Professional cross-priming for ovary and prostate cancer

PROCROP is a European initiative aimed at the development of a novel immunotherapeutic approach for metastasic ovarian and castration resistant prostate cancer. Therapeutic vaccination in cancer aims to enforce the body to recognize abnormal features of tumours as potential pathogenic signals. Vaccination aims to help to enforce the human system to recognize these features as pathogenic/external and react against them. This is an immunotherapeutic strategy that seeks to make the immune system of the patient aware of the tumours that is developing in its body triggering an immune response.
The Project is based on solid knowledge of cancer immunotherapy, which has emerged as a potent therapeutic tool against many cancer types over the results observed in the treatment of patients with the so-called “immune checkpoint blockers”. The fact that residual tumour cells frequently remain following surgery makes it suitable for testing new approaches at clinical level.
PROCROP intends to explore the potential of a particular subset of antigen-presenting cells (XP-DCs) to generate personalized cancer vaccines. Extensive research in animal models and cell cultures has attributed a fundamental role to XP DCs in promoting specific immune responses. In a multicentric coordinated effort PROCROP will develop vaccines by isolation of XP DCs from the blood of ovary and prostate cancer patients. XP DCs isolated from blood will be loaded with tumour material from surgical resections, activated and injected to the patients to promote immune responses against remaining tumour cells in ovary/prostate cancer patients. For this purpose, PROCROP explored the use of these vaccines in preclinical models, develop and optimize a cellular product based on laboratory isolation of these cell subsets from patients’ blood and perform two clinical trials to demonstrate immunogenicity and therapeutic efficacy of XP DC vaccination.
In PROCROP, 6 clinical and academic institutions and an industrial partner with proven expertise in the field joined forces in the pursuit of a novel immunotherapeutic approach.

PROCROP has successfully isolated from the blood a very minor population of cross-presenting dendritic cells (XP-DC) with high purity and efficient recovery. The cell-isolation product including release criteria and the instrumentation were set up. The workflow for XP-DC separation, antigen loading and maturation was implemented to the clinical sites in the project, where adjustments had to be made for practical implementation of the protocols.
Since the beginning of the project preclinical data have shown the relevance of XP DC in immune response against cancer in different mice models and experimental settings. Preclinical research has concluded, assessing efficacy and optimal conditions for delivery in murine models of cancer. The feasibility of the isolation of the XP DCs product loading with antigens extracted from human tumours have been proven. In this regard, induced endogenous CD8+ T cell response in vivo was superior to that in in vitro-generated DCs.
The product was submitted to regulatory agencies in the Netherlands and Spain for evaluation. The protocols for both ovarian and prostate are complete and, upon approval, clinical trials may start. Harmonized protocols between the European institutions will allow the consortium to identify the generation of immune responses against patient tumours after vaccination.

PROCROP has been able to generate a cell therapy product based on XP-DCs for use in cancer patients. While other dendritic cell types are being generated for clinical trials, all these approaches require ex-vivo differentiation. To our knowledge this is the very first approach of its kind. The therapeutic potential of XP DC vaccination in human cancer patients is yet to be ascertained but our preclinical data shows significant superiority of our cellular product as compared to state of the art procedures with other DC subtypes.
Protocols for a Phase I safety cohort for both prostate and ovarian cancer patients are complete. Additional documents (IB, PIF, ABR form), and EUDRACT are also available. The first IMPD dossier was completed in the Netherlands and submitted to the Dutch regulatory authorities September 2019 in the Netherlands.
Upon approval, the prostate cancer trial will be carried out in two phases. Phase I, safety cohort. Phase II, randomized part. Time to PSA progression as the primary clinical endpoint. (According to EUA guidelines) The ovarian cancer trial will be carried out as a Phase I, single centre study with 1 cohort. The primary clinical endpoints: feasibility and safety.
Once the clinical data are available we will better understand the potential of our therapeutic approach to promote a benefit on Ovarian and Prostate cancer patients and potentially other patients suffering from different cancer types.
Impact
•New therapeutic strategy, adapted to the needs of men (prostate) and women (ovary), with potential to improve the therapeutic outcome of two major chronic, highly prevalent and deadly diseases.
•Position of European researchers at the cutting-edge of tumour immunotherapy. The relevance of XP-DC in cancer immunotherapy has been highlighted in high-impact publications. This very much supports the relevance and timeliness of PROCROP
•A prototype clinical-grade cell separation and culture product to be commercially exploited in the preparation of a therapeutic vaccine. This will be marketed by European company Miltenyi, owning IP on the cellular selection technologies and on the selecting mAb. The new PRODIGY™ instrument, allows robotic manipulation in closed systems and standardization for larger trials. Its introduction in clinical centres has already demonstrated the benefit over the standard of care.
•Clinical validation for safety and pharmacodynamics (immunodynamics mode of action) of a novel cell therapy product for prevalent forms of genitourinary cancer afflicting males and females, with current unsatisfactory treatment.
•Commercial impact for an EU company, able to market devices and procedures to hospitals worldwide. With a business assumption of just 1-2% penetrance in the market in Europe and USA for the indications of the project, 4,800-9,600 individualized vaccine treatments are expected per year leading to profits, while being cost-effective for Public Health Systems. In addition, it could be a proof of principle for application to other tumours, as DC vaccination is not restricted to a type of tumour.

Periodic Reporting for period 4 - PROCROP (Professional cross-priming for ovary and prostate cancer)

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