Engineered IL-7 synergizes with IL-12 immunotherapy to prevent T cell exhaustion and promote memory without exacerbating toxicity

Abstract

Cancer immunotherapy is moving toward combination regimens with agents of complementary mechanisms of action to achieve more frequent and robust efficacy. However, compared with single-agent therapies, combination immunotherapies are associated with increased overall toxicity because the very same mechanisms also work in concert to enhance systemic inflammation and promote off-tumor toxicity. Therefore, rational design of combination regimens that achieve improved antitumor control without exacerbated toxicity is a main objective in combination immunotherapy. Here, we show that the combination of engineered, tumor matrix-binding interleukin-7 (IL-7) and IL-12 achieves remarkable anticancer effects by activating complementary pathways without inducing any additive immunotoxicity. Mechanistically, engineered IL-12 provided effector properties to T cells, while IL-7 prevented their exhaustion and boosted memory formation as assessed by tumor rechallenge experiments. The dual combination also rendered checkpoint inhibitor (CPI)–resistant genetically engineered melanoma model responsive to CPI. Thus, our approach provides a framework of evaluation of rationally designed combinations in immuno-oncology and yields a promising therapy.

Senescent T Cells in Age-Related Diseases

“…In contrast, in older adults, chromatin closure is observed in genes involved in the IL-7 signaling cascade, such as Janus kinase (JAK)1, JAK3, signal transducer and activator of transcription (STAT)5A, and STAT5B [78,79]. IL-7 is crucial in maintaining T cell expansion and homeostasis and is the most effective cytokine in increasing CD8 + T cell cytotoxicity [80][81][82]. Inhibition of the IL-7 signaling pathways might account for the reduced proliferation and immune responsiveness of CD8 + T cells in older adults [83].…”