The discovery of mechanisms by which the cancer cells avoid the host immune attack (immune checkpoints) as well the capability of the monoclonal antibodies (mAbs) to blockade the checkpoint proteins on cancer and tumor-infiltrating cells (CTLA-4, PD-1, and PD-L1) promised new breakthroughs in the cure of cancer. After these mechanisms of cancer escaping the host immunity were undoubtedly confirmed in numerous experimental and clinical studies, the FDA approval of CTLA-4 and PD-1/PD-L1 mAbs for systemic treatment thought to revolutionize the outcome of cancer treatment. However, as of today, the anticipated curative effect of anti-CTLA-4 and PD-1/PD-L1 mAb treatments has been observed only in a small population of patients. In addition, systemic administration of mAbs in clinics has been found associated with new toxicity profiles, sometimes very severe. The main obstacle that hinders the mAbs therapy appears to be the inability of delivering mAbs to a sufficient number of cancer cells and tumor infiltrating cells. As an alternative to the systemic administration (or as a complement to it), local intratumoral delivery of mAbs has been anticipated to resolve that issue. However, unlike the systemic mAbs administration, for which formidable but surmountable obstacles (big size of mAbs ~150 kD, high interstitial fluid pressure in solid tumors, etc.) have been known to hamper mAbs delivery to cancer and tumor-infiltrating cells, the lack of effects of intratumoral mAbs administration remains completely incomprehensible and needs a new theoretical reconsideration that we have attempted in our analysis. It can be suggested that the limited benefits of the intratumoral mAbs administration appeared to be rooted in the same problem that hindered the effects of systemic mAbs administration: the inability to reach a sufficient number of cancer cells and tumor-infiltrating cells. We hypothesize that the core of the problem stems from the fact that the single-needle intratumoral injection forms a very localized, jet-like distribution of the drug (mAbs) that constitutes only a small fraction of the total volume of the tumor. In this light we are re-evaluating the theoretical reasonableness of the single-needle intratumoral injection approach. We propose that multi-needle injection will circumvent this limitation and for that we analyze the behavior of an injectant in tissues using different configurations of the injection needles. To accomplish this goal, we created a model of injectant distribution in a solid tissue based on the traditional technique of single-needle injection and then extended that model to a case of simultaneous multi-needle injection. To develop the model of drug delivery and transport in biological tissues, we followed a frequently used approach of modeling the diffusive transport of liquid through a porous media using the Darcy's law that relates the flow velocity, the pressure gradient, and the tissue permeability. The analysis demonstrates that a multi-needle injection setup provides a significantly more widespread and homogeneous injectant distribution within a solid tumor than that for a single needle injection for the same tumor size. Adding separate draining needles can further improve the delivery of injectant to cancer and tumor-infiltrating cells.
Keywords: Cancer; checkpoint inhibition; immunotherapy; intratumoral injection; liquid transport; mAbs; solid tumor.
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