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Messenger RNA vaccination in NSCLC: Findings from a phase I/IIa clinical trial.

2584 Background: CV9201 is a therapeutic cancer vaccine for non small cell lung cancer (NSCLC) based on a novel vaccination technology using self-adjuvanted mRNA molecules. It comprises five mRNAs encoding NSCLC associated tumor antigens (NY-ESO1, Mage-C1, Mage-C2, Survivin, 5T4). Here, we report interim results of a phase I/IIa trial with CV9201 in stage IIIb/IV NSCLC patients that responded or stabilized after first line (chemo-) radiotherapy. Primary endpoint was assessment of safety and tolerability of CV9201 and secondary endpoints were evaluation of induction of immune response and assessment of anti-tumor activity.


METHODS
Patients were vaccinated intra-dermally up to five times in max. 15 weeks. Blood samples were taken before the first vaccination and two weeks after the 3rd and 5th vaccination. 3 patients were vaccinated in the phase I part of the study at each of three different dose levels (400µg, 800µg and 1600µg total mRNA administered). Enrollment was then expanded at the highest dose level within the phase IIa part. Peripheral blood mononuclear cells were analyzed for induction of effector and memory T cell subsets, B cells and CD4+CD25++ T regulatory cells during the course of vaccination. Antigen-specific B and T-cell responses against all antigens were analyzed by IgM and IgG ELISA, IFN-g ELISPOT, ICS and tetramer analysis.


RESULTS
Phase I safety analysis showed mainly treatment related grade 1 injection site reactions and grade 2 fever. Neither dose-limiting toxicity nor vaccine-related serious adverse events were reported. B-cell frequency increased and a significant (P< 0.004) shift from IgD+CD38+/- naïve B-cells towards IgD+CD38++ germinal center founder B-cells by > 2 fold was detected in 50% of 16 intermediate analyzed patients after 3 vaccinations. T-cell population shifted from effector to memory subtype 2 weeks after the final vaccination. Antigen-specific B cell, CD4+ and CD8+ T cell responses were detected during and after vaccination with CV9201.


CONCLUSIONS
The interim analysis indicated that vaccination with CV9201 was safe and well tolerated by the study participants. Moreover, CV9201 led to an adaptive immune activation, and detectable antigen-specific humoral and cellular immune responses.