Order of administration of combination cytokine therapies decouples toxicity from efficacy in syngeneic mouse tumor models 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 *Corresponding author
As combination immunotherapies emerge to harness multiple arms of the immune system against cancer, careful consideration must be given to designing treatment schedules that harmonize with the natural timing of the immune system. An efficacious combination therapy of extended half-life IL2 (eIL2), tumor targeting antibody, and staggered interferon alpha (IFNα) was recently shown to offer strong tumor control in several mouse models (Tzeng et al.). Despite the carefully timed elegance of this combination therapy, mice experienced significant toxicity and lost 10-20% of their body weight. In the current work, the order and timing of those three agents were shown to decouple both toxicity and efficacy. Delaying the administration of eIL2 to be concurrent with or after the staggered IFNα eliminated toxicity without affecting the efficacy in multiple syngeneic tumor models and mouse strains. The toxicity of administering eIL2 before IFNα was dependent on multiple systemic inflammatory cytokines including IL6, IL10, IFNγ, and TNFα. Natural killer (NK) cells were the main cellular source of toxicity and did not contribute to tumor control. When pre-conditioned with eIL2, splenic NK cells became hyper-activated and upregulated IFNα signaling proteins that caused an excessive and toxic response to subsequent IFNα exposure. This work shows that accounting for the temporal dynamics of the immune system in combination therapy treatment schedule design can decouple efficacy and toxicity of clinically approved cancer immunotherapies.
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 Reports. 2016, 17(10):2503-2511.
This material is based upon work supported by the NIH/NIGMS T32 GM008334, Interdepartmental Biotechnology Training Program.