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Vaccination of metastatic prostate cancer patients using mature dendritic cells transfected with mRNA encoding hTERT or an MHC class II targeted hTERT/LAMP fusion protein: Results from a phase I clinical trial.

2507 Background: hTERT, human telomerase reverse transcriptase, is overexpressed in 90% of all solid tumors and therefore represents a prime target for cancer immunotherapy. We have recently shown that hTERT RNA-transfected DC represent potent stimulators of hTERT-specific T cells and anti-tumor activity in vitro and in in vivo models. Based on these observations, we conducted a phase I clinical trial evaluating this strategy in patients with hormone-refractory prostate cancer.


METHODS
DCs were administered by intradermal injection of 1x107 cells in weekly intervals with total of 3 or 6 doses. In parallel, a cohort of patients received DC transfected with an RNA encoding a chimeric hTERT/LAMP protein, allowing for concomitant induction of hTERT-specific CD8+ and CD4+ T cell responses.


RESULTS
Results from 18 vaccinated patients have revealed no dose-limiting or adverse effects in any patients. After vaccination with hTERT or hTERT/LAMP RNA-transfected DC, high frequencies of hTERT-specific CD8+ and CD4+ T cells was observed in all subjects. Vaccination was associated with both molecular clearance of circulating tumor cells in the majority of evaluable patients, as well as a positive impact on reducing PSA velocity in selected patients. Furthermore, patients treated with the chimeric hTERT/LAMP vaccine demonstrated higher frequencies of hTERT-specific CD4+ T cells than those receiving the unmodified hTERT template. Additionally, the cytotoxic T lymphocytes (CTL) from these patients exhibited greater cytolytic activity against their cognate targets, suggesting that an enhanced hTERT-specific CD4+ response is capable of augmenting CTL-mediated tumor cell killing and, therefore, vaccine efficacy.


CONCLUSIONS
Our demonstration of vaccine safety, successful in vivo induction of hTERT-specific immunity, and favorable impact on surrogate clinical endpoints, including PSA velocity, provides a scientific rationale for further clinical investigation of hTERT-transfected DC in the treatment of metastatic prostate cancer. [Table: see text].