MYC inhibition by OMO-103 induces immune cell recruitment in preclinical models of NSCLC and modulates the cytokine and chemokine profiles of Phase I patients showing stable disease

Background: Despite the promise of targeted therapies and immunotherapy, many cancer patients do not respond to treatment and are still in need of effective therapeutic options. We propose a revolutionary strategy based on the inhibition of MYC, a central molecule that drives multiple aspects of tumor progression and immune evasion. Although MYC has long been considered undruggable, we have demonstrated the safety and dramatic therapeutic potential of its inhibition using a MYC dominant negative, termed Omomyc. We showed that the Omomyc mini-protein abrogates tumor progression in a KRAS-driven Non-Small Cell Lung Cancer (NSCLC) mouse model, modulates chemokine/cytokine profiles and recruits T cells to the tumor site. These results have granted further development of the Omomyc mini-protein towards ongoing Phase I/IIa clinical trials (MYCure). Materials and Methods: We used a well-characterized KrasG12D transgenic NSCLC mouse model, a syngeneic KrasG12V/p53KO NSCLC mouse model and PBMC-humanized KRAS and EGFR-driven xenograft mouse models. Tumor growth was measured by microCT or caliper measurements. Immune cell infiltration was evaluated by immunohistochemistry and flow cytometry. In addition, patient samples were obtained from the ongoing Phase I study and soluble immune modulators were measured by Luminex®. Results: Here we show for the first time that, in our preclinical models, the infiltrating T cells consequence of Omomyc treatment are mainly CD4+ T cells expressing PD-1, Tim-3, OX-40 and 4-1BB, suggesting that Omomyc induces the expansion of this tumor-reactive cell population. Interestingly, mice treated intranasally with Omomyc display higher proportions of Th1-Th17 hybrid population, effector memory T cells, cytolytic NK cells and activated dendritic cells. Importantly, this immune stimulatory effect is also observed upon systemic intravenous Omomyc administration in a p53/ KRAS-mutated NSCLC model. Finally, we confirmed that Omomyc treatment also induces CD4+ and/or CD8+ T cell recruitment in PBMC-humanized xenograft lung cancer models independently of their driving mutation. Most notably, immune engagement was also seen in Phase I patients receiving OMO-103 and showing stable disease after 9 weeks of treatment. In particular, they display a cytokine signature that was not observed in patients with progressive disease. In addition, OMO-103 treatment also modified serum levels of other soluble immune modulators, including bona fide MYC targets. Of note, none of the patients showed anti-drug antibodies throughout the treatment. Conclusions: Our findings support the therapeutic opportunity to induce a potent antitumor immune response in NSCLC by pharmacological MYC inhibition with Omomyc. In addition, they suggest that OMO-103 can also induce immune activation in patients displaying stable disease. Conflict of interest: Ownership: L. Soucek and ME. Beaulieu are co-founders of Peptomyc S.L. Board of Directors: L. Soucek and ME. Beaulieu are members of the BoD of Peptomyc S.L. Other Substantive Relationships: S. Casacuberta-Serra, S. López-Estévez, M F. Zacarías-Fluck, L. Foradada, J. R. Whitfield, M. Niewel, ME. Beaulieu and L. Soucek are shareholders of Peptomyc S.L. S. Casacuberta-Serra, S. Martínez-Martín, S. López-Estévez, L. Foradada, J. Grueso, H. Thabussot, V. Castillo Cano, J. Morales, M. Niewel, ME. Beaulieu and L.Soucek are employees of Peptomyc S.L.