DNA fusion gene vaccination, delivered with or without in vivo electroporation – a potent and safe strategy for inducing anti-tumour immune responses in prostate cancer


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Christian Ottensmeier

University of Southampton, UK

Abstract

DNA fusion gene vaccination, delivered with or without in vivo electroporation - a potent and safe strategy for inducing anti-tumour immune responses in prostate cancer

We are undertaking a phase I/II, two arm, dose escalation study in HLA A2+ patients with recurrent prostate cancer. Patients are eligible at biochemical failure after radical treatment, if their tumour expresses PSMA. 3 monthly doses of DNA are delivered either by im injection (800, 1600, 3200µg) or by intramuscular electroporation (EP) (400, 800, 1600µg) with 5 patients at each dose level. Booster doses are given 6 and 12months.

The study builds on our preclinical development of DNA fusion gene vaccines, encoding a strong immune alert signal derived from a plasmid domain of Fragment C of tetanus toxin (FrC-DOM), linked to a peptide sequence from the tumour antigen. This design breaks tolerance and controls the development of tumours in murine models. Delivery by EP increases the potency of the DNA vaccine significantly.

We are now testing this concept in a two centre clinical trial with a vaccine encoding FrC-DOM linked to a PSMA peptide (PSMA27). We have chosen PSMA as it is expressed in >95% of primary tumours and metastases and is up-regulated following treatment with anti-androgens. To date the vaccine has been well tolerated and the use of EP does not add significant toxicity.

Immunological monitoring is being undertaken with ELISA and ELISPOT assays, validated to GCLP. Anti-FrC-DOM antibody responses were detected in 4/10 patients receiving DNA only, compared to 8/9 patients with EP and in 3 of this latter group the increase exceeded >100 fold increases compared to baseline by week 16. 10 patients at the first dose level in both arms of the study have been evaluated for cellular responses against FrC-DOM. 8 patients developed significant CD4 responses, with a suggestion that CD4 responses may occur earlier and last for longer if the DNA is delivered by electroporation. While the data is more limited at the time of writing, robust CD8+ T cellular responses against the PSMA27 epitope have been identified in 4/5 patients evaluated to date. The evaluation of CD4 and CD8 responses is ongoing and more data will be presented at the meeting.

The study data confirm that a DNA vaccine delivered alone or with EP induces, significant, robust and reproducible humoral and cellular immune responses can safely in patients with prostate cancer.