Progress and opportunities for enhancing the delivery and efficacy of checkpoint inhibitors for cancer immunotherapy

Abstract

Despite the advent of immune checkpoint blockade for effective treatment of advanced malignancies, only a minority of patients responds to therapy and significant immune-related adverse events remain to be minimized. Innovations in engineered drug delivery systems and controlled release strategies can improve drug accumulation at and retention within target cells and tissues in order to enhance therapeutic efficacy while simultaneously reducing drug exposure in off target tissues to minimize the potential for treatment-associated toxicities. This review will outline basic principles of the immune physiology of checkpoint signaling, the existing knowledge of dose-efficacy relationships in checkpoint inhibition, the influence of administration route on treatment efficacy, as well as the resulting checkpoint inhibitor antibody biodistribution profiles amongst target versus systemic tissues. It will also highlight recent successes in the application of drug delivery principles and technologies towards augmenting checkpoint blockade therapy in cancer. Delivery strategies that have been developed for other therapeutic and immunotherapy applications with as-of-yet underexplored potential in checkpoint inhibition therapy will also be discussed.

Keywords: Cancer immunotherapy; Controlled release; Cytotoxic T lymphocyte antigen-4; Drug delivery systems; Immune-related associated toxicity; Lymph node; Programmed cell death-1; Therapeutic antibody; Tumor immunology.

Figure 1

In the context of cancer, checkpoints are active within tumors and secondary lymphoid tissues. Left, Canonical and non-canonical checkpoint signaling in tumors and secondary lymphoid tissues. Right, Routes of drug administration and drug delivery systems that improve mAb delivery to target tissues with their relative advantages and limitations in conferring enhanced drug bioactivity and potential for toxicity. I.V., intravenous; I.T., intratumoral; S.C., subcutaneous; LN, lymph node. Green and purple syringe, mAb and lines roughly indicate distribution profiles resulting from i.v. and i.t. administration of mAb, respectively.

Figure 2

Checkpoint expression and checkpoint blockade mAb biodistribution in naïve and tumor bearing mice. (A) PET images of BALB/c mice implanted with CT26 tumors 48 hours post administration of radiolabeled anti-CTLA-4 mAb (top row) or radiolabeled control IgG (bottom row). Coronal view (a) and sagittal view (b) are shown. (B) ImmunoPET/CT sections using radiolabeled anti-PD-1 mAb 24 hours post injection in naïve wildtype mice (C57BL/6) (WT), PD-1 blocked (Blocked) and PD deficient mice (PD-1−/−). White ticks in the coronal sections indicate the position of the Transverse section. (C) Quantification of B in various organs. * indicates significance relative to the Block and/or PD-1−/− groups using one-way ANOVA with Tukey’s multiple comparison test. P-values < 0.05 considered significant. (D) 10 days following implantation of C57BL/6 mice with wildtype CD133-expressing B16F10 melanoma cells on the left and CD133-expressing, PD-L1 knockout B16F10 melanoma cells on the right, radiolabeled anti-PD-L1 mAb was administered. ImmunoPET/CT images 24 hours post injection are shown here (coronal, transverse, and sagittal). (D) Reproduced from REF 46 (A) and REF 51 (B–D) with permission.

Figure 3

Retention in skin is size dependent and remains relatively unchanged by tumor growth and progression. (A) Total exposure (AUC calculated from measured tissue concentrations) of tracers injected into naïve skin of C57Bl6 mice increases with increasing hydrodynamic size. * indicates significant for 5–12 vs 25, 50, and 500 nm tracers by one-way ANOVA and posthoc Fisher’s LSD tests. (B) Tracer retention and resulting exposure within the skin or melanoma site of injection is relatively unchanged by tumor growth. (C) Micro-computed tomography 3D reconstructions of the remodeling tumor blood vasculature in naïve skin and B16F10 melanomas. Day refers to day post B16F10 implant. Reproduced from REF 55 (B,C) and REF 56 (A) with permission.

Figure 4

Size-based principles of lymph node drug targeting are conserved in tumors. Time-resolved accumulation of tracers in draining lymph nodes (dLN) (A) and ratio of accumulating tracer concentrations within dLN to systemic tissues (B). * indicates significance relative to all other tracers at the same time point by two-way ANOVA and post-hoc Tukey’s tests. § indicates significance for 500 nm tracer relative to all other time points, ‡ for 50 nm tracer relative to all other time points, † for 30 nm tracer vs all other time points by one-way ANOVA and post-hoc Fisher’s LSD tests. One, two, three, and four symbols denoting statistical significance represent p < 0.05, 0.01, 0.001, and 0.0001, respectively. Tumor growth reduces tracer exposure within dLN (C) and increases systemic tracer accumulation in the spleen, lungs, and liver, and kidneys (D). C, *p<0.05 and **p<0.01 relative to all other tracers within same tumor day group by one-way ANOVA with post-hoc Fisher’s LSD test. D, *** indicates significance for 5 nm tracer at day 9 in kidney vs all other groups by two-way ANOVA and post-hoc Tukey’s tests. (E) Despite these distribution and transport changes resulting from tumor growth, the relative enrichment of 30 nm but not 5, 50, or 500 nm exposure within dLN relative to systemic tissues (AUC calculated from measured levels of concentrations of injected tracers in individual tissues 1–72 h p.i) seen in naïve skin is conserved. Reproduced from REF 55 with permission.