Intratumorally anchored cytokine therapy

ABSTRACT

Introduction

On-target, off-tumor toxicity severely limits systemic dosing of cytokines and agonist antibodies for cancer. Intratumoral administration is increasingly being explored to mitigate this problem. Full exploitation of this mode of administration must include a mechanism for sustained retention of the drug; otherwise, rapid diffusion out of the tumor eliminates any advantage.

Areas covered

We focus here on strategies for anchoring immune agonists in accessible formats. Such anchoring may utilize extracellular matrix components, cell surface receptor targets, or exogenously administered particulate materials. Promising alternative strategies not reviewed here include slow release from the interior of a material depot, expression following local transfection, and conditional proteolytic activation of masked molecules.

Expert opinion

An effective mechanism for tissue retention is a critical component of intratumorally anchored cytokine therapy, as leakage leads to decreased tumor drug exposure and increased systemic toxicity. Matching variable drug release kinetics with receptor-mediated cellular uptake is an intrinsic requirement for the alternative strategies mentioned above. Bioavailability of an anchored form of the administered drug is key to obviating this balancing act.

KEYWORDS:

• Cancer immunotherapy
• cytokines
• agonists
• intratumoral
• anchoring

Article highlights

• Intratumoral administration is increasingly being explored to overcome poor therapeutic indices with immune agonist drugs for cancer.

• In the absence of a retention mechanism, localization of protein drugs is rapidly lost.

• Anchored, bioavailable cytokines solve the problem of matching local drug supply with cellular demand.

• Agonists have been bioavailability anchored to extracellular matrix, biomaterials, or cell surfaces.

• Systemic adaptive immune responses to intratumoral agonists have been observed preclinically and in humans.

• Tumor anchored cytokines are a critical tool for rational spatiotemporally programmed immunotherapy.

Declaration of interest

KD Wittrup & DJ Irvine are inventors on patent applications filed by the Massachusetts Institute of Technology in the areas described in this review. HL Kaufman and MM Schmidt are employees of Ankyra Therapeutics, which has licensed MIT IP on alum-anchored cytokines, and is clinically translating this technology. KD Wittrup, DJ Irvine, HL Kaufman, and MM Schmidt hold equity in Ankyra Therapeutics. DJ Irvine is an Investigator of the Howard Hughes Medical Institutes. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the National Cancer Institute 5R01CA174795 (to KDW), the National Institute of Biomedical Imaging and Bioengineering Grant 1R01EB031082 (to DJ Irvine and KD Wittrup).