Community Research and Development Information Service - CORDIS

Periodic Report Summary 2 - HEPAVAC (Cancer Vaccine development for Hepatocellular Carcinoma)

Project Context and Objectives:
PROBLEM: Hepatocellular carcinoma - HCC is a disease with high unmet medical need. Indeed it accounts for about 6% of all new cancer cases diagnosed worldwide (nearly 750,000 new cases/year), and is the third and the fifth leading cause of death from cancer globally in men and women, respectively. Given the current lack of available effective treatments, the overall prognosis for patients with HCC is poor with a dismal 5-year survival rate of approximately 5-6%. In such a framework, development of innovative and novel therapies for HCC is mandatory and immunotherapeutic interventions, including cancer vaccines, may represent a valuable strategy.
AIM: The main objective of HepaVac is to develop a novel cancer vaccine approach for HCC based on epitopes naturally processed and presented by HLA class I and class II molecule (HLA-ligandome), to elicit both CD4+ T helper and CD8+ CTL tumor-specific effector and memory responses. Such an approach aims at improving clinical outcome in adjuvant HCC patients after standard treatment. Feasibility, safety and immunogenicity will be evaluated in a randomised, controlled European multi-centre phase I/II clinical trial.
EXPERIMENTAL APPROACH: The experimental approach undertaken by the HepaVac Consortium is based on development of an “off-the-shelf” vaccine comprising multiple newly identified tumor-associated peptides (TUMAPs) naturally presented on the surface of primary HCC cells. Upon immunological validation of HCC-specific TUMAPs, a peptide cocktail made of up to 40 HLA class I and II restricted epitopes will be designed for a multi-epitope and multi-HLA allele strategy, aiming at inducing both tumor-specific CD4+ T helper cell and cytotoxic CD8+ lymphocyte effector and memory immune responses. Furthermore, a sub-set of patients will be boosted with newly identified patient-specific HCC-associated mutated epitopes in an actively personalized vaccine (APVAC) approach. The “off-the-shelf” as well as personalized vaccine will be combined with a novel and potent RNA-based immunomodulator (RNAdjuvant®). Safety, feasibility and immunogenicity of the suggested approach will be tested in a randomised, controlled European phase I/II multi-centre clinical trial. A comprehensive T-cell immunomonitoring and biomarker program will be implemented to assess in detail the mechanism-of-action (MoA), identify immunological prediction markers of responsiveness and support further clinical development.
This will be one of the very few vaccine trials for HCC and the first multi-epitope, multi-target and multi-HLA allele therapeutic cancer vaccine for such a frequent and aggressive disease. Targeting the tumor with such a wide range of naturally occurring antigens will minimize the likelihood for tumor escape in vaccinated patients.

Project Results:
HEPAVAC is based on seven work packages (WPs) establishing a continuous workflow from tumor antigen identification to vaccine development and evaluation in a phase-I/II clinical trial.
The first task encountered in the implementation of a large project is the coordination of the activities of the different WPs in a given time frame. In the second reporting period of 18 months (total 36 months from the beginning of the project), Partners have met in one meeting and discussed in conference calls. The reserved area of the HEPAVAC website has been pivotal for sharing information among participants and archiving a spectrum of project-related documents. The website has also a public domain, which informs on the project features and provides information on issues of general interest.
The results so far obtained can be summarized as follows:
WP1 – Discovery of the hepatocellular carcinoma HLA class I-ligandome
Tumor associated antigens (TUMAPs) have been identified from primary HCC samples. Tumor association was determined by mass spectrometry as well as gene expression profiling. These data sets supplemented by literature research led to the selection of vaccine peptide candidates for non GMP synthesis and immunogenicity validation. After integration of all data sets, seven (7) HLA-A*02 positive TUMAPs and five (5) HLA-A*24 positive TUMAPs were chosen for the composition of the HepaVac vaccine cocktail. Assessment of spontaneous immunogenicity of the selected TUMAPs has been performed in PBMCs from healthy subjects.
WP2 – HLA class II-ligandome identification
Most of the objectives related to this time frame (18 months) have been fulfilled. In addition to 12 HLA class I TUMAPs selected for the composition of the HepaVac cocktail in WP1, four HLA class II-bound peptides were finally selected for inclusion in the HepaVac cancer vaccine (IMA970A) based on data from task 3 of this work package as well as task 3 of WP1. During the present reporting period IMM additionally analysed the tumor cell lines provided by UNINS and additional tumor samples from patients infected with HBV and HCV. Thereafter the selection of class II-restricted peptides was repeated and revealed 4 class II-bound peptides. Assessment of spontaneous immunogenicity of the selected TUMAPs has been performed in PBMCs from healthy subjects.
WP3 – Development and GMP manufacturing of an off-the-shelf multi-epitope vaccine
Sixteen TUMAPs were selected within WP1/WP2 and characterized regarding their physico-chemical characteristics. Respective analytical method- and formulation development was completed. GMP manufacturing of peptides for use as active pharmaceutical ingredient (API) has been subcontracted by INTNA through public tenders. Likewise, further manufacturing activities (GMP compliant vaccine manufacturing; Drug Supply activities) have been subcontracted by INTNA through public tenders. GMP processes and release methods for manufacturing of RNAdjuvant® are in place and approved by the national regulatory agency. Initial experiments were performed to investigate comparability and the in-use stability of potential HepaVAC vaccine formulations mixed with RNAdjuvant®. The comparability and the in-use stability of the final HepaVAC vaccine candidate mixed with RNAdjuvant® has to be further investigated.
WP4 – Establishment, preparation and GMP manufacture of an actively personalised boost vaccine complementary to the HepaVAC vaccine
During the first 18 months of the project the initial objective to discover naturally presented HLA-ligands from distinct tumor mutations (neo-epitopes) in HCC could not be reached, which is endorsed by the current state of the art. In order to deal with this situation, we devised a supplementary strategy, enabling the selection of alternative immunological targets for the APVAC approach in case no mutation-derived HLA-ligands can be validated. We established a flexible stepwise approach to select the best optional peptides from a given tumor, which has been set up being implemented into a pre-existing bioinformatics environment called OptiTope, allowing an automated and controlled selection of vaccine peptides according to predefined criteria, supported by an extended set of liver cancer/ benign tissue pairs analyzed during the second reporting period. This platform can be adapted according to further requirements (for instance following guidance of regulatory authorities) and used iteratively. A committee of experts in the field will approve the final peptide selection. Further, we have set up quality parameters required for selection of suitable immune targets before manufacturing of a personalized vaccine. Indispensable prerequisite for a clinical trial involving APVACs is small scale, on-demand GMP manufacturing of patient specific peptides and their release for clinical trial use, which is unique for TUE. Preparatory work has been undertaken to allow fast on demand small scale GMP manufacturing. This has involved optimization of manufacturing processes and their validation, implementation of new devices and respective qualification steps such as training of personnel according to revised SOPs. Further, stability testing, allowing storage of drug products over time for subsequent human use was performed. A variety of prerequisite analyses and preparative work adjusted to the HepaVac APVAC production forming the quality part of the clinical trial documentation was performed. Central documents as the investigational medical product dossier (IMPD; advanced draft) have been advanced substantially as well as contributions to the quality and manufacturing part of the investigator´s brochure (IB). In this regard all necessary preparations have been finalized in time during the second reporting period forming the required basis for clinical trial application, whereas the manufacturing and release of the first batch of APVAC peptides was not yet reached due to a delay with regard to starting the clinical trial.
WP5 – European multi-centre phase-I/II clinical trial
The Plan-start was originally set at month 24. However, the actual-start was at month 1. Indeed, in view of the definition of clinical trial design (D5.1 at month 24, Aug 31st, 2015) and the start of the clinical trial (at month 30, Feb 28th, 2016), all partners have been actively involved from Month 1 in activities focused on definition of the clinical trial. Such activities have been conducted through telephone calls, participation to Kick off Meeting (Naples, Nov 14-15 2013) First Annual Meeting (Tubingen, Oct 16-17, 2014), PEI Scientific Advice Preparation Meeting (Mainz, May 12th, 2015) followed by the Scientific advice meeting with the Paul-Ehrlich-Insitute (PEI, Germany in July 21st, 2015) as well as Second Annual Meeting, Antwerpen, Oct. 15th-16th, 2015. All these activities have been extremely fruitful and the clinical trial design (D5.1) was finalized at the Second Annual Meeting in Antwerpen. Thereafter, work on the draft clinical trial core documents could be intensified and at present all required documents (Clinical Study Protocol, Investigator Brochure, Investigational Medicinal Product Dossier (IMM and CureVac) are in a pre-final stage planned to be signed shortly followed by a centralized regulatory submission according to the Voluntary Harmonization Procedure (VHP procedure). The operational set up of sites is progressing with 5 out of 6 PBMC labs ready to start working (see scientific report to WP6). Moreover, all vendors (drug substance manufacturer, drug product manufacturer, secondary packaging and release, clinical research organization) required for the clinical trial were selected. The clinical trial is planned to start in Q4 2016 and a CRO has been identified and subcontracted by INTNA. In the meantime, preclinical studies have been conducted to assess the efficacy of combinatorial immunotherapy strategies (chemotherapy + checkpoint inhibitors and vaccine) (INTNA). Moreover, ex vivo evaluations have been performed to validate the potency of the RNAdjuvant® on antigen presenting cells derived from HCC patients (INTNA).
WP6 - Immune monitoring and biomarker identification to determine immunological efficacy of HepaVAC
To achieve the aim of extensive immune monitoring of patients during the Hepavac clinical trial, task 1, task 2 and task 4 of WP6 have been started. This included:
• Planning of design and setup of immunomonitoring assays to allow evaluation of the immunogenicity endpoint of the clinical trial;
• Technical setup and implementation of cell-saving methods to allow for highly sensitive potential ex vivo measurement of vaccine-induced immune responses;
• A blood drawing time point for PBMC collection before and after standard therapy application (e.g. radio frequency ablation / TACE) is included into the clinical trial to assess vaccine effects to immunological effects of standard of care procedures for HCC patients.
• Establishment of PBMC aliquoting table to ensure optimal use of PBMCs
• Establishment of PBMC collection laboratory network, training and release of PBMC laboratories.
WP7 – Coordination and dissemination
The overall coordination of the project has been pursued with continuity and a balanced attention to both scientific and administrative aspects at INTNA by the Scientific Coordinator Dr. Luigi Buonaguro supported by the Project Manager Dr. Serena Salerno and the Research Services Office (RSO), and with the contribution at IMM provided by the co-coordinator Dr. Harpreet Singh.

Potential Impact:
Expected impacts listed in the work programme
The overall aim of HepaVAC is to further support the goals of FP7 by contributing to significant improvements in public health in the member states as well as worldwide, and to strengthen the competitiveness of the European industry for the benefit of EU citizens.
Relevance to work programme
To date, despite the large number of preclinical studies and the number of ongoing clinical trials based on tumour antigens as anti-cancer vaccines, clinical data showing an effective anti-tumour activity are still unsatisfactory. This is even more dramatically true for hepatocellular carcinoma which is one of the most frequent and aggressive cancers with a dismal 5-year survival rate. Including 9 key European immune-translational and clinical leaders in HCC treatment, HepaVAC will take the immunotherapy for HCC to the next step, by developing a novel multi-target approach combined with increased efficacy through effective immune modulation. In particular, it will be based on an multi-target, multi-epitope “off-the-shelf” vaccine comprising class I and II restricted, naturally presented tumour associated peptides (TUMAPs) selected in a multi-HLA allele strategy, to elicit both CD4+ T helper and CD8+ CTL tumour-specific effector and memory responses. The “off-the-shelf” immunotherapeutic treatment will be further complemented by an actively personalised vaccination (APVAC). The APVAC approach, indeed, will identify individual mutated, naturally processed and presented epitopes in tumours from a subset of HCC patients enrolled in the HepaVAC clinical trial, which will be formulated in a complementary individualised vaccine. This will be one of the very few vaccine trials for HCC and the first multi-epitope, multi-target and multi-HLA allele therapeutic cancer vaccine for such a frequent and aggressive disease. No other approach is using such an extent (in terms of numbers) and quality (natural presentation) of antigens.
The multi-target vaccination approach will be combined with a completely novel and highly potent RNA-based adjuvant developed within the consortium (RNAdjuvant®). Preclinical data clearly show superiority of this new class of substances over other innovative adjuvants like poly I:C in inducing and strengthening anti-tumour T-cell responses. Additionally, combined immunotherapy will address the immunosuppressive environment in HCC patients by reducing suppressive regulatory T cells using the immune modulator cyclophosphamide. This has approach will increase the translation of anti-tumour immune responses into clinical benefit of patients.
Thus, HepaVAC fulfils: “The successful consortia will advance pre-clinical and/or clinical research concerning cancer immunotherapy towards improved treatment efficacy of future immunotherapeutic strategies”. The proposal specifically targets the area “therapeutic cancer vaccines directed against clinically relevant tumour and/or host antigens” and “immune evasion impacting on clinically relevant tumour-host microenvironment interactions in localised or systemic disease”.
The SMEs and industrial partners of the consortium (IMM and CURE), both being spin-off companies from European universities, will provide their specific expertise and will benefit by generating shared IP as well as reaching an advanced stage of clinical development for a new multi-peptide vaccine in a completely new indication and a novel highly efficient immune modulator.
Thus, this proposal fulfils the expected impact: ‘The expected results of research in this area will contribute to improving the efficacy of cancer immunotherapeutic regimens and clearly be of interest and potential benefit to SMEs.’
HepaVAC holds the promise that a multi-disciplinary approach, integrating clinical, molecular biological, chemical and immunological technologies, is feasible to treat patients according to their disease-specific inherent needs with only marginal expected toxicities. The project therefore exploits cutting-edge technological platforms, specifically HLA-peptidomics by XPRESIDENT™, gene expression analysis and next generation sequencing technologies (NGS) to identify and validate new drug targets. Combined with a centralised T-cell immunomonitoring and biomarker program using beyond state-of-the-art methods HepaVAC will enable comprehensive description of the mechanism-of-action of the new cancer vaccination approach and support further development. The biomarker program will pave the way to identify predictive biomarkers for a successful HCC immunotherapy.
Thus, this proposal fulfils ‘Research in this area will focus on disease aetiology; identification and validation of drug targets; prevention, early diagnosis, prognosis and treatment biomarkers; as well as on assessment of preventive, diagnostic, prognostic, and therapeutic interventions. In the long term, this area will contribute to reducing cancer incidence, morbidity and mortality and to improving the patients’ and survivors’ quality-of-life and treatment with fewer side-effects
HepaVAC opens the opportunity of a randomised controlled European multi-centre phase I/II clinical trial of a sufficient large dimension to investigate safety, feasibility and first signs of efficacy of a totally novel approach of immunotherapy targeting HCC, one of the most frequent and aggressive cancers. For assessment of efficacy, tumour response criteria will be considered. Moreover, this pioneering cooperation of European scientists and physicians will also support the preparation of a regulatory framework for future guidance for the development of APVACs.
Combined with a high quality harmonised and standardised immune monitoring and biomarker program, including the standardised collection of biological samples, a comprehensive description of the mechanism-of-action of the new cancer vaccination approach will be achieved. The sample collection as well as the immune monitoring and biomarker program will follow standard operating procedures established at the SME partner IMM, with proven track-record in accomplishing these tasks in several international multi-centre clinical trials. Partner IMM is actively engaged in European (Association for Immunotherapy of Cancer, CIMT) and US-based (Cancer Immunotherapy Consortium, CIC) assay harmonization efforts. Through regular participation in harmonization panels, assay standardization and validation is maximized. The output from the immune monitoring T cell assays will be captured in a well-defined, community-adopted minimum-information standard “MIATA” ( Quality control for generated data and statistical tools for data analysis and integration from patients will be applied to generate intangible data supporting further development.
Thus, HepaVAC fulfils: ‘Where appropriate, tumour response criteria must be considered. Assays must be harmonised to validate cancer immunotherapeutic regimens in models or first-in-human trials. Involvement of industry, in particular SMEs, is strongly recommended”.
To conclude, HepaVAC specifically answers all key aspects of the call HEALTH.2013.2.4.1-2: Strengthening the cancer patient's immune system in a 5-year project.

Impact for life science and medical use
HCC is the most common and aggressive primary liver malignancy with urgent unmet medical need. It accounts for about 6% of all new cancer cases diagnosed worldwide and is the third and the fifth leading cause of death from cancer globally in men and women, respectively. The overall prognosis for HCC patients is poor using current standard treatments, with a dismal 5-year survival rate of approximately 5-6%. Although promising in general, the still limited outcomes of recent cancer immunotherapies, including the only FDA-approved approach (Provenge®), need to be significantly improved. The HepaVAC Consortium aims to develop a novel cancer vaccine approach to improve treatment of hepatocellular carcinoma (HCC) patients. This will be one of the very few vaccine trials for HCC and the first multi-epitope, multi-target and multi-HLA allele therapeutic cancer vaccine for this frequent and aggressive disease. The cancer patient’s immune system will be strengthened by concurrent strategies, such as 1) Identifying new tumour associated antigens (TAA) and increasing the target structures (including personalised ones) within one comprehensive vaccination approach; 2) addressing and inhibiting the tolerogenic environment and tumour suppressive mechanisms (combinatorial immunotherapy); 3) selecting novel potent adjuvants able to increase the immunogenicity of the vaccine and to specifically elicit appropriate immune responses; 4) selecting early-stage patients with contained involvement of the liver organ and full immune competence and 5) Use a standardized vaccine approach instead of elaborate and costly cellular therapies to guarantee broad access of HCC patients to treatment.

HepaVAC will address all these 5 key points to create an efficient immunotherapy for hepatocellular carcinoma patients within the timeframe of the project.

A peptide-based “off-the-shelf” vaccine will be developed including a cocktail of up to 40 peptides comprising multiple class I and class II-restricted naturally presented tumour associated peptides (TUMAPs). A subgroup of patients will be further boosted by a personalised T cell epitope cocktail (APVAC for actively personalised vaccine) identified by integrated genomics and HLA-ligandomics. Both, the off-the-shelf as well as personalised vaccination will be combined with a novel and potent RNA-based immunomodulator (RNAdjuvant®). HepaVAC has chosen a multi-HLA-allele approach to assure that the novel therapeutic option will reach the broad majority of patients. The clinical trial design will assure that patients with sufficient immune competence are selected who will be able to maximally benefit from HepaVAC treatment. Furthermore, the project will include a comprehensive T-cell immunomonitoring and biomarker program to describe the mechanism-of-action (MoA) and support further clinical development. As an additional benefit, this will enable the development of new tools to monitor and predict the clinical outcome of patients, and thus to identify patients more likely to respond to immunotherapy.

To our knowledge, therapeutic approaches incorporating such a large spectrum of naturally presented epitopes (both HLA class I and II restricted) together with tumour-specific and molecularly defined attributes of the individual patient (i.e. beyond sizeable subgroups of patient populations) are still unexplored not only in Europe, but throughout the world. HepaVAC would be the first trial globally, where such a complex immunotherapeutic approach will be specifically designed. This is of special interest in HCC, where therapeutic options are limited. However, successful completion of the safety and feasibility profiles of this trial would open a new class of immunotherapy applicable for a majority of European HCC patients with the principal goal to extend survival of cancer patients measurable for years and not just weeks or months. Importantly, HepaVAC would give rise to new hope for HCC patients, affected by an up to now incurable disease, without expected toxicities, as demonstrated in recent clinical trials with peptide based-immunotherapy56,77. HepaVAC will intensify the direct cooperation of leading HCC centres all over Europe with regard to patient care and translational research. The implementation of such a network has the potential to move Europe to an internationally leading position in the field of next-generation cancer therapy not only for HCC but also for any other tumour entities.
Thus, if successfully accomplished, HepaVAC will have a substantial medical and scientific impact for the European and global community in the field of clinical and translational development in cancer research and tumour immunology. Not only would European research profit from this novel approach, but also and mainly patients: a new treatment for European patients affected by an aggressive, non-curable cancer would be generated.

Impact for industry
The consortium will support close collaborations between European SMEs and academia taking advantage of the expertise on both sides. The design of the HepaVAC vaccination concept will make use of IMM’s peptide antigen identification (plus proven expertise in performing multi-centre trials including extensive immune monitoring and biomarker programs) and CURE’s adjuvant development expertise. High standards for GMP manufacturing combined with an enormous flexibility required for on-demand manufacturing will be covered by a novel and unique academic GMP manufacturing facility at partner TUE dedicated to the fast and small-scale synthesis of personalised vaccinations. In addition to the medical and scientific impact of the results generated by HepaVAC, it is important to note that European SMEs, which are holding respective intellectual property rights, will generate the multi-target “off-the-shelf” vaccine and produce the novel immune modulating agent RNAdjuvant® in Europe. In particular, IMM gained international recognition by successful accomplishment of 3 phase I and II studies and the initiation of a phase III study with therapeutic cancer vaccines. CURE has developed a unique standardized GMP production facility, allowing the production of long-chain RNA molecules which are employed as RNA-based adjuvant. HepaVAC will take advantage of their complementary expertise and will also establish new foundations for development of a novel type of immune therapy relevant to HCC but with a transfer possibility to other tumour entities.
Thus, HepaVAC will demonstrate that such an innovative effort requiring truly multi-disciplinary expertise with specialist organizations in the field of peptidomics, genomics, small- and large-scale peptide manufacturing, and adjuvant development can be only achieved in a collaborative and industry-led effort.
The randomised, controlled Phase I/II clinical trial will be performed at centres of excellence in the management and treatment of HCC throughout Europe; with internationally recognized investigators selected for their long-standing commitment in this field. A successful phase I/II clinical trial will demonstrate the capacity of the European network and therefore will not only allow attraction of further funding and private investments into SMEs but particularly follow-up clinical trials leading multi-peptide vaccines based on naturally presented epitopes to the market in the next step. For the fully personalised APVAC approach, HepaVAC will demonstrate feasibility and safety and will generate important proof of concept by immunogenicity analysis. Partner TUE, in a joint effort with partner IMM and CURE, is committed to develop actively personalised vaccines beyond this phase I/II study.
Thus, HepaVAC, if successful, will be the most relevant starting step to promote private investments into “off-the-shelf” multi-peptide vaccines based on naturally presented epitopes (HLA-peptidome) as well as APVACs in HCC. HepaVAC will provide a solid base for further advanced clinical development up to marketing authorization and eventually commercialization. In case of a successful conclusion of this project, the companies IMM and CURE of this consortium intend to advance in a joint fashion the commercial development of the “off-the-shelf” HepaVAC vaccine that will be generated through this European cooperative.

Impact for other areas of research
Competitiveness and increased productivity of the European research community and industry should be improved by the Lisbon strategy. HepaVAC will have a substantial impact on the standing of the European Community in the field of clinical and translational R&D in cancer research, tumour immunology, including personalised therapy. This project will intensify cooperation within European clinical centres with regard to patient care and translational research including several cutting edge technologies. The implementation of a network of European organizations will strengthen the importance of European researchers in the field of HCC in comparison to centres in other areas of the world. Most clinical trials are set-up by large pharmaceutical companies and often led by US investigators, which leads to a systematic advantage of US research groups in the competition for research subsidies. Demonstration of a well-functioning European network that is able to conduct a clinical trial in such a relevant and frequent cancer within a short range of time will improve the standing of European groups in general, especially if hurdles can be resolved in a novel approach of personalised medicine.
Thus, HepaVAC will help to strengthen the collaborative framework of clinical development in Europe. This is, of course, true for any multi-centre trial in Europe, but particularly for the proposed complex, randomised controlled trial with a novel vaccine approach and an additional personalised vaccination strategy, which requires much stronger interaction between developing SMEs and universities, manufacturing units, subcontractors and academic clinical centres compared to development of standard drug products.
Discussions with regulatory agencies how to regulate specifically the new personalised approach have been started already by the Association of Cancer Immunotherapy (CIMT) (Britten, Singh et al., ‘Towards the Development of Actively Personalised Immunotherapy for the Treatment of Cancer - Focus on the Regulatory Landscape in Europe’, manuscript submitted, minutes of meeting with EMA published at CIMT website). Partners IMM and TUE of this consortium contribute actively to those discussions with the European Medicines Agency’s (EMA) Innovation Task Force in January 2012. They resulted in the positive conclusion that the regulatory hurdles to develop APVACs are manageable (meeting minutes are published on CIMT’s website With the approach to develop a drug manufacturing process that will result in an infinitive number of differently composed drug products, the HepaVAC consortium enters a new area of medicine and regulation. Considering the personalised APVACs, both target and lead structures for each individual patient will not be known/defined prior to the recruitment of the patient. Therefore, currently existing paradigms defining aspects of quality and preclinical testing will not be applicable for APVACs. The successful consortium will contribute to development of a first blue-print for the clinical development of highly variable drug products originating from a standardized process. The principles applicable to HepaVAC might apply to any form of future approach in which molecular information on a patient’s genotype, disease stage, tumour and immune status are integrated to determine a personalised therapeutic approach. Implications reach far beyond therapeutic peptide-based cancer vaccines.
Thus, HepaVAC will allow translating the first ongoing positive discussions between partners of the consortium and the leading European regulatory authority EMA, into a real and clinical project which will further help to draft the regulatory framework for APVACs and advance the field of regulatory research for this complex type of intervention.

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