigens PSA (prostate specific antigen), PSCA, PSMA and STEAP1 as self-adjuvanted full-length mRNAs. Methods: Patients with castrate resistant PCA with rising PSA and predominantly existing metastases (> 80%) were enrolled into a first-in-man phase I/IIa study. The primary endpoint was safety, the secondary immunogenicity. Three different dose levels (256µg, 640µg and 1280µg total mRNA) were tested in the phase I. Patients were vaccinated intradermally in weeks 1, 3, 7, 15 and 23. Blood samples were taken before the first and two weeks after the 2nd to 4th vaccination. Immune responses were assessed by ELISPOT (IFN-g), intracellular cytokine staining (IFN-g, TNFa), tetramer analysis (all ex vivo) or ELISA (PSA). Results: Three patients each were accrued at the low and medium dose level. One dose limiting toxicity, urinary retention, was observed at the high dose level which was expanded to six patients. A maximum tolerated dose was not defined. 389 AEs were reported, and 282 were classified as related. Of these, most were injection-site reactions or flu-like symptoms such as chills and fever. Of 21 serious adverse events, 7 were classified as related. With safety established, the high dose level was expanded by 32 patients (phase IIa). Immunomonitoring was possible in 33 of the 38 patients enrolled at the high dose level. Antigen-specific T-cells were detected in 79% of patients independent of their HLA-background. Importantly, 58% of the immunological responders reacted against multiple antigens. Immune responses were detected against all antigens regardless of cellular localization. The frequency of antigen-unspecific B-cells was increased in 74% patients. In 3 patients, an increase of preexisting anti-PSA antibody levels was measured. NK-cells showed a tendency for increased activation (CD25 and CD69). Individual patients had prolonged stabilization of PSA-levels after initial rises. One patient had a greater than 85% drop in his PSA-level. Conclusions: CV9103 was safe and well-tolerated and displayed an unexpectedly high level of cellular immunogenicity.