Novel immune checkpoints for cancer immunotherapy with tumor infiltrating lymphocytes
Unmet Need
Adoptive cell therapy (ACT), or cellular immunotherapy, uses immune cells to combat cancer. Since 2017, CAR-T therapies have been rapidly adopted for hematological malignancies. However, for treating solid tumors, which account for 90% of adult cases, TIL therapy is emerging as the most promising due to its broad antigen recognition and lower complexity. In TIL therapy, tumor-recognizing immune cells are harvested, cultured in vitro, and reintroduced to the patient. The efficacy of this approach hinges on the in vitro expansion of cytotoxic lymphocytes, particularly CD8+ T cells, highlighting the need for methods to enhance their proliferation and activation during TIL expansion for optimal therapeutic outcomes.
Technology
Duke inventors have developed a method to stimulate the proliferation and activation of CD8+ T cells by targeting a novel immune checkpoint, specifically the complement-IL-10 pathway. This approach is intended for use in treating various cancers, including solid tumors, lymphoma, leukemia, and myeloma. While IL-10 typically inhibits most immune cells, it uniquely activates CD8+ T cells. Normally, CD8+ T cells remain inactive because they produce complement, which inhibits IL-10. By inhibiting complement signaling or exposing CD8+ T cells to IL-10, these cells can be activated. This has been demonstrated in patient-derived tumor explants and mouse models, showing increased proliferation and tumor-killing ability of CD8+ T cells. Additionally, combining this method with PD1-PDL1 pathway blockade has shown synergistic antitumor effects.
Other Applications
This technology could also be applied as a combination therapy with various other cancer treatments including complement inhibitors, chemotherapy agents, kinase inhibitors, immune checkpoint inhibitors, and monoclonal antibodies. Additionally, in vivo activation of CD8+ T cells by IL-10 can be accomplished using fusion proteins.
Advantages
- Synergizes with existing cancer treatments
- Complement inhibition produces IL-10 at the tumor site, avoiding toxic effects of systemic IL-10 administration.
- Optimal cellular immunotherapy for treating solid tumors
- Increases CD8+ cell proliferation, effectiveness, and tumor killing ability