Community Research and Development Information Service - CORDIS

Periodic Report Summary 3 - 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 randomized, 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 third reporting period of 18 months (total 54 months from the beginning of the project), Partners have met in two meetings 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
Almost all the objectives related to this WP have been successfully fulfilled. Tumor associated antigens (TUMAPs) have been identified from primary HCC samples and tumor association was determined by mass spectrometry as well as gene expression profiling. These data sets supplemented by literature research lead to the selection of vaccine peptide candidates for non GMP synthesis and immunogenicity validation. After integration of all data sets, seven HLA-A*02 positive TUMAPs and five HLA-A*24 positive TUMAPs were chosen for the composition of the HepaVac cocktail. Additionally, the assessment of spontaneous immunogenicity of the selected TUMAPs has already been performed in peripheral blood mononuclear cells (PBMC) from healthy subjects.

WP2 – HLA class II-ligandome identification
Similar to WP1, almost all WP2 related objectives were achieved during this time frame. Briefly, four HLA class II-bound peptides were selected for inclusion in the HepaVac cancer vaccine (IMA970A). IMM additionally analyzed the tumor cell lines provided by UNINS and additional tumor samples from patients infected with hepatitis B and C viruses (HBV and HCV) to confirm the suitability of the IMA970A TUMPAs for these patients. Thereafter the selection of class II-restricted peptides was repeated and revealed 4 class II-bound peptides. The synthesis and purity testing of HCC class II-restricted TUMAPS were achieved. Additionally, the assessment of spontaneous immunogenicity of the selected TUMAPs has already been performed in PBMC samples from healthy subjects.

WP3 – Development and GMP manufacturing of an off-the-shelf multi-epitope vaccine
WP3 related objectives were so far completely achieved. During the third 18 months of the project the formulation/development and the GMP manufacturing of an off-the-shelf multi-epitope vaccine (IMA970A) was successfully completed (GMP vendors were selected and contracted). Likewise, the GMP manufacturing of RNAdjuvant® was reached. Additionally, the way of applying the vaccine was evaluated, as well as its in vivo tolerance (in vivo safety). Both IMPs (IMA970A and RNAdjuvant®) were successfully study-specific labeled, packaged and received final release by a Qualified Person. At the moment IMPs are ready to be delivered to the clinical sites involved in the HepaVac-101 clinical trial.

WP4 – Establishment, preparation and GMP manufacture of an actively personalised boost vaccine complementary to the HepaVAC vaccine
Most of the objectives related to this time frame have been fulfilled. A data processing and discovery platform for the APVAC approach was successfully established, as well as the required sample workflows and SOPs covering all relevant activities for the discovery steps. Modifications to the selection process for APVAC have been foreseen as precautionary measures in case no or only insufficient numbers of mutated HLA-ligands (neo-epitopes) are discovered and can be validated by mass spectrometry during the clinical trial (identified as a critical aspect in dry runs). Processes for manufacturing, labeling and QP release of GMP-grade on demand small batch multi-peptide vaccines for patients according to individual specifications (actively personalized boost vaccine; HepaVac APVAC) are in place and maintained. All required permissions and documentation as well as a respective quality control (QC) system is in place, allowing for the manufacture of ready to use GMP-grade vaccine cocktails based on individual specifications. This has been shown by means of sample peptides and described in a dedicated IMPD for regulatory submission. Evaluation of the adjuvanted vaccine (peptides mixed with RNAdjuvant®) stability, was omitted since the RNAdjuvant® was shown unsuitable for mixing with IMA970A peptides, invalidating a mixing step and requiring a strategy of separate delivery for human use that has been put in place.
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. Since then, the definition of the clinical trial has been extensively discussed by all partners through many meetings and currently all clinical trial related documents are finalized and in place. The clinical trial application (CTA) was already submitted in all five countries involved in the trial (Belgium, Germany, Italy, Spain and UK). Additionally, regulatory approval was reached in all five countries and ethical committee approval was achieved in 4 countries (approval in UK is pending). Five from the six clinical sites have already had the Site Initiation Visit and the initiation of the remaining clinical site in UK will be performed by the end of Q2 2018. So far 16 patients were successfully screened: 9 of them did not meet the inclusion/exclusion criteria or did not present required HLA phenotyping (HLA was not suitable for the trial and could not be included in the study), 4 of them remain in screening 1 (S1) phase, 2 of them are receiving HCC’s standard treatment or are recovering from that, and 1 has already received the first IMA970A plus CV8102 vaccination (on 26th February 2018 in Antwerp, Belgium).

WP6 - Immune monitoring and biomarker identification to determine immunological efficacy of HepaVAC
The design and the setup of immune-monitoring assays, as well as the design of the PBMC isolation/collection and of the logistic network involved in all six participants clinical sites were successfully achieved. Currently at least one PBMC laboratory close/at every clinical site was identified, trained and released, allowing them to perform PBMC isolation. The isolation of 14 PBMC samples from patients screened in the HepaVac-101 clinical trial has been performed so far. Additionally, the setup of study-specific immune-monitoring and immunogenicity biomarker evaluation, as well as technical setup and implementation of cell-saving methods in order to allow a highly sensitive potential ex vivo measurement of vaccine-induced immune responses have been achieved.
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. At the end of 2017, Dr. Salerno left the project for another job and the role of the Project Manager has been taken over by Dr. Maria Luigia Mazzone.
Potential Impact:
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, with both viral and non-viral pathogenesis, and accounts for about 6% of all new cancer cases diagnosed worldwide (nearly 750,000 new cases/year). It is the third and the fifth leading cause of death from cancer globally in men and women, respectively. The age-standardized incidence rate (ASR) per 100,000 men per year for HCC greatly varies in different regions. It is about 9.5 in Southern Europe and Northern America but increases to 31.9 and 22.2 in Eastern and South-Eastern Asia, respectively (
There is a growing incidence of HCC worldwide mostly due to long-lasting chronic HBV and HCV infections acquired in the last century, although incidence and mortality rates are greatly heterogeneous. The most frequent risk factors for HCC include chronic viral hepatitis (types B and C), alcohol intake and aflatoxin exposure. However, even though their geographical distribution is uneven, more than 50% of HCC cases can be attributed to HBV infection, more than 30% can be attributed to HCV infection and approximately 15% can be associated with other causes.
The overall prognosis for HCC patients is poor, with a dismal 5-year survival rate of approximately 5-6%. Indeed, the number of medical interventions tested in HCC are significantly lower compared to other cancers with a high prevalence/incidence worldwide (e.g., lung, breast, colorectal cancers). Therefore, a limited range of therapies are available to be used in the management of HCC according to the extent and severity of liver disease.
Surgery (i.e. liver resection and transplantation) represents the first choice of treatment for HCC in patients with early tumors on an intention-to-treat perspective, achieving a survival of 60–80% at 5 years. However, 70% of patients undergoing liver resection show tumor recurrence within 5 years characterized by either intrahepatic metastases or appearance of de novo tumor lesions and several adjuvating treatments to prevent recurrence have been evaluated, but none of these has provided a clear body of evidence for efficacy.
However, the majority of patients are diagnosed when disease is not treatable by surgical strategies anymore and can be approached only with loco-regional therapies which include a large panel of choice. Among such panel, local ablation is the first option for HCC patients at early stages and radiofrequency ablation (RFA) provides up to a 40-70% survival rate at 5 years. Indeed, RFA has been considered a possible alternative to surgical resection in HCC patients with single small lesions but results on clinical outcome have been contrasting. Transcatheter chemoembolization (TACE) is the first option for treatment of intermediate stage and unresectable HCC. Partial response is observed in almost 50% of patients treated with TACE showing a delayed tumor progression, although survival benefits have not been fully established.
Finally, systemic therapeutic options in advanced unresectable HCC are limited to Sorafenib which is the only approved therapy confirmed to provide a limited increase in survival of 2.3–2.8 months. Different studies have addressed the HCC pathogenesis in order to identify possible additional targets for systemic therapies, suggesting that multiple concurrent molecular mechanisms or pathways (e.g. vascular growth factor [VEGF] signaling; epidermal growth factor [EGF] signaling; Ras MAPK signaling; insulin-like growth factor receptor [IGFR] signaling) are involved, requiring a combination or targeted therapies to possibly achieve a clinical improvement.
All of the above highlights an urgent unmet medical need for new therapeutic strategies to confer durable clinical benefit for HCC patients. To this aim, the main goal of HEPAVAC is to develop a novel therapeutic cancer vaccine strategy for HCC based on a cocktail of newly identified HLA class I and II restricted tumor-associated peptides – TUMAPs (“off-the-shelf” vaccine) boosted by an actively personalized vaccine (APVAC) approach, including patient-specific naturally presented mutated peptides (
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