2308P - CyPep-1 reprograms the tumor microenvironment and enhances the efficacy of immune checkpoint inhibitors

Background

Immune checkpoint inhibitor (ICI) therapy produce durable responses in patients with metastatic cancer. However, most patients do not benefit from ICIs, promting the need for new treatment strategies. CyPep-1, a synthetic 27-D-amino acid peptide, selectively targets tumor cell plasma membranes, inducing pore formation and immediate membrane destabilization. With demonstrated activity across a broad range of tumor types, CyPep-1 exhibits a strong therapeutic potential. Here we describe the membrane perturbing activity of CyPep-1 on ICI refractory tumors in vitro and in vivo, and demonstrate its ability to release tumor neoantigens, stimulate the immune system and sensitize tumors to anti-PD1 therapy.

Methods

The release of cytoplasmic antigens was quanitified following exposure of CyPep-1 to various cancer cell lines that do not respond to ICI therapy in vivo. Syngeneic tumors were established in vivo, followed by CyPep-1 injections as monotherapy or in combination with anti-PD1 antibodies. Immune activation was assessed by Flow-Cytometry and Mass Cytometry (CyTof).

Results

CyPep-1 treatment resulted in the release of functional cytoplasmic proteins, indicative of tumor antigen release. Intratumoral CyPep-1 administration triggered cytokine release and a significant infiltration of various anti-tumor immune effector cells, consequently reducing tumor growth. Anti-PD1 monotherapy, however, had no impact on tumor growth. CyPep-1, in combination with anti-PD-1 potentiated the therapeutic effects of CyPep-1, leading to a significant systemic anti-tumor immunity and tumor growth inhibition.

Conclusions

CyPep-1 treatment specifically targets tumor cells, promoting pro-inflammatory cytokine upregulation and subsequent infiltration of immune effector cells within the tumors. This process results in a systemic immune response, transforming immunological “cold” tumors into “hot” ones. A clinical trial based on these findings has been initiated (NCT05383170).

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Cytovation ASA.

Funding

Cytovation ASA.

Disclosure

L. Prestegarden: Financial Interests, Personal and Institutional, Full or part-time Employment: Cytovation ASA. C. Pico-Navarro: Other, Institutional, Full or part-time Employment: Cytovation ASA. All other authors have declared no conflicts of interest.