This invention is a method of depleting or over-expressing the transcription factor, interferon regulatory factor 4 (IRF4), in T cells as therapeutic strategy for conditions which are highly regulated by the immune system. The inventors have established that IRF4 represses PD-1, Helios, and other molecules associated with T cell function, representing a novel role for IRF4 in dictating effector T cell fate decisions. In one example, ablation of IRF4 drives T cell dysfunction and represents a potential therapeutic strategy for the treatment of T cell-mediated transplant rejection and autoimmune disorders. Alternatively, over-expression of IRF4 in therapeutic T cells suppresses cancer growth by promoting tumor infiltration and effector function of both therapeutic and endogenous anti-tumor T cells.
Stage of Development
In vitro data: Microarray and ChIP analysis revealed that IRF4 was capable of repressing a set of molecules associated with T cell dysfunction, including but not limited to Helios and PD-1. Over-expression of IRF4 in cancer studies was achieved using retroviral transduction and validated by flow cytometry. Additional studies to alternatively over-express IRF4 in T cells and define the mechanisms of IRF-engineered T cells are underway.
In vivo data: Mouse studies demonstrated that heart allografts were able to survive indefinitely in genetically-engineered IRF4 depleted mice which were not treated with any immunosuppressive therapies. Pharmaceutical inhibition of IRF4, using trametinib, also prolonged allograft survival and was able to abolish experimental autoimmune encephalomyelitis development, suggesting the potential of IRF4 as a therapeutic target for autoimmune diseases. In cancer models, adoptive transfer of IRF4-expressing T cells inhibited melanoma tumor growth in mice. Furthermore, IRF4-engineered T cell therapy in combination with PD-L1 blockade exhibited potent antitumor efficacy compared to PD-L1 blockade alone, suggesting a highly efficacious combination therapy.
Competitive Landscape - Transplant Acceptance/Autoimmune Disease
Prior methods to ameliorate transplant rejection by the recipient’s immune system or treat autoimmune diseases include use of immunosuppressant therapeutics. Unfortunately, immunosuppressants often lead to an increased risk of serious infection and malignancy because the recipient’s immune system is suppressed from forming effective responses to invading pathogens and cancer. The enclosed therapeutic strategy addresses these limitations by directly modulating alloimmune and autoimmune responses.
Competitive Landscape - Cancer Suppression
Currently, the most potent immunotherapies for solid tumors are immune checkpoint blockades, such as antibodies against PD-1/PD-L1 or CTLA-4. Unfortunately, these immunotherapies only partially and transiently reverse the "dysfunction" of tumor-reactive T cells and are only effective in 20-30% of cancer patients. A major factor driving the resistance to immune checkpoint inhibitors is the lack or paucity of tumor T cell infiltration. The disclosed therapeutic approach addresses this limitation by directly modulating the functional impairment through the expression of IRF4.
Competitive Advantages - Transplant Acceptance/Autoimmune Disease
• Reduced risk of infections and malignancies
• Increased transplant acceptance
• Improved symptoms related to autoimmune disorders
• Increased survival
Competitive Advantages - Cancer Suppression
• Improved overall outcomes alone or in combination with other anti-cancer therapies
• Enhance the patient’s own immunity
• Reduced tumor growth/progression
• Decreased doses of toxic chemotherapy when used as a combination therapy
