Maximizing response to intratumoral immunotherapy in mice by tuning local retention

Noor Momin, Joseph R. Palmeri, Emi A. Lutz, Noor Jailkhani, Howard Mak, Anthony Tabet, Magnolia M. Chinn, Byong H. Kang, Virginia Spanoudaki, Richard O. Hynes and K. Dane Wittrup ()
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Noor Momin: Massachusetts Institute of Technology
Joseph R. Palmeri: Massachusetts Institute of Technology
Emi A. Lutz: Massachusetts Institute of Technology
Noor Jailkhani: Massachusetts Institute of Technology
Howard Mak: Massachusetts Institute of Technology
Anthony Tabet: Massachusetts Institute of Technology
Magnolia M. Chinn: Massachusetts Institute of Technology
Byong H. Kang: Massachusetts Institute of Technology
Virginia Spanoudaki: Massachusetts Institute of Technology
Richard O. Hynes: Massachusetts Institute of Technology
K. Dane Wittrup: Massachusetts Institute of Technology

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Direct injection of therapies into tumors has emerged as an administration route capable of achieving high local drug exposure and strong anti-tumor response. A diverse array of immune agonists ranging in size and target are under development as local immunotherapies. However, due to the relatively recent adoption of intratumoral administration, the pharmacokinetics of locally-injected biologics remains poorly defined, limiting rational design of tumor-localized immunotherapies. Here we define a pharmacokinetic framework for biologics injected intratumorally that can predict tumor exposure and effectiveness. We find empirically and computationally that extending the tumor exposure of locally-injected interleukin-2 by increasing molecular size and/or improving matrix-targeting affinity improves therapeutic efficacy in mice. By tracking the distribution of intratumorally-injected proteins using positron emission tomography, we observe size-dependent enhancement in tumor exposure occurs by slowing the rate of diffusive escape from the tumor and by increasing partitioning to an apparent viscous region of the tumor. In elucidating how molecular weight and matrix binding interplay to determine tumor exposure, our model can aid in the design of intratumoral therapies to exert maximal therapeutic effect.

Date: 2022
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DOI: 10.1038/s41467-021-27390-6

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