Temporal Programming of Immunomodulatory Agents to Optimize Efficacy and Lower Toxicity of the Anti-Cancer Immune Response
Adrienne Rothschilds1,2, Alice Tzeng1-2, Naveen Mehta1-2, Kelly Moynihan1-3, Darrell J. Irvine1-5, K. Dane Wittrup1,2,6,*
1Dept. of Biological Engineering, MIT, 2Koch Institute for Integrative Cancer Research, 3Ragon Institute of Massachusetts General Hospital, 4Dept. of Materials Science and Engineering, MIT, 5Howard Hughes Medical Institute, 6Dept. of Chemical Engineering, MIT, Cambridge, MA
As combination immunotherapies emerge to harness multiple arms of the immune system against cancer, careful consideration must be taken to design treatment schedules that dose each agent at the right times to balance efficacy and toxicity. To investigate treatment schedule timing and improve survival rates of a synergistic anti-cancer combination therapy (1), the clinically approved immuno-stimulatory cytokine interferon alpha (IFNα) was added to the extended half-life (eIL2) and tumor-specific antibody treatment in syngeneic mouse tumor models. The triple combination therapy’s efficacy was improved by staggering IFNα (2). Resulting toxicity was abrogated without affecting therapeutic efficacy by dosing eIL2 at the same time or after the delayed IFNα. Natural killer cells and inflammatory cytokines including IL-6, IL-10, IFNγ, and TNFα were responsible for the significant weight loss toxicity associated with staggering eIL2 and IFNα.
(1) Zhu EF, Gai SA, Opel CF, Kwan BH, Surana R, Mihm MC, Kauke MJ, Moynihan KD, Angelini A, Williams RT, Stephan MT, Kim JS, Yaffe MB, Irvine DJ, Weiner LM, Dranoff G, Wittrup KD. Synergistic innate and adaptive immune response to combination immunotherapy with anti-tumor antigen antibodies and extended serum half-life IL-2. Cancer Cell. 2015, 27(4):489-501.
(2) Tzeng A, Kauke MJ, Zhu EF, Moynihan KD, Opel CF, Yang NJ, Mehta N, Kelly RL, Szeto GL, Overwijk WW, Irvine DJ, Wittrup KD. Temporally Programmed CD8α+ DC Activation Enhances Combination Cancer Immunotherapy. Cell Rep. 2016, 17(10):2503-2511.
This material is based upon work supported by the NIH/NIGMS T32 GM008334, Interdepartmental Biotechnology Training Program.
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