Maximizing response to intratumoral immunotherapy in mice by tuning local retention

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.

A cell membrane-targeting AIE photosensitizer as a necroptosis inducer for boosting cancer theranostics

“…These results demonstrate that the intratumor injection of TBMPEI dots showed an ultra-long retention time in the tumor region, and the dots may be slowly metabolized through the liver and kidney. 58 …”

Proactive Immunotherapeutic Approaches against Inflammatory Breast Cancer May Improve Patient Outcomes

“…Although IL-2 and IL-12, which expand and stimulate T cells and natural killer (NK) cells to mediate antitumor immunity, have demonstrated promising therapeutic effects, their clinical use is limited by severe systemic adverse effects [ 59 ]. The Wittrup group has developed IL-2 and IL-12 cytokine fusion proteins anchored to collagen, which is abundantly and ubiquitously expressed in tumors, and tagged the cytokines with canine serum albumin to increase the molecular weight of the proteins in order to prolong their intratumoral retention and effectively eliminate toxic systemic exposure [ 60 , 61 ]. This smart design demonstrated high activity and tolerability in large canine soft tissue sarcoma (STS) and canine oral melanoma (OM) patients [ 55 ].…”

Reprogramming brain immunosurveillance with engineered cytokines

“…[18][19][20][21] In rodent models of peripheral cancers, cytokines fused to substrates with high residence times in tumors have been shown to trigger immune infiltration and activation while eliminating toxicity associated with systemic administration. 20,22,23 However, in contrast to the periphery, the ability of engineered cytokines to be retained in the brain and reprogram neuroinflammation is unknown given the putative immuneprivileged status of this organ. Here, we test the hypothesis that extending the residence time of cytokines in the brain can similarly enhance immune rejection of established brain tumors and demonstrate anchored cytokines as a promising platform for neuroimmune engineering.…”

“…Our model adopts features from recent brain transport simulations 24 into a proton mass transport model we recently reported. 25 To capture the consequences of molecular weight on protein permeability, we rescaled a permeability model recently used to study protein transport in and out of flank tumors 23,[26][27][28] The model predicts that lumican, which binds to collagen IV, fused to a cytokine of interest (IL-2 chosen as an example) increases its residence time in the brain compared to IL-2 alone or mouse serum albumin (MSA) fused to IL-2 (MSA-IL-2) (Fig. 1b).…”

“…Our model adopts features from recent brain transport simulations 24 into a proton mass transport model we recently reported. 25 To capture the consequences of molecular weight on protein permeability, we rescaled a permeability model recently used to study protein transport in and out of flank tumors 23,26–28…”