Deciphering synergistic treatment effects by combining immunecheckpoint targeted therapy with TLRs and adoptive cellular therapy in lung cancer

• Applicant: Professor Dr. Roland Tillmann Ullrich
• Subject Area: Hematology, Oncology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 455261855

Cancer is the leading cause of death worldwide and its numbers are projected to rise further, resulting in an estimated 12 million deaths in 2030. Lung cancer is the most frequent cause of cancer-related death. Current standard therapies, such as chemo and radiation therapy have yielded significant benefit in lung cancer patients, but long-term survival gains are uncommon, especially for advanced disease. Recent studies indicated that tumor cells inhibit the infiltration of immune cells to escape from an effective anti-tumor immune reaction. This tumor cell mediated inhibition of anti-tumor immune cells is mainly mediated by coinhibitory receptors such as programmed death receptor 1 (PD-1) or cytotoxic T lymphocyte associated protein 4 (CTLA 4). Targeting these immune check points induce an antitumor T cell response resulting in effective T cell mediated killing of tumor cells. However, less than 20% of patients with lung cancer respond to treatment to immune check point inhibitors. Resistance against check point inhibitors is associated with low infiltration of effector antitumor lymphocytes, low antigen presentation and therefore missing signals for effector T cell trafficking. Thus, there is a high clinical need to design immunotherapeutic strategies to overcome resistance against anti-PD-1 treatment. We sought to use adoptive cell therapy (ACT) to increase the number of effective tumor infiltrating lymphocytes. We expanded ACT in vitro that are simultaneously selected to recognize the tumor and harbor effector functions required to mediate cancer regression. In order to increase tumor immunogenicity and to activate innate immunity in the tumor microenvironment we apply local therapy with retinoic acid-inducible gene I (RIG-I) or Toll-like receptor (TLR) agonists that have been shown to engage mechanisms that initiate adaptive immune responses. Our preliminary data strongly indicate synergistic treatment effects by combining anti-PD-1 therapy with TLR agonists and ACT in anti-PD-1 refractory lung cancer models. Whereas single treatment with anti-PD-1 therapy, TLR agonists or ACT alone showed only modest treatment response. We now aim to investigate molecular mechanisms that regulate immune cell response and investigate the combination of immunotherapeutic approaches to overcome resistance to immune checkpoint inhibition. To this end, we will elucidate synergistic treatment protocols combining immune checkpoint inhibition with local TLR agonists or RIG-I therapy and ACT to finally decipher potential synergistic immunotherapeutic effects in genetically annotated lung cancer mouse models. Single treatment targeting anti-PD-1, TLR agonists and ACT has been already shown to be feasible in patients with cancer. Thus, this treatment strategy would be directly translatable into a clinical trial in lung cancer patients.

• DFG Programme: Research Grants