Small Molecule Modulation Strategy for Enhancing Memory T Lymphocyte Immune Responses
Cytotoxic T cells (T cells) are a type of immune cell that provide immunological protection by destroying cells that are perceived as abnormal. T cell exhaustion or inhibition is often observed in patients with chronic viral infections or cancer, resulting in a decreased ability of the patient to overcome such diseases. One strategy to enhance T cell responsiveness is to target inhibitory signaling pathways, such as the recently FDA approved PD-1 inhibitor pembrolizumab. This strategy has been shown to effectively reverse T cell exhaustion/inhibition and provides a tactic to boost patient resistance. In addition, studies have also shown that targeting T cell inhibitory pathways concurrent with vaccination may also enhance the efficacy of prophylactic vaccines, demonstrating several broad applications for T cell immunomodulators.
Description of Technology
Similar to that of PD-1, activation of CRACC receptors dampens T cell mediated immune responses. CRACC-Fc is a novel immunomodulator capable of enhancing T cell mediated immune responses by preventing inhibitory effects of CRACC activation on T cells. This inhibitory protein may be administered as a therapeutic to enhance T cell immune responses, or may be co-administered/co-expressed with an antigen to boost T cell responses for prophylactic vaccines. Preliminary studies have demonstrated that T cell proliferation and the production of antigen-specific cytokines are enhanced in CRACC-Fc treated mice, indicating an overall increase in T cell responsiveness. Although current work has been focused on the effects of the inhibitory protein on T cell responses, the CRACC receptor is expressed in multiple innate and adaptive immune cells (DCs, macrophages, NK cells, B cells) and it is possible that CRACC inhibition modulates the function of these immune cells as well, collectively resulting in enhanced immune response.
- Broad applications: This immunomodulator may be used in the treatment of a variety of diseases, or as a vaccine adjuvant
- Acceptable by the FDA: Several Fc fusion proteins are FDA approved therapeutics
- PD-1 synergy: CRACC and PD-1 feed into the same pathway with both dampening T cell immune responses upon activation. When both receptors are inhibited, an additive effect on T cell responsiveness is observed suggesting that co-administration may be used for further enhancement of T cell responses
- Translatable: Although current in vivo studies have been in mouse, Fc-CRACC protein was designed for use in human without further modification
- Cancer immunotherapy
- Treat T cell exhaustion
- Vaccine adjuvant
- Use in conjunction with other therapies to produce synergistic effects
Patent application published, publication number WO2016049022
Andrea Amalfitano, Yasser Aldhamen
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Michigan State University