Induction of Tumor-Eradicating Systemic Immunity via Leukocyte-Targeted Cytokine Therapy

ASPIRE Award (2023-Present)

Darrell Irvine, PhD; Dane Wittrup, PhD, Massachusetts Institute of Technology

Darrell Irvine, PhD

The immune response is a complex process which is mediated by a large number of soluble, protein-based cell signaling molecules called cytokines and their receptors. Harnessing the power of cytokines to improve antitumor immunity has been a long-sought goal in the clinic with some limited success so far. One of the major hurdles to this approach is that systemic administration of many of these cytokines causes severe toxicity. Harnessing the power of these cytokines without these side effects is therefore a major goal of research.

Previously, Darrell Irvine and Dane Wittrup discovered that antibodies to the universal lymphocyte marker CD45 can be used to stably tether therapeutic cytokines to the surfaces of immune cells, enabling their sustained stimulation. When directly injected into tumors, these antibody-cytokine fusion molecules attach to lymphocytes in the tumor and lymph nodes, triggering a T cell response that exhibits robust efficacy in both the treated tumors and distant untreated lesions in mouse models of cancer. Importantly, these molecules do not enter the systemic circulation, alleviating concerns about overall toxicity. Building on these promising preliminary findings, the researchers aim to investigate the mechanisms of action underlying this lymphocyte-targeted cytokine therapy and optimize its effectiveness in murine models of metastatic disease. The well-established field of antibody engineering offers a clear pathway for translating these preclinical studies into clinical applications.