Community Research and Development Information Service - CORDIS

Periodic Report Summary 2 - IMPROVE (Improving Prostate Cancer Outcome with Vectored Vaccines)

Project Context and Objectives:
Cancer immunotherapy, and immunotherapy of prostate cancer in particular, has recently emerged as a viable and attractive treatment strategy. The only licensed therapeutic prostate cancer vaccine, Sipuleucel-T, provides a modest survival benefit of 4 months. This vaccine has been shown to induce immune responses which are likely causatively involved in vaccine efficacy. However, the cellular immune responses reported were very modest. Encouragingly, though, this modest immunogenicity correlated with vaccine efficacy suggesting that more potent immunisation regimes should be more effective. Heterologous prime-boost vaccination regimes, for example, were shown to induce substantially enhanced T cell responses and efficiently break tolerance to a self-cancer antigen in pre-clinical models. Low dose cyclophosphamide, which can diminish the impact of regulatory T cells, could also make immunotherapy more effective. Histological analysis of prostate tissue samples (from diagnostic prostatic biopsies and radical prostatectomy specimens) can be utilised as a potential measure of efficacy, and an early impact of immunotherapy can be measured by comparing multi-parametric magnetic resonance images at the time of diagnosis and following immunisation. Thus, in this project we are clinically evaluating the most potent vaccine technology available for inducing cellular immunity to target prostate cancer. This highly immunogenic vaccination platform deploys the replication-deficient simian adenovirus, ChAdOx1, as a priming agent and attenuated poxvirus, MVA, as a boosting vaccine. Both viral vectors encode the tumour associated antigen 5T4 overexpressed in prostate tumours. We are developing and assessing an accelerated protocol for immunisation in clinically localised low and intermediate risk prostate cancer patients. The approach allows biochemical, histological and radiological efficacy measures to be obtained in just 12 weeks. Following this, we hope to correlate the efficacy observed with these measures to treatment effectiveness measured by the established indicator of biochemical relapse-free survival. Participants are randomised to receive, or not, low dose cyclophosphamide prior to immunisation to assess whether this enhances the immunogenicity of the vectors, likely by down-regulating regulatory T cells. MVA.5T4 homologous immunisation has been the subject of an extensive clinical development programme by Oxford BioMedica (OBM). Here, we are comparing this homologous regime to a heterologous prime boost regime to determine if this can improve the immunogenicity of the MVA vector alone, and to what extent. A phase I/II clinical trial is planned for patients with intermediate risk disease or with metastatic disease with progression after hormone therapy, where the vaccine will be combined with an anti PD-1 checkpoint inhibitor (Nivolumab).
In parallel, we are undertaking a preclinical programme on comparative immunogenicity and efficacy assessment of a range of new and old cancer antigens in mouse models of prostate cancer to identify the most effective antigen(s) for clinical development as an immunotherapeutic. This four year programme combines the most potent vaccine technology available for inducing cellular immunity in humans with leading cancer antigens to target prostate cancer, for which there is substantial evidence that vaccine immunotherapy is feasible.

Project Results:
Two recombinant viral vectors (ChAd and MVA) expressing the murine tumour-associated antigen 5T4 have been generated (WP1). Both are immunogenic in mice. A heterologous prime boost vaccination regime based on the two recombinant viral vectors, ChAdOx1 and MVA, encoding a self-antigen m5T4 breaks immunological tolerance to this antigen.
The clinical batch of the ChAdOx1.5T4 vaccine to be used in the phase I and phase I/II trials has been manufactured (WP2) and was shown to be well tolerated, not associated with any adverse effects and able to elicit strong cellular immune responses in mice. All necessary ethical and regulatory approvals were obtained to set up the phase I trial (WP3). The trial has been open to recruitment for 18 months now, and 32 subjects were enrolled and had completed the vaccination course as of 31st March 2017. The safety profile of this first-in-human heterologous ChAd-MVA 5T4 vaccination regime was good with only mild side effects observed. The analysis of cellular and humoral immune responses against the vaccine antigen, 5T4, is currently underway with very encouraging immunogenicity data. Detailed immunomonitoring has been successfully performed to map individual CD4+ and CD8+ T cell epitopes within the 5T4 antigen in patients who mounted vaccine-specific immune responses (WP5).
A clinical protocol for the second planned study, a phase I/II trial to evaluate vaccine efficacy in combination with immune checkpoint inhibitors PD-1 and PD-L1, is in advanced development.
In the context of the preclinical programme, three antigens from a panel of seven antigens originally discovered by Externautics (CRISP3, CNPY2 and DPY19L3) have been characterised (WP7). Overall, the study reinforced the association of these antigens with prostate cancer and provided a first indication of antigen expression in early prostate cancer and pre-cancerous stages. The ChAd and MVA vectors expressing these novel antigens have been manufactured and their immunogenicity has been compared to the one of defined prostate-associated antigens in a mouse model. Due to unexpectedly low T cell responses against the novel antigens, the viral vector constructs to be taken into further preclinical development within WP8 were identified as STEAP1, PSA and ERG. The vaccine efficacy assessment in a transplantable mouse tumour model demonstrated that the STEAP1 expressing vaccine administered in combination with anti PD-1 checkpoint inhibitor significantly delays progression of established TRAMP-C1 tumours (WP8). Work is ongoing on construction and testing of a polyvalent vaccine encoding several prostate cancer associated antigens.
A Project Steering Committee (PSC) and an Independent Scientific Advisory Committee (ISAC) have been formed and a data safety monitoring board (DSMB) established (WP9). A consortium agreement was finalised and signed by all partners. The majority of Deliverables due during the second reporting period were delivered on time. The project web site is live and up-to-date.

Potential Impact:
Prostate cancer is one of the most common tumours in males and with increasing lifespans is becoming an ever greater public health problem. The prostate cancer vaccine recently licensed by the US FDA, Sipuleucel-T, is an individualized treatment that costs over $90,000 per patient and provides a modest survival benefit of 4 months. Taking into account the cost-benefit ratio, a less expensive more effective prostate cancer vaccine is highly desirable. The likely outcome of this project is a product that will considerably outperform other less immunogenic vaccination approaches and will be significantly cheaper to manufacture. A successful delivery of this project is likely to lead towards licensure of a new cancer immunotherapy for prostate cancer. Provided that a vaccine has mild side effects, which previous studies of similar vaccines suggest, it should be feasible to treat all patients at risk of recurrence, instead of treating the recurrent disease. If the vaccine proves efficacious for reducing recurrences after surgery and is associated with mild side effects only, it may also eventually be used in prophylactic settings analogous to the current use of the vaccine to reduce the risk of cervical cancer in women. And finally, if immunogenic and efficacious in prostate cancer, this vaccination platform is broadly applicable to other types of tumours. Additionally, this work will contribute to the cancer research field by improving our understanding of immunological responses induced by vaccination against tumour self-antigens and required for protection and treatment of cancer. The study findings would be of significant interest to the public, and to cancer patients in particular, and will be disseminated through web-based resources, public lectures and patient involvement group meetings with the aim of promoting awareness of translational research.
List of Websites:
http://www.project-improve.eu/home

Reported by

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
United Kingdom

Subjects

Life Sciences
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