Advanced Drug Delivery Reviews 114 (2017) 1–2
Contents lists available at ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Preface
Immuno-engineering: The Next Frontier in Therapeutics Delivery
A rapidly emerging field of research is the design of new therapeutic
strategies and synthetic and natural materials that modulate and con-
trol the immune response to treat a variety of disease conditions. Over
the past decade the focus of many bioengineers, pharmaceutical scien-
tists, and clinicians has been continuously shifting towards immuno-
engineering approaches that target immune cells and their intracellular
compartments in organs like skin, mucosal surfaces, and lymph nodes.
Approaches that simultaneously deliver multiple immune-modulatory
biomolecules that manipulate the extent of the humoral and cellular
immune responses. Approaches that develop engineered surrogate
immune-tissues to study immunobiology or discover new therapeutic
targets. Drug delivery systems have emerged as implantable or inject-
able materials for delivery of biological therapeutics that actively regu-
late the kinetics of multiple steps in the immune response. Newer
immuno-engineering approaches have focused on concepts of lymphat-
ic flow and lymphatic vessel permeability, design of biomimetic artifi-
cial antigen presenting cells, lymph node-targeted vaccine adjuvants,
structure-based programming of lymph-node, cells as immunothera-
peutic “drugs”, oral vaccines, immunotherapy and immune tolerance,
prolonged retention and release of therapeutics to reduce inflamma-
tion, and organoids and high-throughput drug/biologic screening sys-
tems that involve immune cells in surrounding of stem cells or
somatic cells used in regenerative medicine.
Against this backdrop, we present this themed collection of articles.
The hope is to reach a broad audience – not only pharmaceutical and
drug delivery scientists across many disciplines – but also clinicians
and immunologists. The collection primarily showcases state-of-the-
art and expert perspectives on immuno-engineering at the interface of
biomaterials, drug delivery, drug discovery, and biomanufacturing.
This collection provides a broad understanding of the emerging ther-
apeutic strategies to harness the patient’s own immune system and how
various biomaterials and drug delivery technologies interact with the
immune system to control and modulate that response. Collier and col-
leagues [1] describe approaches around a progression from single-
target strategies to those that engage increasingly complex and multi-
factorial immune responses. These approaches include targeting of spe-
cific individual cytokines, active immunotherapies, non-biological
complex drugs such as randomized polyamino acid copolymers for au-
toimmunity, and biologically derived matrices and materials for tissue
repair. Bellamkonda and colleagues [2] discuss current approaches
and critical barriers to immuno-engineering brain tumor therapies
and discuss possible solutions to these challenges. The review by Thom-
as et al [3] outlines immune physiology and dose-efficacy relationships
of checkpoint inhibition signaling, and role of administration route on
treatment efficacy. Along these lines, a review by Swartz and colleagues
[4] discusses the therapeutic approaches to exploit the lymphatic
http://dx.doi.org/10.1016/j.addr.2017.08.005
0169-409X/© 2017 Published by Elsevier B.V.
system for immunotherapy. The first section concludes with a critical
review by Jewell et al [5] on self-assembly of therapeutics to synthesize
materials with well-defined compositions and physical arrangement of
molecular building blocks, and their interaction with immune cells and
tissues.
While cancer immunotherapy is now widely recognized as a power-
ful clinical reality, with upcoming new drug approvals and clinical trials,
Irvine et al [6] describe how modulation of the immune system can be a
double-edged sword. They critically review mechanisms of toxicity for
clinically-relevant immunotherapeutics, and rational design of drug de-
livery technology towards safer immunotherapy. Green et all [7] re-
views strategies for surface engineering of biomolecules for proper
balance of physical, chemical, and biological interactions for lymphocyte
programming. A select few articles discuss alternative
immunomodulation strategies such as delivery routes and use of bacte-
rial outer membrane vesicles. Peppas et al [8] address the advantages
and challenges of engineering oral vaccines over traditional injection-
based formulations, and describe key biological and physicochemical
considerations for next-generation oral vaccines. Putnam and col-
leagues [9] describe new adjuvants that direct the immune response
in a more coordinated fashion. Specifically, they review the use the
outer membrane vesicles (OMVs) of bacteria for effective
immunomodulation. Lastly, Al Jamal et al [10] describe nanotechnology
based carriers for nitrogen-containing bisphosphonates as sensitizers of
γδ T cells for anticancer immunotherapy. Two review articles discuss
how single drug approaches are often incompletely effective, likely be-
cause of limited mechanistic understanding and disease heterogeneity.
Keselowsky et al [11] reviews recent advances in immunotherapy and
highlights newly explored combinatorial drug delivery approaches.
Tunnel et al [12] further describe immune checkpoint immunotherapy
combined with nanoparticle-assisted localized hyperthermia.
The themed collection further aims to synergize efforts in the field of
immuno-engineering across emerging strategies to harness innate and
adaptive responses to treat a variety of diseases. Along these lines,
Elisseeff et al [13] describe recent research on the role of multiple
arms of immune system in tissue repair and its potential relevance to
scaffold design. Liu et al [14] discuss engineered approaches for modu-
lating macrophage activity, targeting drugs to macrophages, and deliv-
ering macrophages as therapies. Pun et al review [15] aspects in
development and evaluation of tumor-associated macrophages
(TAMs) -targeted therapeutics in pre-clinical and clinical stages for
immunomodulating in tumor microenvironment.
In recent years, the concept of “therapeutics” has broadened from
small molecule drugs to protein biologics and now into living patient-
or donor-derived cells. Roy and colleagues [16] describe how immune
cell-based therapies, e.g. T cell, dendritic cell or mesenchymal stromal
2 Preface
cell based therapies have emerged as transformative strategies to treat
chronic and often incurable diseases. They highlight how, for cell-
based therapies to be successful, innovation is critically needed in engi-
neering technologies that enable cost-effective, consistent manufactur-
ing of high-quality therapeutic cells at large-scale.
Innovations in drug delivery and biomaterials-based technologies
that induce antigen-specific immune tolerance have the potential to
revolutionize the treatment of autoimmunity, allograft rejection, and al-
lergy. Select reviews from this issue further focus on immune tolerance
and immunomodulation for successful engraftment. In a very interest-
ing article, Shea and colleagues [17] describe natural mechanisms of in-
ducing peripheral tolerance and review technological advances in
inducing antigen-specific immune tolerance in vivo. To further bridge
the fields of type 1 diabetes immunology and biomaterials engineering,
a review by three experts Phelps, Hubbell, and Baekkeskov [18] dis-
cusses recent trends in the etiology of type 1 diabetes immunopatholo-
gy and emerging bioengineered strategies in the fight against beta cell
autoimmunity in type 1 diabetes. Garcia et al [19] further describe
emerging synthetic biomaterials as immunomodulatory platforms that
provide excellent control over material properties, molecule presenta-
tion, and therapeutic release to facilitate islet transplantation. Lastly,
De Vlaminck and colleagues [20] review recent and rapid advances in
precision and genomic medicine approaches to monitor immunother-
apies post-transplant. This particular review highlights precision mea-
surements of pharmacological immune-suppression, plasma and gut
microbiome; monitoring of allograft injury and post-transplant malig-
nancies and measurements of the B and T cell immune cell repertoire.
Lastly, the themed collection explores malignancies of B and T cells,
that arise due to aberrant mutations or during the process of mounting
an immune response. This review by Stephenson and Singh [21] aims to
summarize advances in targeting lymphoma, leukemia, and myeloma
and emphasize new therapy and drug delivery technology development
in the areas of antibody engineering, epigenetic small molecule
inhibiting drugs, vaccine development, and chimeric antigen receptor
cell engineering. The review further describes the need for emerging tis-
sue engineered constructs for tumors of B and T cell origin for targeted
drug discovery.
It has been a pleasure and an honor to put this themed issue togeth-
er. Many thanks to all the authors and to the Elsevier team for their gen-
erous time. We believe that this collection of reviews serves not only as
a testimony to the enormous promise of immune-based therapeutics
but also as a foundation for understanding the challenges and barriers
for making these therapies a clinical reality. It is that goal of helping pa-
tients that brings this community together. It is our sincere hope that
the next generation of drug delivery scientists will find inspiration
from this collection and working closely with clinicians and immunolo-
gist, contribute transformative new ideas to further advance this field.
References
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Ankur Singh
Sibley School of Mechanical and Aerospace Engineering, Cornell University,
Ithaca, NY 14853, USA
Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY
14853, USA
E-mail address: as2833@cornell.edu
Krishnendu Roy
Wallace H. Coulter Department of Biomedical Engineering, Georgia Insti-
tute of Technology, Atlanta, GA 30332, USA
Marcus Center for Therapeutic Cell Characterization and Manufacturing,
Georgia Institute of Technology, Atlanta, GA 30332, USA
Center for ImmunoEngineering, Georgia Institute of Technology, Atlanta, GA
30332, USA
E-mail address: krish.roy@gatech.edu