Boosting antitumor response with PSMA-targeted immunomodulatory VLPs, harboring costimulatory TNFSF ligands and GM-CSF cytokine

Soledad Palameta; Andrea J Manrique-Rincón; Jessica M Toscaro; Isadora F Semionatto; Matheus C Fonseca; Rhubia S M Rosa; Luciana P Ruas; Paulo S L Oliveira; Marcio C Bajgelman

doi:10.1016/j.omto.2022.02.010

Boosting antitumor response with PSMA-targeted immunomodulatory VLPs, harboring costimulatory TNFSF ligands and GM-CSF cytokine

Mol Ther Oncolytics. 2022 Feb 17:24:650-662. doi: 10.1016/j.omto.2022.02.010. eCollection 2022 Mar 17.

Authors

Soledad Palameta^{1

2}, Andrea J Manrique-Rincón^{1

3}, Jessica M Toscaro^{1

3}, Isadora F Semionatto^{1

4}, Matheus C Fonseca^{1

2}, Rhubia S M Rosa^{1

4}, Luciana P Ruas¹, Paulo S L Oliveira^{1

2}, Marcio C Bajgelman^{1

4

3}

Affiliations

¹ Brazilian Biosciences National Laboratory, Center for Research in Energy and Materials, Campinas, SP, Brazil.
² Institute of Biology, University of Campinas, Campinas, SP, Brazil.
³ University of Campinas Medical School, Campinas, SP, Brazil.
⁴ Faculty of Pharmaceutical Sciences, University of Campinas, Campinas, SP, Brazil.

Abstract

Therapeutic strategies based on immunomodulation have improved cancer therapy. Most approaches target co-stimulatory pathways or the inhibition of immunosuppressive mechanisms, to enhance immune response and overcome the immune tolerance of tumors. Here, we propose a novel platform to deliver targeted immunomodulatory signaling, enhancing antitumor response. The platform is based on virus-like particles derived from lentiviral capsids. These particles may be engineered to harbor multifunctional ligands on the surface that drive tropism to the tumor site and deliver immunomodulatory signaling, boosting the antitumor response. We generated virus-like particles harboring a PSMA-ligand, TNFSF co-stimulatory ligands 4-1BBL or OX40L, and a membrane-anchored GM-CSF cytokine. The virus-like particles are driven to PSMA-expressing tumors and deliver immunomodulatory signaling from the TNFSF surface ligands and the anchored GM-CSF, inducing T cell proliferation, inhibition of regulatory T cells, and potentiating elimination of tumor cells. The PSMA-targeted particles harboring immunomodulators enhanced antitumor activity in immunocompetent challenged mice and may be explored as a potential tool for cancer immunotherapy.

Keywords: 4-1BB; GM-CSF; OX40; PSMA; VLP; cancer; immunotherapy; lentivirus.