Dr. Azad’s presentation delved into the realm of drug-based immunotherapy, offering a comprehensive journey from fundamental concepts to clinical applications. The discussion commenced with a general introduction to the fundamentals of immunotherapy before honing in on the potential of combination therapies to amplify its effectiveness.
The immune system’s complexity lies in its ability to carefully balance between maintaining self-tolerance and actively safeguarding against infections and cancer. The activation of T cells is intricately regulated through a dual-signal mechanism, which mandates the identification of antigens presented by antigen-presenting cells and the simultaneous interaction of co-stimulatory molecules.
The immune system deploys various immune checkpoints to prevent autoimmune reactions, a defensive strategy that cancer cells often exploit to evade immune attacks. Immunotherapy harnesses the immune system’s antitumor ability by blocking immune checkpoints like CTLA-4 and PD-1. While some patients experience substantial and lasting benefits from immunotherapy, resistance remains a formidable challenge. To expand the scope of patients benefiting from immunotherapy, researchers are vigorously exploring diverse combination approaches, resulting in a large immunotherapy market with multiple agents targeting the same immune checkpoints.
After providing an overview of the landscape of immunotherapy, Dr. Azad’s talk focused on the resistance mechanisms and approaches to overcome it. To understand the patterns of immunotherapy response, the tumor immune phenotype spectrum has been broadly classified into three types: the immune-desert phenotype, characterized by a lack of T cells within the tumor and poor response to immunotherapy; the -immune-excluded phenotype, where T cells reside in the tumor stroma and the immune inflamed phenotype, featuring T cells in the tumor center and strong immunotherapy response.
Based on growing literature evidence, Dr. Azad proposed that tailoring immunotherapy combinations to specific immune phenotypes, rather than employing generic combinations may enhance efficacy. For instance, a gene expression study in intrahepatic cholangiocarcinoma revealed four distinct tumor microenvironment-based subtypes linked to immune escape mechanisms and correlated with patient outcomes.
One approach to heighten immunotherapy response is using epigenetic modifiers to alter tumor tissue’s immune phenotype. The study of histone deacetylase inhibitor entinostat in murine models of pancreatic cancer, known for its strong immunosuppressive tumor microenvironment, showed promising results. The combination of entinostat with anti-PD1 and/or anti-CTLA-4 shifted the population of myeloid-derived suppressor cells to a less immunosuppressive type. This modulation of tumor immune phenotype led to an increase in tumor-free survival in murine models. These successful findings in in vivo models were followed by a phase II clinical trial combining entinostat with nivolumab. This combination resulted in a remarkable 15% response rate, with patients experiencing durable responses.
Furthermore, an alternative strategy to enhance immunotherapy response involves combining it with targeted therapies. As an example, Dr. Azad discussed the use of MEK inhibitor, cobimetinib in combination with immunotherapy. In murine models, MEKi was shown to inhibit tumor growth in an immune dependent manner. Further elucidation of systemic MEKi effects revealed that MEK inhibition impairs effector T cell function which may impede immunotherapy response. In light of this finding, the addition of agonist therapy with anti-4-1BB to cobimetinib and anti-PD-1 in murine models was studied. This combination rescued T cell function and led to longer survival in mice.
The presentation concluded with an exploration of an innovative approach that used in vivo competition assays to identify somatic mutations responsible for immune evasion, pinpointing PIK3CA activation as a possible resistance mechanism against PD-1.
In summary, Dr. Azad’s presentation shed light on various immune resistance mechanisms and offered inspiration by showcasing the development of combinatory studies in immunotherapy, starting from in vitro discoveries, and advancing into clinical trials.