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.
