Progress and opportunities for enhancing the delivery and efficacy of checkpoint inhibitors for cancer immunotherapy☆,☆☆
Graphical abstract
Introduction
Immune checkpoint blockade with anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4, anti-programmed cell death (PD)-1, and anti-PD-ligand (PD-L) monoclonal antibody (mAb) drugs have emerged as a successful treatment approach that induces durable objective responses in patients with advanced melanoma, squamous cell lung cancer, renal cell carcinoma, and classical Hodgkin lymphoma due to role of these molecules in costimulatory signaling to T cells [1] that suppresses anti-tumor immunity in human cancers. However, despite clinical successes, objective tumor responses are achieved in only a minority of patients. Several complementary/overlapping tiers of immune regulation can contribute to anti-tumor immune suppression [2] that may limit treatment efficacy. Accordingly, biomarkers are in development to identify individuals most likely to benefit from checkpoint blockade [3], [4]. Furthermore, considerable preclinical and clinical research focuses on how the efficacy of checkpoint inhibition may be improved when used in combination with agents with orthogonal but synergistic signaling activity, for example targeted therapies [5], [6] and cancer vaccines [7], which expand the population of tumor antigen-specific lymphocytes. Significant immune-related adverse events (iRAE) and toxicities associated with treatment with checkpoint inhibitors when used alone or in combination (e.g. vemurafenib and ipimumab [8]) also remain to be minimized [9], [10], [11].
To this end, an emerging area of investigation aiming to augment checkpoint blockade therapy is the development of engineered delivery systems and controlled release innovations to improve mAb accumulation and retention within target cells and tissues in order to enhance immunotherapeutic efficacy and reduce off-target effects. This review will highlight such methods and their successes and, within the context of the basic principles of the immune physiology of checkpoint signaling, the known effects of delivered mAb dose and route of administration on treatment efficacy, as well as checkpoint inhibitor mAb biodistribution amongst target versus systemic tissues, delivery strategies that have been developed for other therapeutic applications with underexplored potential in checkpoint inhibition therapy.
Section snippets
Checkpoints and their tissues of action
CTLA-4 and PD-1 as well as their ligands exhibit discrete expression profiles, signaling pathways, and molecular mechanisms that underlie their physiological and pathophysiological roles [12], [13] (Fig. 1). CTLA-4 attenuates T cell responses largely by inhibiting co-stimulatory signaling through CD28. This is facilitated in part by its out-competing CD28 binding to CD80 and CD86 [14], molecule's whose expression is restricted to antigen presenting cells. Accordingly, CTLA-4′s suppression of
Dosing effects on checkpoint blockade efficacy and toxicity
The dosage of mAb administered is an important criterion that can greatly affect therapeutic response. Accordingly, clinical studies have established a dose-toxicity relationship for anti-CTLA-4 therapy indicating that higher doses lead to better response rates but with concurrent increases in iRAE. In a study with patients with advanced melanoma, anti-CTLA-4 mAb ipilimumab was administered at doses of 0.3, 3, or 10 mg/kg with the highest tested dose resulting in better overall response rates as
Biodistribution of non-specific and checkpoint inhibitor mAb
Given the established dose-response relationships for some checkpoint inhibitor mAb with respect to both therapeutic and side effects, mAb biodistribution profiles within target versus off-target tissues may critically influence their effects both locally in addition to distant tissues resulting from the abscopal effects intrinsic to immunotherapy (Fig. 1). When intravenously (i.v.) administered, IgG rapidly distributes throughout the body leading to accumulation primarily within blood-rich
Route of administration effects on the efficacy of checkpoint inhibition cancer therapy
The route of administration is another important parameter with potential to influence the effects of mAb therapy. Therapeutic mAb are administered i.v. clinically, however i.t., peri-tumoral (p.t.), and s.c. injection routes have been shown to improve mAb immunotherapy efficacy both by enhancing mAb delivery locally to the tumor as well as reducing systemic accumulation in preclinical models. For example, Fransen et al. showed that s.c. injection of anti-CTLA-4 mAb led to an effective
Drug delivery systems improving checkpoint blockade mAb delivery to target tissues
Due to iRAE and the requirement for repeated dosing in clinical checkpoint blockade therapeutic protocols, drug delivery platforms that improve mAb delivery to the tumor and achieve sustained release have garnered recent interest (Table 1). To this end, microparticle-based formulations aiming to prolong the retention of therapeutic agent at the site of injection have emerged as an attractive strategy since increasing carrier size enhances and prolongs retention at the site of injection [55],
Opportunities and potential strategies for improving checkpoint blockade cancer immunotherapy
Despite recent successes, enhancing checkpoint inhibitor mAb delivery to target tissues remains challenging. There are several excellent review papers that outline the challenges in mAb delivery to tumors that the reader is referred to [68], [69] with two prevailing schools of thought that will be highlighted. First, tumors undergo significant remodeling that results in high levels of variation in the composition of the tumor vasculature and interstitium. Specifically, the tumor is comprised of
Conclusions
Engineered drug delivery systems offer the significant advantages of enabling more finely tuned control of tissue and cell targeting as well as rate of therapeutic agent release within target tissues to improve the immunotherapeutic effects of checkpoint inhibitor mAb drugs. The success of such systems will likely be defined as either increasing the proportion of patients who respond to treatment or enhancing drug safety profiles, though ideally both. With checkpoint inhibition likely to be
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Immuno-engineering”.
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Financial support: This work was supported by National Institutes of Health (NIH) Grant R01CA207619, CCR15330478 grant from Susan G. Komen®, and Department of Defense Grant CA150523.