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

https://doi.org/10.1016/j.addr.2017.04.011Get rights and content

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.

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

References (105)

  • S. Rahimian et al.

    Polymeric microparticles for sustained and local delivery of antiCD40 and antiCTLA-4 in immunotherapy of cancer

    Biomaterials

    (2015)
  • V.B. Lokeshwar et al.

    Hyaluronidase: Both a tumor promotor and suppressor

    Semin. Cancer Biol.

    (2008)
  • G.F. Nash et al.

    Platelets and cancer

    Lancet Oncol.

    (2002)
  • C. Wang et al.

    In situ activation of platelets with checkpoint inhibitors for post-surgical cancer immunotherapy

    Nat. Biomed. Eng.

    (2017)
  • G.M. Thurber et al.

    Antibody tumor penetration: transport opposed by systemic and antigen-mediated clearance

    Adv. Drug Deliv. Rev.

    (2008)
  • E.R. Pereira et al.

    The lymph node microenvironment and its role in the progression of metastatic cancer

    Semin. Cell Dev. Biol.

    (2015)
  • S.N. Thomas et al.

    Overcoming transport barriers for interstitial-, lymphatic-, and lymph node-targeted drug delivery

    Curr. Opin. Chem. Eng.

    (2015)
  • C. Oussoren et al.

    Lymphatic uptake and biodistribution of liposomes after subcutaneous injection. II. Influence of liposomal size, lipid composition and lipid dose

    Biochim. Biophys. Acta Biomembr.

    (1997)
  • M.A. Swartz

    The physiology of the lymphatic system

    Adv. Drug Deliv. Rev.

    (2001)
  • L.M. Kaminskas et al.

    PEGylation of polylysine dendrimers improves absorption and lymphatic targeting following SC administration in rats

    J. Control. Release

    (2009)
  • G.M. Ryan et al.

    PEGylated polylysine dendrimers increase lymphatic exposure to doxorubicin when compared to PEGylated liposomal and solution formulations of doxorubicin

    J. Control. Release

    (2013)
  • F. Shima et al.

    Size effect of amphiphilic poly(??-glutamic acid) nanoparticles on cellular uptake and maturation of dendritic cells in vivo

    Acta Biomater.

    (2013)
  • P.A. Ott et al.

    CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients

    Clin. Cancer Res.

    (2013)
  • S.L. Topalian et al.

    Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy

    Nat. Rev. Cancer

    (2016)
  • W.J. Lesterhuis et al.

    Dynamic versus static biomarkers in cancer immune checkpoint blockade: unravelling complexity

    Nat. Rev. Drug Discov.

    (2017)
  • D.J. Hermel et al.

    Combining forces: the promise and peril of synergistic immune checkpoint blockade and targeted therapy in metastatic melanoma

    Cancer Metastasis Rev.

    (2017)
  • A. Ribas et al.

    Hepatotoxicity with combination of vemurafenib and ipilimumab

    N. Engl. J. Med.

    (2013)
  • J.S. Weber et al.

    Management of immune-related adverse events and kinetics of response with ipilimumab

    J. Clin. Oncol.

    (2012)
  • S.L. Topalian et al.

    Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab

    J. Clin. Oncol.

    (2014)
  • G.Q. Phan et al.

    Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma

    Proc. Natl. Acad. Sci. U. S. A.

    (2003)
  • S.L. Topalian et al.

    Immune checkpoint blockade: a common denominator approach to cancer therapy

    Cancer Cell

    (2015)
  • S. Hu-Lieskovan et al.

    Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma

    Sci. Transl. Med.

    (2015)
  • G.J. Randolph et al.

    Dendritic-cell trafficking to lymph nodes through lymphatic vessels

    Nat. Rev. Immunol.

    (2005)
  • S.N. Thomas et al.

    Impaired humoral immunity and tolerance in K14-VEGFR-3-Ig mice that lack dermal lymphatic drainage

    J. Immunol.

    (2012)
  • S.N. Thomas et al.

    Implications of lymphatic transport to lymph nodes in immunity and immunotherapy

    Annu. Rev. Biomed. Eng.

    (2016)
  • C.B. Jago et al.

    Differential expression of CTLA-4 among T cell subsets

    Clin. Exp. Immunol.

    (2004)
  • D.V. Chan et al.

    Differential CTLA-4 expression in human CD4 + versus CD8 + T cells is associated with increased NFAT1 and inhibition of CD4 + proliferation

    Genes Immun.

    (2014)
  • K. Wing et al.

    CTLA-4 control over Foxp3 + regulatory T cell function

    Science (80-)

    (2008)
  • K.S. Peggs et al.

    Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies

    J. Exp. Med.

    (2009)
  • S. Spranger et al.

    Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells

    Sci. Transl. Med.

    (2013)
  • G. Thangavelu et al.

    Control of in vivo collateral damage generated by T cell immunity

    J. Immunol.

    (2013)
  • K.S. Sfanos et al.

    Human prostate-infiltrating CD8 + T lymphocytes are oligoclonal and PD-1 +

    Prostate

    (2009)
  • M.E. Keir et al.

    PD-1 and its ligands in tolerance and immunity

    Annu. Rev. Immunol.

    (2008)
  • H. Dong et al.

    Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion

    Nat. Med.

    (2002)
  • M.V. Goldberg et al.

    Role of PD-1 and its ligand , B7-H1 , in early fate decisions of CD8 T cells role of PD-1 and its ligand , B7-H1 , in early fate decisions of CD8 T cells

    Blood

    (2014)
  • S.J. Im et al.

    Defining CD8 + T cells that provide the proliferative burst after PD-1 therapy

    Nature

    (2016)
  • S.A. Quezada et al.

    CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells

    J. Clin. Invest.

    (2006)
  • B. Kavanagh et al.

    CTLA4 blockade expands FoxP3 + regulatory and activated effector CD4 + T cells in a dose-dependant fashion CTLA4 blockade expands FoxP3 + regulatory and activated effector CD4 + T cells in a dose-dependant fashion

    Online

    (2008)
  • J.R. Brahmer et al.

    Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates

    J. Clin. Oncol.

    (2010)
  • O. Hamid et al.

    Supplementary - safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma

    N. Engl. J. Med.

    (2013)
  • Cited by (0)

    This review is part of the Advanced Drug Delivery Reviews theme issue on “Immuno-engineering”.

    ☆☆

    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.

    View full text