A select group of patients with hepatocellular carcinomas (HCC) benefit from surgical, radiologic, and systemic therapies that include a combination of anti-angiogenic and immune-checkpoint inhibitors. However, because HCC is generally asymptomatic in its early stages, this not only leads to late diagnosis, but also to therapy resistance. The nucleoside analogue 6-thio-dG (THIO) is a first-in-class telomerase-mediated telomere-targeting anticancer agent. In telomerase expressing cancer cells, THIO is converted into the corresponding 5′-triphosphate, which is efficiently incorporated into telomeres by telomerase, activating telomere damage responses and apoptotic pathways. Here, we show how THIO is effective in controlling tumor growth and, when combined with immune checkpoint inhibitors, is even more effective in a T-cell-dependent manner. We also show telomere stress induced by THIO increases both innate sensing and adaptive antitumor immunity in HCC. Importantly, the extracellular high-mobility group box 1 protein acts as a prototypical endogenous DAMP (Damage Associated Molecular Pattern) in eliciting adaptive immunity by THIO. These results provide a strong rationale for combining telomere-targeted therapy with immunotherapy.

Telomerase is an attractive therapeutic target due to its expression in most cancer cells. This study focuses on harnessing the potential of telomerase to alter telomeres as a therapeutic modality. We designed and synthesized divalent dinucleotide prodrugs comprised of 6-thio-2′-deoxyguanosine (6-thio-dG; THIO) and 5-fluoro-2′-deoxyuridine (5-FdU) nucleosides. Although dinucleotides containing 5-FdU pharmacophores showed better activity in vitro versus compounds containing only THIO pharmacophores, we observed greater activity for THIO-containing compounds in vivo. The homopurine compounds MAIA-2022–12 and MAIA-2021–20, with two 6-thio-dG pharmacophores, linked by 3′, 5′- and 5′, 5′-phosphodiester bonds, respectively, demonstrated the greatest anticancer efficacy among the compounds tested and induced host immune-memory responses in vivo. The sequential combination of MAIA-2022–12 or MAIA-2021–20 with the immune anti-PD-1 or anti-PD-L1 checkpoint inhibitors demonstrated superior anticancer efficacy compared with the corresponding monotherapies. We conclude that MAIA-2022–12 and MAIA-2021–20 are promising candidates for future preclinical and potential clinical studies.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Nonetheless, deeper molecular understanding of NSCLC has resulted in novel therapeutic approaches, including targeted therapy and immunotherapy, which have improved patient prognosis and outcomes in recent years. Immune checkpoint inhibitors (ICIs), with or without chemotherapy, are now considered valuable components of treatment for NSCLC cases that do not have specific actionable genetic mutations. Patients with actionable genetic mutations are candidates for targeted therapies. The primary focus of this review is the rationale for using ICIs in the perioperative setting for patients with resectable NSCLC and in advanced disease settings. Furthermore, we compare the benefits of using ICIs with the challenges associated with their clinical implementation in resectable and advanced NSCLC. Finally, we emphasize the development of novel treatment strategies that potentially provide an optimal treatment choice for patients with advanced NSCLC.

Figure S1-S5 from Activating an Adaptive Immune Response with a Telomerase-Mediated Telomere Targeting Therapeutic in Hepatocellular Carcinoma

A select group of hepatocellular carcinomas (HCC) patients benefit from surgical, radiological, and systemic therapies that include a combination of anti-angiogenic and immune-checkpoint inhibitors. However, since HCC is generally asymptomatic in its early stages, this not only leads to late diagnosis, but also to therapy resistance. The nucleoside analogue 6-thio-dG (THIO) is a first-in-class telomerase-mediated telomere-targeting anticancer agent. In telomerase expressing cancer cells, THIO is converted into the corresponding 5’-triphosphate, which is efficiently incorporated into telomeres by telomerase, activating telomere damage responses and apoptotic pathways. Here, we show how THIO is effective in controlling tumor growth and, when combined with immune checkpoint inhibitors, is even more effective in a T-cell dependent manner. We also show telomere stress induced by THIO increases both innate sensing and adaptive anti-tumor immunity in HCC. Importantly, the extracellular HMGB1 (high-mobility group box 1) protein acts as a prototypical endogenous DAMP (Damage Associated Molecular Pattern) in eliciting adaptive immunity by THIO. These results provide a strong rationale for combining telomere-targeted therapy with immunotherapy.