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ENGINEERING TECHNOLOGIES
AND CLINICAL TRANSLATION

ENGINEERING TECHNOLOGIES
AND CLINICAL TRANSLATION
Volume 3 of Delivery Strategies and Engineering
Technologies in Cancer Immunotherapy
Edited by
MANSOOR M. AMIJI
University Distinguished Professor, Professor of Pharmaceutical
Science, and Professor of Chemical Engineering, Northeastern
University, Boston, Massachusetts, United States
LARA SCHEHERAZADE MILANE
Bouve College of Health Sciences Distinguished Educator, Assistant
Teaching Professor, Department of Pharmaceutical Sciences
Northeastern University, Boston, Massachusetts, United States

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Dedication
This book is dedicated to my teachers and mentors, especially Professor Kinam Park and
Dr. Haesun Park who remain an inspiration for their intellect, passion, generosity, and
kindness. I stand on the shoulders of these giants!
Mansoor M. Amiji
I dedicate this work in loving memory to my twin sister, Samantha Tari Jabr; thank you
for being my soulmate and for your unwavering love that keeps me going. I also dedicate
this work to my daughter, Mirabella; you are the light of my life and I thank you for your
eternal brilliance.
Lara Scheherazade Milane

Contents
Contributors xiii
Preface xvii
Acknowledgments xix
1. Engineering solutions to design CAR-T cells 1
Irene Uboldi, Praseet Poduval, and Jai Prakash
1. Introduction 2
2. Pharmacological aspects of CAR-T cells 8
3. What can be engineered in CAR T-cells? 10
4. Gene delivery to engineer CAR-T cells 17
5. Universal/SUPRA CAR-T cells 23
6. Critical aspects for clinical development 23
7. Conclusion 25
References 26
2. Engineered microbes for cancer immunotherapy 33
Aoife M. Brennan, Anna Sokolovska, Ning Li, and Vincent M. Isabella
1. Microbes as tumor immunotherapy 33
2. Application of synthetic biology to therapeutics 38
3. Synthetic biology techniques to engineer safety and control growth 43
4. Application of synthetic biology to engineer microbial therapeutics for cancer 46
5. Regulatory considerations in the development of engineered bacteria as
therapeutics 54
6. Conclusion 56
References 56
3. Polymeric scaffolds for antitumor immune cell priming 63
Khushbu Bhatt, Loek J. Eggermont, and Sidi A. Bencherif
1. Introduction 63
2. Polymeric materials and scaffold systems 66
3. Polymeric scaffolds for DC priming and activation 75
4. Polymeric scaffolds for T-cell activation 81
5. Conclusion and future perspectives 86
References 87
vii

viii Contents
4. Biomaterials and devices for immunotherapy 97
Emily M. Jordan, Mario Milazzo, Sue Anne Chew, and Serena Danti
1. Introduction 98
2. Immunotherapy and chemotherapy combinations 99
3. Nanoscale biomaterial-based strategies applied 108
4. Introduction to micro/nanorobots 113
5. Propulsion engines for MNRs 115
6. Applications of MNRs 118
7. Conclusion and future outlook 123
References 125
5. Engineered devices for tumor microenvironment immune
modulation 135
Alexander M. Cryer and Natalie Artzi
1. Introduction 135
2. Local delivery of engineered devices for tumor immune modulation 136
3. Transdermal delivery of engineered devices for tumor immune modulation 145
4. Systemic delivery of engineered devices for tumor immune modulation 149
5. Limitations, perspectives and future work 151
References 152
6. Tumor-on-a-chip devices for cancer immunotherapy 155
Xuan Mu and Yu Shrike Zhang
1. Introduction 155
2. Microfluidics 157
3. Recapitulating the tumor microenvironment 161
4. Predicating therapeutic efficacy 171
5. Production of therapeutic cells 174
6. Screening immune cells 181
7. Conclusion 184
References 185
7. Challenges and opportunities of nanotechnology in cancer
immunotherapy 197
DaeYong Lee, Kristin Huntoon, Wen Jiang, and Betty Y.S. Kim
1. Background in cancer immunotherapy 197
2. Immunogenic cell death with nanotechnology 199
3. Vaccination with nanotechnology 209
4. Activation of innate immunity 216

5. T cell activation 225
6. Targeting strategies 230
7. Perspective 234
References 234
8. Stromal modulation strategies to improve immunotherapy response
in cancer 241
Kai Shi
1. Background 241
2. Tumor stroma mediated immunosuppression 245
3. Stromal modulation strategies with nanotechnology to improve immunotherapy 262
4. Conclusions 280
Acknowledgments 281
References 281
9. Spatial mapping of the tumor immune microenvironment 293
Yi-Chien Wu, Joanna Pagacz, Samantha C. Emery, Stephen J. Kron,
and Steve Seung-Young Lee
1. Introduction 293
2. Conventional tissue preparation and processing for cancer histology 295
3. Mapping proteins and transcripts in the TIME 299
4. Spatial ‘omics 310
5. Conclusions and future prospects 320
Acknowledgments 321
References 321
ixContents
10. Nucleic acid biomarker technology for cancer immunotherapy 331
Sashana Dixon, Alice Tran, Matthew Schrier, and Malav Trivedi
1. Introduction 331
2. NGS and cancer 332
3. Transcriptional signatures 339
4. Single cell 343
5. CRISPR based 344
6. Current challenges in immunogenomics 345
7. Conclusion 345
Acknowledgment 346
References 346

x Contents
11. Proteomic biomarker technology for cancer immunotherapy 357
Reilly Fankhauser, Nicholas DePatie, Rachel Berryman, Olivia M. Lucero,
and Rajan P. Kulkarni
1. Introduction and background 358
2. Proteomic technologies 362
3. Proteomic analysis of immune-related adverse events 383
4. Discussion and future directions 386
References 388
12. Personalized cancer immunotherapy 399
Amrendra Kumar, Kevin P. Weller, and Anna E. Vilgelm
1. Part I. Identifying immune checkpoint blockade therapy-responsive patients 399
2. Biomarkers based on tumor “foreignness” 403
3. Tumor immune microenvironment and immunotherapy response 406
4. “Omics” technologies in personalized immunooncology 407
5. Immunotherapy response biomarkers not directly measured in tumor 408
6. Integrating biomarkers to reach “precision” and tailor therapy to patient’s unique
immunome 408
7. Part II. Highly personalized immunotherapy 410
8. Adoptive T cell transfer: A highly personalized therapy for human cancers 410
9. Tumor-infiltrating lymphocytes: A rich source of tumor specific T cells 411
10. Tumor neoantigens and their role in tumor immunity 414
11. Neoantigen reactive T cells; broadening the landscape of personalized cancer
immunotherapies 417
12. Neoantigen vaccines 418
13. Neoantigen-specific T cells for adoptive cellular therapies 419
14. Concluding remarks 420
References 420
13. Image-guided cancer immunotherapy 427
Thomas S.C. Ng and Miles A. Miller
1. Introduction 427
2. Clinically relevant imaging modalities to assess anatomic and functional tumor
response 428
3. Imaging approaches to probe the immune system 430
4. Imaging targets for immunotherapy 432
5. Imaging of other immune targets 442
6. Imaging immune cellular subsets 442
7. Imaging to guide bispecific T-cell engager therapy (BiTE) 454

8. Image-guided interventional immunotherapies 454
9. Summary and future directions 456
References 456
Further reading 467
14. Clinical translation and challenges in cancer immunotherapies 469
Amit Singh
1. Introduction 469
2. Challenges in developing cancer immunotherapies 470
3. Drug development considerations for clinical translation 482
4. Conclusion 487
References 488
Index 491
xiContents
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