The cancer immunotherapy field has been reinvigorated by the discovery of immune checkpoint inhibitor agents that release the brakes on the immune system and allow for natural immune defence to combat tumours. Despite their tremendous success in some cancer types like melanoma where the response rate is >40%, not all patients respond to this treatment, and some important cancer types are not very susceptible to checkpoint inhibitor immunotherapies.
Prostate cancer, which is a very cancer in men and the second leading cause of cancer death in the Western world, so far has not been considered a good target for checkpoint blockade. One of the reasons for that is that prostate tumours have relatively low level of mutations and therefore are not expressing many mutated neoantigens that can be recognised and targeted by the immune system. But this approach may be clinically beneficial for prostate cancer as well if combined with a vaccine capable of inducing effective T cell immune responses against prostate tumour associated self-antigens. Oxford has developed one of the world’s leading T cell-inducing vaccine technologies, based on potent viral vectors, and this is now being applied to cancer therapeutic vaccination.
This DPhil project presents an exciting opportunity to join the team that is assessing such combination therapies in mouse models and running the phase I/II clinical efficacy trial in prostate cancer patients undergoing treatment with a leading prostate cancer vaccine in combination with PD1 checkpoint inhibition (NCT03815942). The project will provide opportunities to study immune responses with this and related combination immunotherapies and identify biomarkers of vaccine clinical efficacy in both humans and pre-clinical models.
Both specialised subject training and generic research capabilities will be developed,
including but not limited to:
All students will be expected to analyse, interpret and present their data internally and at appropriate conferences. This project will provide a broad range of transferable skills with a unique insight into exciting translational research.
Project reference number: 1073
|Irina Redchenko||Jenner Institute||Oxford University, Old Road Campus Research Building||GBRemail@example.com|
|Benoit Van Den Eynde||Oxford Ludwig Institute||Oxford University, Old Road Campus Research Building||GBRfirstname.lastname@example.org|
The tumour-associated antigen 5T4 is an attractive target for cancer immunotherapy. However to date, reported 5T4-specific cellular immune responses induced by various immunisation platforms have been largely weak or non-existent. In the present study, we have evaluated a heterologous prime boost regime based on the simian adenovirus ChAdOx1 and modified vaccinia virus Ankara (MVA) expressing 5T4 for immunogenicity and tumour protective efficacy in a mouse cancer model. Vaccination-induced immune responses were strong, durable and attributable primarily to CD8+ T cells. By comparison, homologous MVA vaccination regimen did not induce detectable 5T4-specific T cell responses. ChAdOx1-MVA vaccinated mice were completely protected against subsequent B16 melanoma challenge, but in therapeutic settings this regime was only modestly effective in delaying tumour outgrowth. Concomitant delivery of the vaccine with monoclonal antibodies (mAbs) targeting immune checkpoint regulators LAG-3, PD-1 or PD-L1 demonstrated that the combination of vaccine with anti PD-1 mAb could significantly delay tumour growth and increase overall survival of tumour-bearing mice. Our findings support a translation of the combinatorial approach based on the heterologous ChAdOx1-MVA vaccination platform with immune checkpoint blockade into the clinic for the treatment of 5T4-positive tumours such as prostate, renal, colorectal, gastric, ovarian, lung cancer and mesothelioma. Hide abstract
Prostate cancer possesses several characteristics that make it a suitable candidate for immunotherapy; however, prostate cancer vaccines to date demonstrate modest efficacy and low immunogenicity. The goal of the present pre-clinical study was to explore the immunogenic properties and protective efficacy of a novel prostate cancer immunotherapy based on the heterologous prime-boost viral-vectored vaccination platform. The simian adenovirus, ChAdOx1, and modified vaccinia Ankara virus, MVA, encoding a prostate cancer-associated antigen, the six transmembrane epithelial antigen of the prostate 1 (STEAP1), induced strong sustained antigen-specific CD8+ T-cell responses in C57BL/6 and BALB/c male mice. Unexpectedly, the high vaccine immunogenicity translated into relatively low protective efficacy in the murine transplantable and spontaneous models of prostate cancer. A combination of the vaccine with PD-1 blocking antibody significantly improved survival of the animals, with 80 % of mice remaining tumour-free. These results indicate that the ChAdOx1-MVA vaccination regime targeting STEAP1 combined with PD-1 therapy might have high therapeutic potential in the clinic. Hide abstract