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Contributors
Natalie Artzi
Department of Medicine, Division of Engineering in Medicine, Brigham and Women’s Hospital,
Harvard Medical School, Boston; Institute for Medical Engineering and Science, Massachusetts
Institute of Technology, Cambridge, MA, United States
Sidi A. Bencherif
Department of Chemical Engineering, Northeastern University, Boston; Harvard John
A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge;
Department of Bioengineering, Northeastern University, Boston, MA, United States; Sorbonne
University, UTC CNRS UMR 7338, Biomechanics and Bioengineering (BMBI), University of
Technology of Compie`gne, Compie`gne, France
Rachel Berryman
Department of Dermatology, Oregon Health & Science University (OHSU), Portland, OR,
United States
Khushbu Bhatt
Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, United States
Aoife M. Brennan
Synlogic Operating Company, Inc., Cambridge, MA, United States
Sue Anne Chew
University of Texas Rio Grande Valley, Brownsville, TX, United States
Alexander M. Cryer
Department of Medicine, Division of Engineering in Medicine, Brigham and Women’s Hospital,
Harvard Medical School, Boston; Institute for Medical Engineering and Science, Massachusetts
Institute of Technology, Cambridge, MA, United States
Serena Danti
Scuola Superiore Sant’Anna, Pisa, Italy; Massachusetts Institute of Technology, Cambridge, MA,
United States; University of Pisa, Pisa, Italy
Nicholas DePatie
Department of Dermatology, Oregon Health & Science University (OHSU), Portland, OR,
United States
Sashana Dixon
Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University,
Fort Lauderdale, FL, United States
Loek J. Eggermont
Department of Chemical Engineering, Northeastern University, Boston, MA, United States
Samantha C. Emery
Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL, United
States
xiii
xiv Contributors
Reilly Fankhauser
Department of Dermatology, Oregon Health & Science University (OHSU), Portland, OR,
United States
Kristin Huntoon
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston,
TX, United States
Vincent M. Isabella
Synlogic Operating Company, Inc., Cambridge, MA, United States
Wen Jiang
Department of Radiation Oncology, The University of Texas Southwestern Medical Center,
Dallas, TX, United States
Emily M. Jordan
University of Texas Rio Grande Valley, Brownsville, TX, United States
Betty Y.S. Kim
Department of Neurosurgery; Department of Experimental Radiation Oncology, The
University of Texas MD Anderson Cancer Center, Houston, TX, United States
Stephen J. Kron
Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL,
United States
Rajan P. Kulkarni
Department of Dermatology, Oregon Health & Science University (OHSU); Oregon Health &
Science University, Knight Cancer Institute; Cancer Early Detection Advanced Research Center
(CEDAR), Knight Cancer Institute (KCI); Operative Care Division, Department of Veterans
Affairs Portland Health Care System, Portland, OR, United States
Amrendra Kumar
Department of Pathology; The Arthur G. James Cancer Hospital and Richard J. Solove Research
Institute, The Ohio State University, Columbus, OH, United States
DaeYong Lee
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston,
TX, United States
Steve Seung-Young Lee
Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL, United
States
Ning Li
Synlogic Operating Company, Inc., Cambridge, MA, United States
Olivia M. Lucero
Department of Dermatology, Oregon Health & Science University (OHSU); Oregon Health &
Science University, Knight Cancer Institute, Portland, OR, United States
Mario Milazzo
Scuola Superiore Sant’Anna, Pisa, Italy; Mass achusetts Institute of Technology , Cambridge, MA,
United States
Miles A. Miller
Center for Systems Biology; Department of Radiology, Massachusetts General Hospital, Harvard
Medical School, Boston, MA, United States
Xuan Mu
Division of Engineering in Medicine, Brigham and Women’s Hospital, Department of Medicine,
Harvard Medical School, Cambridge, MA, United States
Thomas S.C. Ng
Center for Systems Biology; Department of Radiology, Massachusetts General Hospital, Harvard
Medical School, Boston, MA, United States
Joanna Pagacz
Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL,
United States
Praseet Poduval
Lonza, Urmonderbaan 20b, Geleen, The Netherlands
Jai Prakash
Targeted Therapeutics, Department of Biomaterials, Science and Technology, Faculty of Science
and Technology, University of Twente, Enschede, The Netherlands
Matthew Schrier
Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University,
Fort Lauderdale, FL, United States
Kai Shi
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University,
Tianjin, China
Amit Singh
Intergalactic Therapeutics, Boston, MA, United States
Anna Sokolovska
Synlogic Operating Company, Inc., Cambridge, MA, United States
Alice Tran
Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University,
Fort Lauderdale, FL, United States
Malav Trivedi
Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University,
Fort Lauderdale, FL, United States
Irene Uboldi
Targeted Therapeutics, Department of Biomaterials, Science and Technology, Faculty of Science
and Technology, University of Twente, Enschede, The Netherlands
Anna E. Vilgelm
Department of Pathology; The Arthur G. James Cancer Hospital and Richard J. Solove Research
Institute, The Ohio State University, Columbus, OH, United States
xvContributors
xvi Contributors
Kevin P. Weller
The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State
University, Columbus, OH, United States
Yi-Chien Wu
Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL, United
States
Yu Shrike Zhang
Division of Engineering in Medicine, Brigham and Women’s Hospital, Department of Medicine,
Harvard Medical School, Cambridge, MA, United States
Preface
We are currently in the Age of Immunology. Never before has there been such rampant
discoveries and advancements in immunotherapies. For example, 1 year ago the World
Health Organization declared a COVID-19 pandemic. In less than 1 year, hundreds of
SARS-CoV-2 (causative virus of COVID-19) vaccines have been developed and four
have already received emergency use approval around the globe. This rapid and effective
vaccine development clearly depicts the current state and capabilities in the field of
immunotherapy. Tremendous advancements are being made daily, not only in vaccine
and drug development for the current COVID-19 pandemic but also for cancer. It is an
exciting and critical time for the development of immunotherapies for treating cancer.
Cancer immunotherapy lies at the intersection of many disciplines including oncology,
immunology, pharmaceutical science, biomedical engineering, and clinical research.
This series Delivery Strategies and Engineering Technologies in Cancer Immunotherapy includes
three volumes; Volume 1: Cancer Immunology and Immunotherapy, Volume 2: Systemic Drug Delivery Strategies, and Volume 3: Engineering Technologies and Clinical
Translation.
Volume 3 of this series details exciting engineering advancements in cutting-edge
technologies for cancer such as immune priming with polymeric scaffolds and tumoron-a-chip devices. To recruit tissue and lymph node dendritic cells, hydrogels of IL15 alginate mixed with dendritic cells recruited CD8 + T cells to the injection site.
Although dendritic cell priming is the goal, more practical applications of scaffolds, such
as for cancer vaccines, are being explored. Critical tools, such as tumor-on-chips, provide
invaluable testing capacities for improving immunotherapies. Unlike stationary cell culture, microfluidic techniques more closely resemble the tumor microenvironment, allow
the production of therapeutic cells, enable cell screening, and immune surveillance.
Microfluidic approaches have been critical in measuring the IL-8 migratory stimulation
of neutrophils. Tumor-on-a-chip is a powerful technology at the intersection of in vitro
and in vivo studies that allows the immune-cancer interface to be probed for specific
molecular interactions. This technology is aiding in a range of studies, from cytokine signaling to drug delivery and efficacy. An exciting advancement that aligns with the previous “-omics” era is the mapping of the tumor-immune microenvironment. This is an
exciting undertaking and although the tumor microenvironment has been well characterized, it has not been completely characterized in the context of immune involvement.
Although the cancer-immune spectrum ranges from “hot” inflamed tumors to “cold”
immune barren tumors, there are many different profiles along this spectrum and heterogeneity within the same tumor. Classifying the cellular and molecular signatures of the
tumor immune microenvironment are discussed along with techniques and the future of
this mapping endeavor. This volume also discusses CAR-T therapy, the applications of
xvii
xviii Preface
microbes in cancer immunotherapy, protein biomarkers, and stromal targeting. Optimizing biomaterials, devices, and nanotechnology approaches are discussed as we move
toward personalized medicine and the clinical translation of immunotherapies. The challenges of clinical translation (such as validating identity, purity, potency, variability, and
quality) will need to be overcome for each new immunotherapy, but as more therapies
progress through the clinical pipeline, the value of immunotherapy approaches for
improving patient outcomes will drive future successes.
Acknowledgments
First and foremost, we are deeply grateful to all the individual chapter authors who have
contributed immensely to the success of Delivery Strategies and Engineering Technologies in
Cancer Immunotherapy. The three volume series came about because of the time and effort
that these authors put into their respective chapters. Each one of them is a leader in his or
her field and we are forever in their debt. Special thanks to the amazing team at Elsevier
Press starting with Erin Hill-Parks, Susan Ikeda, and Kavitha Balasundaram who took an
idea and made it into reality.
We hope that the three volume series Delivery Strategies and Engineering Technologies in
Cancer Immunotherapy will ignite more questions and create greater research opportunities
in the field of cancer immunotherapy and lead to the development of novel solutions that
can improve patient’s outcomes.
Mansoor M. Amiji
Lara Scheherazade Milane
xix
CHAPTER ONE
Engineering solutions to design
CAR-T cells
Irene Uboldi
a
Targeted Therapeutics, Department of Biomaterials, Science and Technology, Faculty of Science and Technology, University of
Twente, Enschede, The Netherlands
b
Lonza, Urmonderbaan 20b, Geleen, The Netherlands
a,∗
, Praseet Poduval
b,∗
, and Jai Prakash
a
Contents
1. Introduction 2
1.1 The generations of CAR 2
1.2 Current approved CAR-T cell therapies 5
1.3 Pharmaceutical manufacturing process of CAR-T cell 5
2. Pharmacological aspects of CAR-T cells 8
2.1 Mechanism of action of CAR-T cell therapy 8
2.2 Efficacy of current CAR-T therapies (Kymriah and Yescarta) 8
2.3 Side effects of current therapies (Kymriah and Yescarta) 8
2.4 Challenges in CAR-T cell therapy 9
3. What can be engineered in CAR T-cells? 10
3.1 Engineering CAR-T cells to secrete a product 10
3.2 CAR-T cells engineered with LOGIC gates 13
3.3 Engineering the chimeric antigen receptor 16
4. Gene delivery to engineer CAR-T cells 17
4.1 Viral vectors to engineer CAR-T cells 17
4.2 Transposon systems to engineer CAR-T cells 18
4.3 Genome editing technology in CAR-T cells 20
4.4 CRISPR-Cas9 to engineer CAR-T cells 21
4.5 Other technologies to engineer CAR T-cells 21
4.6 Nanotechnologies to engineer CAR-T cells 22
5. Universal/SUPRA CAR-T cells 23
6. Critical aspects for clinical development 23
6.1 CAR-T cells produced with an automated process 24
7. Conclusion 25
References 26
∗
The authors have contributed equally to the work.
Engineering Technologies and Clinical Translation Copyright © 2022 Elsevier Inc.
All rights reserved.https://doi.org/10.1016/B978-0-323-90949-5.00001-2
1
2 Irene Uboldi et al.
1. Introduction
The ongoing advances in chimeric antigen receptor (CAR) as a technology have
emerged as a revolution in the modern-day immunological treatment of cancer. This is a
unique and promising treatment strategy, that until a few decades ago could only be
imagined. The evolution of scientific and engineering advances coupled with the
ever-growing strength in fundamental research has opened new doors for this novel
and promising treatment modality.
Recent clinical outcomes with CAR-T cells immunotherapy have proven therapeutic success in treating specific hematologic malignancies. However, the success of
CAR-T cell therapy is limited in solid tumors, which is due to differences in the expression of the antigen on the tumor cell surface. Therefore, considerable scientific effort
and financial investments are required to extend the success of CAR-T therapy for
the treatment of solid tumors. The future will see an improvement in the efficacy of
the next-generation CAR-T cells with the ability to targeting multiple sites using
complex artificial CAR receptors. The future will also inevitably see the expansion of
this treatment strategy to almost all cancer types.
The treatment begins with the isolation of T cells from the patient, which are
engineered with CAR to be presented on the T cell surface and infused back to the
patient. Although these T cells were originally extracted from patients, modified, and
multiplied ex-vivo, these cells now possess enhanced capabilities. These modified
T cells are now better equipped to detect and eliminate cancer cells, toward which it
was previously unresponsive. Since these CAR-T cell therapies are not synthetic compounds but are living cells, some pharmacologists rightly refer to CAR-T cells as “living
drugs” which is dawning a unique perspective in pharmacology. In this chapter, we will
discuss different generations of CAR-T cells and explore their mechanisms of action.
Furthermore, we will discuss in detail the engineering of CAR-T cells, in particular,
characteristics to engineer and different technologies to engineer them.
1.1 The generations of CAR
Chimeric antigen receptors (CARs) have the unique ability to bind to a specific target
antigen using their extracellular receptor domains while at the same time are tuned to
activate T cells. CARs are not found in nature but are artificially engineered using genetic
manipulation tools. These genetic manipulations allow T cells to express the desired
combination of transmembrane protein receptors that have a high-level specificity
toward a target antigen on the surface of the tumor cells. These receptors are also cleverly
designed to not display binding domains that target healthy cells. This is key in ensuring
the health safety profile of the engineered CAR-T cells.
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