Intratumoral injection and retention hold promise to improve cytokine therapies for cancer

Abstract

As powerful activators of the immune system, cytokines have been extensively explored for treating various cancers. But despite encouraging advances and some drug approvals, the broad adoption of cytokine therapies in the clinic has been limited by low response rates and sometimes severe toxicities. This in part reflects an inefficient biodistribution to tumors or a pleiotropic action on bystander cells and tissues. Here, we first review these issues and then argue for the intratumoral delivery of engineered cytokine fusion proteins that have been optimized for tumor retention as a potential solution to overcome these limitations and realize the potential of cytokines as highly effective therapeutics for cancer.

Keywords: CLN-617; IL-12; IL-2; cancer; collagen; cytokine; immunotherapy; intratumoral.

Figure 1

Cytokine modalities for i.t. administration include free or lipid nanoparticle-loaded DNAs or RNAs encoding cytokines (A), cytokine expressing OV or other viruses (B), and cells engineered to express exogenous cytokines (C). Additional modalities engineered for cytokine stabilization and retention at sites of injection include immuno-cytokines containing both cytokines and tumor antigen-binding moieties (typically an antibody, D), cytokine fusions with tumor matrix/collagen-binding domains such as LAIR2 (E) or with bulky domains such as human serum albumin (HSA, F) or multi-functional fusions of several cytokines with both collagen-binding and bulky domains (G, ref. 43), liposomes or exosomes “presenting” cytokines on their surface (H) and cytokines anchored to exogenous biomaterial deposits in tumors (I, shown is a cytokine fused to a phosphorylated alum-binding peptide [ABP] whose phosphate residues [P] undergo ligand-exchange reactions with alum deposits (49)). For details, see text. Created with BioRender.com.