Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - EVOLVE (Extracellular Vesicle-Internalizing Receptors (EVIRs) for Cancer ImmunoGeneTherapy)

Teaser

In the last decade we have witnessed transformative results in the clinical application of both cancer immunotherapies and gene transfer technologies. Tumor vaccines are a specific modality of cancer immunotherapy. Similar to vaccination against pathogens, tumor vaccines are...

Summary

In the last decade we have witnessed transformative results in the clinical application of both cancer immunotherapies and gene transfer technologies. Tumor vaccines are a specific modality of cancer immunotherapy. Similar to vaccination against pathogens, tumor vaccines are designed to elicit a specific immune response against cancer. They are based on the administration of inactivated cancer cells or tumor antigens, or the inoculation of antigen-presenting cells (APCs) previously exposed to tumor antigens. In spite of significant development and testing, tumor vaccines have largely delivered unsatisfactory clinical results. Indeed, while some patients show dramatic and durable cancer regressions, many do not respond, highlighting both the potential and the shortcomings of current vaccination strategies. Hence, identifying and abating the barriers to effective cancer vaccines is key to broadening their therapeutic reach. The goal of EVOLVE (EVirs to Optimize and Leverage Vaccines for cancer Eradication) is to propel the development of effective APC-based tumor vaccines using an innovative strategy that overcomes several key hurdles associated with available treatments. EVOLVE puts forward a novel APC engineering platform whereby chimeric receptors are used to both enable the specific and efficient uptake of cancer-derived extracellular vesicles (EVs) into APCs, and to promote the cross-presentation of EV-associated tumor antigens for stimulating anti-tumor immunity. EVOLVE also envisions a combination of ancillary ‘outside of the box’ interventions, primarily based on further APC engineering combined with innovative pre-conditioning of the tumor microenvironment, to facilitate the deployment of effective APC-driven, T-cell-mediated anti-tumor immunity. Further to preclinical trials in mouse models of breast cancer and melanoma, our APC platform will be used to prospectively identify novel human melanoma antigens and reactive T cell clones for broader immunotherapy applications.

Work performed

In the first 18 months we have shown that EVIR chimeric receptors enable the specific and efficient uptake of cancer cell-derived EVs by APCs. In particular, we have shown that EVIRs enhance APC presentation of EV-associated tumor antigens to CD8+ T cells primarily through MHCI recycling and cross-dressing. Although preliminary, our results emphasise the significance of APC cross-dressing with pre-formed MHCI/tumor antigen complexes for the activation of specific T-cell responses; such modality of tumor antigen uptake and presentation has promising implications for vaccination protocols, as it should elicit T cell responses against antigens that are efficiently expressed by cancer cells. During the first reporting period we have also made substantial progress with work on establishing suitable APCs for EVIR transduction and vaccination. Furthermore, we have begun constructing EVIRs with new signalling domains and have initiated discussions around experiments involving patient-derived material.

Final results

In addition to APC vaccination protocols, the EVIR platform may be exploited for identifying EV-associated tumor antigens and cognate T cell receptors (TCR) through ex vivo cells assays, or for enhancing the priming of CD8+ T cells toward unknown, patient- and tumor-specific antigens in therapeutic vaccination settings. We are currently discussing these opportunities with potential investors.