Development of a cell immunotherapy targeting non-conventional tumor antigens in ovarian cancer

Project Information

OVACell

Grant agreement ID: 101145335

DOI

10.3030/101145335

Project closed

EC signature date 6 February 2024

Start date 1 March 2024

End date 30 April 2026

Funded under

• The European Innovation Council (EIC)

Total cost

€ 3 650 067,50

EU contribution

€ 2 499 999,00

Coordinated by

ERVIMMUNE
France

Periodic Reporting for period 1 - OVACell (Development of a cell immunotherapy targeting non-conventional tumor antigens in ovarian cancer)

Reporting period: 2024-03-01 to 2024-11-30

Summary of the context and overall objectives of the project

ErVimmune develops breakthrough immunotherapies combining cancer vaccines and T cell-based therapies. The major step is the choice of a target specifically expressed by cancer cells and shared between patients. Human endogenous retroviruses (HERVs) answered to these two criteria. They represent a significant part of the human genome and are kept silent by epigenetic regulation in healthy cells. They represent a reservoir of targetable antigens, especially in tumors with a low or moderate mutational burden. As HERV-derived antigens are shared between patients, they represent a particularly well-suited approach for developing off-the-shelf immunotherapies for solid tumors : ovarian cancer, and Triple Negative Breast Cancer (TNBC)
We focused our discovering epitopes derived from HERVs with an approach based on our proprietary bioinformatics algorithms to identify potential epitopes that are validated by proteomics and immunology assays: from bioinformatics to proteomics.
In Ovarian cancer, a large majority of patients are diagnosed at a late stage. The ideal treatment must be highly effective from the first administration. T cell-based therapies approaches fit perfectly with this requirement by providing a massive immune response against the tumor with one single injection. The TCR-OV1 (EIC Accelerator program) is being developed as a demonstration of the clinical value of targeting HERV antigens in ovarian cancer. HERV-based T-cell therapy will revolutionize ovarian cancer therapy and will address the real societal challenge of fighting this highly lethal disease. The clinical validation of TCR-OV1’s efficacy and safety in patients is expected for Q4 2027 followed by the signature of a co-development and commercialization agreement in Q1 2028.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Scientific:
The assessment of TCR-OV1's safety profile includes the expression profile of our target. We already demonstrated that the target is overexpressed in ovarian cancer compared to peri-tumoral tissues and critical healthy tissues.
We demonstrated that HERV-specific T cells are cytotoxic against ovarian tumor cells in vitro and in vivo, without any toxicity observed. in vivo preclinical studies over an extended period of time revealed suboptimal anti-tumor activity of TCR-OV1 for long-term efficacy. We are developing improved T cell engineering and optimization strategies to address this issue. Adjustment of the therapeutic modality is ongoing to maximize long term therapeutic benefit for patients.
In the ongoing bioinformatic activities, we identified new proprietary targets derived from the same HERV, that are specifically expressed in ovarian cancer samples and found at the peptide level in tumor proteomics and immunoproteomics datasets, supporting the specificity of our targets in ovarian cancer, confirming the translation of our targets with definitive and direct proof. These additional parameters reinforce the reliability and versatility of our platform.
The gap analysis indicated that the additional steps needed to obtain an optimal therapeutic product are feasible but will result in a significant delay and additional cost.

Regulatory:
we held a preliminary meeting with the regulatory agencies for USA (FDA) and Europe (EMA) to introduce all the technical parts of the bioinformatic algorithm use to determine our targets. Both agreed that ErVimmune’s HERV-derived targets, including the target of TCR-OV1, may be of interest to be evaluated in the clinic. This positive first interaction supports the relevance and the safety of our approach.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

We further improved our in-silico target discovery pipeline by implementing the analysis of proteomics and immunoproteomics datasets, strongly supporting the translation of our targets and their expression at a sufficient level to be detected by mass spectrometry.
This demonstrates ErVimmune’s ability to leverage on all available resources to further reinforce the demonstration of the specificity expression of our targets at the protein level.

As long-term efficacy of T cell therapies is a challenge in solid tumors, we performed an in vivo preclinical study where we engrafted subcutaneously OVCAR-3 ovarian tumor cells. We injected TCR-OV1 T cells when the tumor was palpable and monitored tumor growth for an extended period of time, up to 50 days. Although we observed a significant decrease of tumor growth during the first three weeks, correlating with TCR-OV1 injections, this tumor growth inhibition was transitory over time, and tumor volumes were identical in both the treated group and the control group at day 50.
This result suggested an insufficient initial cytotoxic activity or a lack of persistency of TCR-OV1.
To address this issue, we developed three parallel approaches to reinforce the anti-tumor activity of TCR-OV1 based on state of the art technologies: 1) the genetic knock-out of the endogenous TCR, 2) the targeted insertion of the transgene using Adeno-Associated Viruses (AAV), and 3) the co-expression of co-receptors to boost T cell activation and improve cytotoxicity.

The genetic knock-out of the endogenous TCR did improve the TCR expression and the homogeneity of the T cell population obtained. It also improved T cell avidity. When combined to a targeted genetic insertion by AAV-mediated transduction, we observed an increased in transgene expression persistence compared to T cells generated by lentivirus (LTV)-mediated transduction. However, no improved T cell avidity was observed. When we assessed the cytotoxicity against ovarian tumor cells in vitro, no reproducible advantages of AAV-mediated TCR-T cells over LTV-mediated editing TCR-T cells was observed.

We decided to explore the benefit of the co-expression with a co-receptor to potentiate TCR-OV1 cytotoxicity. As ovarian cancer is one of the malignancies with the highest expression level of the protein Mesothelin (MSLN), we designed co-receptors providing an activation boost to T cells upon binding to MSLN.
We provided the proof of concept that these receptors were efficient at improving T cell activation.
We are pursuing the development of these co-receptors to potentiate ovarian cancer cell killing in vitro and in vivo.

In parallel to these T cell engineering optimizations, we propose to explore the therapeutic modality of T cell engagers, based on the recognition of the same specific and safe targets, allowing to recruit endogenous T cells at the tumor site. This therapeutic modality has already proven to be promising in solid tumors. We already identify partners with solid expertise to develop this technology in a time and cost effective manner.