Title: Development of new biological therapies for pancreatic cancer
Funder: Cancer Research UK

Abstract: Background Pancreatic ductal adenocarcinoma (PDAC) is recognised as one of CRUK’s priority cancers for research as there are no effective treatments and less than 5% five-year survival after diagnosis. Therefore, novel therapeutic approaches are urgently needed. Here we propose to combine personalised vaccination and autologous T cell (ATC) transfer approaches with specific targeting of the unique biological features of the PDAC tumour microenvironment (TME) to induce robust anti-tumour immunity. Aims and objectives This programme will develop new personalised viro-immuno-therapeutic regimens based on our established oncolytic virus (OV) platform and recent progress in identification of PDAC-specific neo-antigens through achieving the following objectives: (1) Development of a peptide-based, OV-mediated vaccine platform, targeting the genetic profile of individual patient tumours; (2) Development of ATC therapy by creation of a T-cell receptor (TCR) library targeting the most common mutant KRAS alleles; (3) Development of a novel ‘super’ OV, VV-PC21 based on intravenously deliverable vaccinia virus (VV) that can alter the TME, enhance T cell homing to the tumour and activate T cells. Methods We will create a peptide vaccine library targeting six mutant KRAS neo-antigens and novel immunogenic neo-antigens identified by us. A delivery platform, via electrostatic interactions with OV, will be optimised, negating the need for lengthy and costly neo-antigen cloning for personalised application to patients either as an adjuvant therapy for preventing recurrence and metastasis after surgery, or a therapeutic regimen for inoperable patients. In addition to the vaccination platform, we will develop a TCR library targeted against six KRAS peptide mutants restricted by common MHC Class I alleles. These will be delivered to KRAS-mutant positive patients in whom vaccination is unable to induce robust mutant KRAS immunity due to lack of appropriate T cell repertoire or development of T cell tolerance to KRAS mutants. We also propose to construct a ‘super’ virus, VV-PC21, based on our patented VV backbone that can attract T-cells into the tumours and promote activation. This virus will be assessed in combination with vaccination and autologous TCR-cell transfer (ATC) to provide favourable modification of the TME for maximal therapeutic efficacy. How the results of the research will be used This programme will culminate in the development of two ‘off-the shelf’ therapeutic regimes for rapid clinical translation. Peptide vaccination or an ATC regime will both be potentiated by the use of OV. The outcome of this programme will provide potential new therapies for PDAC patients.

Lay abstract: Background Pancreatic ductal adenocarcinoma (PDAC) is recognised as one of CRUK’s priority cancers for research as there are no effective treatments and less than 5% five-year survival after diagnosis. Therefore, novel therapeutic approaches are urgently needed. Here we propose to combine personalised vaccination and autologous T cell (ATC) transfer approaches with specific targeting of the unique biological features of the PDAC tumour microenvironment (TME) to induce robust anti-tumour immunity. Aims and objectives This programme will develop new personalised viro-immuno-therapeutic regimens based on our established oncolytic virus (OV) platform and recent progress in identification of PDAC-specific neo-antigens through achieving the following objectives: (1) Development of a peptide-based, OV-mediated vaccine platform, targeting the genetic profile of individual patient tumours; (2) Development of ATC therapy by creation of a T-cell receptor (TCR) library targeting the most common mutant KRAS alleles; (3) Development of a novel ‘super’ OV, VV-PC21 based on intravenously deliverable vaccinia virus (VV) that can alter the TME, enhance T cell homing to the tumour and activate T cells. Methods We will create a peptide vaccine library targeting six mutant KRAS neo-antigens and novel immunogenic neo-antigens identified by us. A delivery platform, via electrostatic interactions with OV, will be optimised, negating the need for lengthy and costly neo-antigen cloning for personalised application to patients either as an adjuvant therapy for preventing recurrence and metastasis after surgery, or a therapeutic regimen for inoperable patients. In addition to the vaccination platform, we will develop a TCR library targeted against six KRAS peptide mutants restricted by common MHC Class I alleles. These will be delivered to KRAS-mutant positive patients in whom vaccination is unable to induce robust mutant KRAS immunity due to lack of appropriate T cell repertoire or development of T cell tolerance to KRAS mutants. We also propose to construct a ‘super’ virus, VV-PC21, based on our patented VV backbone that can attract T-cells into the tumours and promote activation. This virus will be assessed in combination with vaccination and autologous TCR-cell transfer (ATC) to provide favourable modification of the TME for maximal therapeutic efficacy. How the results of the research will be used This programme will culminate in the development of two ‘off-the shelf’ therapeutic regimes for rapid clinical translation. Peptide vaccination or an ATC regime will both be potentiated by the use of OV. The outcome of this programme will provide potential new therapies for PDAC patients.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS