Kang, Mansurov, et al. focused on combination IL-7/1L-12 strategies to enhance antitumor immunity without increasing irAEs. Using tumor matrix-binding forms of IL-7 and IL-12 (each conjugated to collagen-binding VWF domain 3), local or systemic treatment of IL-7/IL-12 was effective and synergistic in several poorly immunogenic murine models, without additional immunotoxicity, and was effective in eliminating metastases. IL-7/IL-12 also synergized with anti-PD-1 to suppress tumor growth and extend survival in PD-1 blockade-resistant models. Mechanistically, IL-12 stimulated CD8+ T cell effector function, and IL-7 prevented T cell exhaustion while boosting memory, as confirmed by tumor rechallenge.
Contributed by Katherine Turner
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.
Author Info: (1) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (2) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (3) Pr
Author Info: (1) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (2) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (3) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (4) Committee on Immunology, University of Chicago, Chicago, IL, USA. (5) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (6) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (7) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (8) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (9) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (10) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (11) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (12) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (13) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (14) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (15) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (16) Animal Resource Center, University of Chicago, Chicago, IL, USA. (17) Department of Bioengineering, Imperial College London, London, UK. (18) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. Committee on Immunology, University of Chicago, Chicago, IL, USA. Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA. Committee on Cancer Biology, University of Chicago, Chicago, IL, USA. (19) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. Committee on Immunology, University of Chicago, Chicago, IL, USA. Committee on Cancer Biology, University of Chicago, Chicago, IL, USA.
