The state of combination therapies in immuno-oncology
Improved understanding of the cancer-immunity cycle has provided the basis for novel immunotherapeutic approaches. Individual therapeutic agents designed to intervene at different stages of the cycle have shown significant promise . The list of FDA-approved PD-1 immune checkpoint inhibitors continues to grow and be prescribed for a variety of cancer types. Unfortunately, even in highly immunogenic tumors, the majority of patients do not respond to PD-1 pathway blockade. It is becoming increasingly apparent that combination therapy to target multiple events in the cancer-immunity cycle is an efficacious approach, and could potentially extend the benefit of immunotherapy to a larger population of cancer patients.
The landscape of combination therapies is complex and mostly shaped by the clinical indications for agents already under investigation. The most dominant combination strategy in clinical trials is that of immune checkpoint inhibitors to PD-1 and CTLA-4. A number of clinical trials are focused on these two pathways that operate at different stages of the cancer-immunity cycle. A dual inhibition strategy targeting these cell surface proteins has demonstrated favorable synergistic effects on cancer regression while minimizing toxicities . The scope of immunotherapy combinations extends beyond checkpoint inhibitors to include checkpoint agonists, cancer vaccines, and other promising immunomodulatory agents.
Immunotherapy and oncogenic driver targets
Several notable clinical trials have been conducted to explore the role of immune checkpoint inhibitors in combination with existing targeted cancer therapies. One key example is the combined blockade of PD-1 pathway and angiogenic factors, such as vascular endothelial growth factor (VEGF). In addition to modulating the tumor vasculature, anti-VEGF therapy has potential to improve T cell entry into tumor site and reduce immune suppression in the tumor microenvironment . Enhanced intra-tumoral T cell infiltration has also been observed with BRAF and MEK inhibitors . Similarly, inhibiting oncogenic pathways WNT/β-catenin and PI3K was shown to positively influence anti-tumor immune response . Collectively, these outcomes are anticipated to improve anti-PD-1 efficacy in combinatorial approaches with targeted therapy.2
Immunotherapy and chemotherapy
Chemotherapeutic agents are now being revisited in the context of cancer immunotherapy. Select conventional agents are thought to contribute to the cancer-immunity cycle by eliciting immunogenic tumor cell death and possibly eliminating immunosuppressor cell subsets from the tumor microenvironment . Combined with PD-1 pathway blockade, chemotherapy might prove advantageous for tumor antigen release and subsequent activation of cytotoxic T cells for successful tumor killing.
Immunotherapy and epigenetic targets
DNA methyltransferases (DNMT) and histone deacetylases (HDAC) play a major role in transcriptional regulation, silencing of Th1 immune response genes, and immune evasion. Inhibiting DNMT and HDAC results in a positive effect on anti-tumor immune response through multiple mechanisms. Important modulations include improved antigen processing and presentation by immune cells, and restored production of Th1-type cytokines required for T cell activation and trafficking . Combination of epigenetic therapies with immune checkpoint inhibitors therapy is likely to provide added clinical benefit to patients with cancer.
For any drug combination, selecting non-redundant mechanisms of action with a minimal toxicity profile remains vital to successful clinical study design. Ongoing trials in immuno-oncology might help contribute to finding which combination strategy provides the best outcome. Appreciation for biomarker-driven pairing of therapies associated with improved clinical benefit is gaining momentum. Mutational profiling and expression analysis of clinical cancer samples are fundamental in predictive biomarker analysis of response to single therapeutic agents and for guiding choice of combination modalities for every patient.
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