Precision Cancer Therapies, Volume 2, Immunologic Approaches for the Treatment of Lymphoid Malignancies E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 1584

Veröffentlichungsjahr: 2024

Beschreibung

Presents timely and authoritative information on the development of precision cancer therapies as applied to hematologic malignancies The Precision Cancer Therapies series focuses on how to understand and translate fundamental basic science into information that can be directly applied to patients to advance care. Each volume of the series integrates the relevant biological concepts and principles necessary for translating this science to practitioners of this science. Precision Cancer Therapies, Volume Two, focuses on sophisticated immunotherapies targeting cancers affecting the blood, bone marrow, and lymph nodes. Edited and authored by the foremost authorities in the field, this comprehensive reference text covers targeting of cell surface receptors, antibody-drug conjugates (ADC), targeting immune checkpoint, targeting macrophages, EBV-directed immunotherapies, tumor-associated antigens (TAA), and chimeric antigen receptor T-cells (CAR-T). Divided into nine sections, Volume Two includes an overview of the history of immunotherapy development in cancer, as well as a concluding section addressing the mechanistic basis and role of immunomodulatory drugs, analytical tools to quantitate immune-mediated effects, and other topics in immunotherapy. Chapters on specific therapeutics or therapeutic classes include a basic explanation of the underlying pathway and target, the pharmacology of the drug/class, relevant preclinical and clinical data, and discussion of clinical management and potential predictive biomarkers of response. This book also: * Delivers a definitive, state-of-the-art review of the relevant biology and its importance in the broader context of cancer biology * Focuses on agents that mediate cell killing in lymphoma through a variety of immunologic mechanisms * Covers FDA-approved drugs and their indications, as well as drugs currently in development * Provides information on monotherapy and combination therapy, summary tables of trials, and discussion of toxicity and efficacy * Includes boxed sections highlighting major unique points about the information in the chapter Precision Cancer Therapies, Volume Two: Immunologic Approaches for the Treatment of Lymphoid Malignancies, From Concept to Practice is an indispensable resource for medical, scientific, and allied medical professionals, advanced students, and interested general readers with background knowledge in the subject.

Leseprobe

Precision Cancer Therapies

Volume 2

Immunologic Approaches for the Treatment of Lymphoid Malignancies

From Concept to Practice

Edited by

Owen A. O’ConnorStephen M. AnsellJohn G. Gribben

This edition first published 2024

© 2024 John Wiley & Sons Ltd

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Library of Congress Cataloging-in-Publication Data

Names: O’Connor, Owen A., editor. | Ansell, Stephen M., editor. | Gribben, John G., editor.

Title: Immunologic approaches for the treatment of lymphoid malignancies : from concept to practice / edited by Owen A. O’Connor, Stephen M. Ansell, John G. Gribben.

Other titles: Precision cancer therapies ; v. 2.

Description: Hoboken, NJ : Wiley Blackwell 2023. | Series: Precision cancer therapies ; volume 2 | Includes bibliographical references and index.

Identifiers: LCCN 2023023583 (print) | LCCN 2023023584 (ebook) | ISBN 9781119824541 (hardback) | ISBN 9781119824558 (adobe pdf) | ISBN 9781119824565 (epub) | ISBN 9781119824572 (ebook)

Subjects: MESH: Lymphoma--immunology | Lymphoma--therapy | Immunotherapy--methods | Immunoconjugates--therapeutic use | Immunity, Cellular

Classification: LCC RC280.L9 (print) | LCC RC280.L9 (ebook) | NLM WH 525 | DDC 616.99/446--dc23/eng/20231128

LC record available at https://lccn.loc.gov/2023023583

LC ebook record available at https://lccn.loc.gov/2023023584

Cover Image and Design: Wiley

Set in 9.5/12.5 pt STIXTwoText by Integra Software Services Pvt. Ltd, Pondicherry, India

Contents

Cover

Title Page

Copyright Page

List of Contributors

Volume Foreword

Volume Preface

Series Preface

Section I Historical Perspective

1 The Distinguished History of Immunotherapy Development in Cancer

Take Home Messages

Introduction

The Beginnings of Immunotherapy

The Central Role of the Immune System

Cytokines

Antibody Based Therapy

Immune Checkpoint Therapy

Vaccines

CAR T-cells and Adoptive Cell Therapy

Summary

Must Reads

References

Section II Targeting Cell Surface Receptors

2 Development of Monoclonal Antibodies for the Treatment of Lymphoma: Setting the Stage

Take Home Messages

Introduction

Magic Bullets

Monoclonal Antibodies

Proof of Concept – Anti-idiotype mAb

Chimeric, Humanized, and Human mAb

Rituximab

Anti-lymphoma mAb Mechanisms of Action

Target Epitopes

Enhancing mAb Effector Function

Alternative Target Antigens

Alternative Strategies to Leverage the Unique Aspects of mAb Therapy

Radioimmunotherapy Based on Anti-sera

Mab-based Radioimmunotherapy

Radioimmunotherapy of B Cell Lymphoma

Immunotoxins

Antibody-drug Conjugates

Retargeting T Cells

Bispecific Antibodies

Chimeric Antigen Receptor T Cells

Bispecific Antibodies versus CAR-T

Immune Checkpoint Blockade in Lymphoma

Remaining Questions

Conclusion

Must Reads

References

3 Pharmacology to Practice: The Similarities and Differences of Drugs Targeting CD20

Take Home Messages

Introduction

Anti-CD20 Monoclonal Antibody Development

Rituximab

Ofatumumab

Ublituximab

Obinutuzumab

Resistance to Anti-CD20 Monoclonal Antibodies

Combinations Using Bruton Tyrosine Kinase Inhibitor and Anti-CD20 Monoclonal Antibodies

Radiolabeled Anti-CD20 Antibodies: I-131 Tositumomab and Y-90 Ibritumomab Tiuxetan

Anti-CD20 Antibody Drug Conjugates

CD20 Bispecific Antibodies

Anti-CD20 Chimeric Antigen Receptor (CAR) T-cell Therapy

Conclusion

Must Reads

References

4 Pharmacology to Practice: Targeting CD19 and 22

Take Home Messages

Introduction

CD19 and CD22 Surface Antigens

CD19 Antigen

CD22 Antigen

Therapeutic Targeting: CD19

Approved Agents Targeting CD19

Tafasitamab

Pharmacokinetics and Pharmacodynamics

Clinical Efficacy

Safety and Tolerability

Indication for Tafasitamab

Loncastuximab Tesirine

Introduction to Loncastuximab Tesirine

Pharmacokinetics

Pharmacodynamics and Distribution

Clinical Efficacy

Safety and Tolerability

Indication for Loncastuximab Tesirine

Emerging Agents Targeting CD19

Denintuzumab Mafodotin

Bispecific Antibodies Targeting CD19

Sequencing CD19 Directed Therapies in the Treatment of R/R LBCL

Therapeutic Targeting: CD22

Antibody Drug Conjugates Targeting CD

22

Bispecific Antibody Targeting CD22

Summary

Must Reads

References

5 Targeting Other Promising Cell Surface Receptors: ROR1, CD38, CD25, and CCR4

Take Home Messages

Introduction

Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1)

ROR1 Biology

Role of ROR1 in Cancer

Role of ROR1 in Hematologic Cancers

Therapies Targeting ROR1

Safety of Therapies Targeting ROR1

Future Directions

CD38

CD38 and Its Biological Functions

CD38 Expression in Lymphoid Malignancies

CD38-targeted Treatments in Lymphoid Malignancies

The Interleukin 2 Receptor α Chain (CD25)

The Biology of CD25

CD25 Pathophysiology

Targeting CD25 as a Therapeutic Strategy

C-C Motif Chemokine Receptor 4 (CCR4)

CCR4 Targeting and Therapy

CCR4 Expression in Normal and Cancerous Cells

The Role of CCR4 in Immune Regulation

CCR4 and Hematological Malignancies

CCR4 Targeting/Therapy

Conclusions and Perspectives

Must Reads

References

Section III Antibody Drug Conjugates (ADC)

6 Principles of Antibody Drug Development

Take Home Messages

Introduction

Brief History

Design Principles

Target Antigen Selection

Antibody Characteristics

Cytotoxic Drug Potency

Linker Selections and Conjugation Strategies

ADCs Currently Approved for Lymphoid Malignancies

Brentuximab Vedotin

Inotuzumab Ozogamicin

Polatuzumab Vedotin

Belantamab Mafodotin

Loncastuximab Tesirine

Future

Must Reads

References

7 Targeting CD30 in Lymphoid Neoplasms

Take Home Messages

Introduction

Receptor Function and Structure

Strategies for Targeting CD30

Clinical Experience

Conclusions and Future Directions

Must Reads

References

8 Targeting CD79b in B-cell Malignancies

Take Home Messages

Introduction

Polatuzumab Vedotin Preclinical Development

Clinical Results

Phase 1 and 2 in Patients with Relapsed/Refractory (R/R) Lymphoma

The Randomized Phase 2 Study in Patients with Relapsed or Refractory DLBCL

Moving Polatuzumab Vedotin in the Front-line Management of DLBCL

Polatuzumab Vedotin Combination in Other B-cell Lymphoma Histology

Novel Investigational Combinations of Polatuzumab with Targeted Therapy

Resistance Mechanisms to Polatuzumab Vedotin: Facts and Hypothesis

Conclusion

Must Reads

References

9 Radioimmunotherapy: Is There Any Future Role?

Take Home Messages

Introduction

Principles of Radioimmunotherapy in Non-Hodgkin Lymphomas

90

Y-ibritumomab Tiuxetan

Clinical Experience with

90

Y-IT

Lilotomab Satetraxetan

Conclusion

Must Reads

References

Section IV Targeting Immune Checkpoint

10 The Biology of Immune Checkpoint Blockade

Take Home Messages

Introduction

Recognition of Antigen

T Cells

NK Cells

Failure of Immunosurveillance in Cancer

Induction of Checkpoint Inhibitor Expression

Mechanism of Action of Checkpoint Inhibitor Molecules

Competition and Redirection of Costimulation

Recruitment of Phosphatases

SHP1/SHP2 Phosphatases

PP2A

Unresolved Mechanisms

Mechanism of Action of Checkpoint Inhibitors

Current Areas of Study

Summary

References

11 Mechanism of Action and Pharmacologic Features of Drugs Targeting PD-1/PDL-1 and CTLA-4

Take Home Messages

Introduction

Structure and Effector Functions of mAb Therapeutics

Overview of PD-1 and PD-L1 Molecules

Mechanisms of Action of PD-1 and PD-L1 Inhibitors

Pharmacodynamic Effects of PD-1 and PD-L1 Inhibitors

Overview of the CTLA4 Pathway

Effects of CTLA-4 Blocking Mechanisms Mediated by anti-CTLA-4 mAbs

Fc-dependent Mechanisms of anti-CTLA-4 mAbs

Mechanisms of Action of ICB in B-cell Lymphomas

Expression Pattern and Function of Immune Checkpoints in Normal GCs

Expected Activity of ICB in B-cell Lymphomas Based on Immune Checkpoint Expression

Future Outlook

Must Reads

References

12 Other Immune Checkpoint Targets of Interest

Take Home Messages

Introduction

TIM-3

Structure and Signaling

Ligands

Galectin-9

Ceacam-1

HMGB1

Phosphatidylserine

Expression and Function within the TME

T Helper Cells

T Regulatory Cells

Cytotoxic T Cells

Natural Killer Cells

Monocytes and Macrophages

Dendritic Cells

Myeloid Derived Suppressor Cells

Tumor Cells

Translation into a Clinical Target

Pre-clinical Models of TIM-3 Blockade

Role as a Prognostic Marker

Clinical Experience with TIM-3 Inhibitors

LAG-3

Structure and Signaling

Ligands

MHC Class II

Galectin-3

CLEC4G

FGL1

Expression and Function within the TME

Effector CD4

+

and CD8

+

T Cells

Tregs

Other Cell Types

Tumor Cells

Translation into a Clinical Target

Pre-clinical Models of LAG-3 Genetic Deficiency

Pre-clinical Models of LAG-3 Blockade

Role as a Prognostic Marker

Clinical Experience with LAG-3 Inhibitors

TIGIT

Structure and Signaling

Ligands

CD155

CD112

CD226

Expression and Function within the TME

Effector CD4

+

and CD8

+

T Cells

Regulatory T Cell Populations

NK Cells

Translation into a Clinical Target

Pre-clinical Models of TIGIT Blockade

Role as a Prognostic Marker

Clinical Experience with TIGIT Inhibitors

Remaining Challenges and Opportunities

Balancing Autoimmunity and Anti-tumor Efficacy

Biomarkers for Treatment Response

Other Immune Checkpoints

Conclusions

Conflicts of Interest

Must Reads

References

13 Clinical Experiences with Immune Checkpoint Inhibitors in Lymphomas

Take Home Messages

Rationale for Checkpoint Inhibitors in Lymphomas

CTLA Blockade

PD-1 Blockade

Early Experiences with PD-1 Blockade in Hematologic Malignancies

Phase II Registration Trials of PD-1 Blockade in Hodgkin Lymphoma: A Therapeutic Revolution

Pivotal Trials of Nivolumab and Pembrolizumab in Hodgkin Lymphoma

Real-world Data on PD-1 Blockade in Hodgkin Lymphoma

Addition of PD-1 Blockade to Chemotherapy in Hodgkin Lymphoma: Combination with AVD

Addition of PD-1 Blockade to Brentuximab Vedotin

Which Is the Better Agent to Combine with AVD Chemotherapy in New HL: Nivolumab or Brentuximab Vedotin?

Allogeneic Stem Cell Transplantation for Hodgkin Lymphoma in Era of PD-1 Blockade

Other anti-PD-1 Antibodies Approved for Use in Hodgkin Lymphoma

Phase I and II Trials of PD-1 Blockade in Non-Hodgkin Lymphoma

Nivolumab

Nivolumab Plus Ipilimumab in Lymphomas

Phase II Trials of Nivolumab in DLBCL and FL: Missing the Mark

Pembrolizumab

Special Populations of NHL Responsive to PD-1 Blockade

Primary Mediastinal B Cell Lymphoma

Richter’s Transformation

Primary Central Nervous System (CNS) and Testicular Lymphomas

T Cell and Natural killer/T (NK/T) Cell Lymphomas

Post-transplant Lymphoproliferative Disease (PTLD)

Burkitt Lymphoma

Combination of Checkpoint Inhibitors with Other Agents in Lymphomas

Combinations with CTLA-4 Inhibitors

Rituximab

Combinations with PD-1 and PD-L1 Inhibitors

Rituximab

Bruton’s Tyrosine Kinase (BTK) Inhibitors

Chimeric Antigen Receptor (CAR) T Cells

Bispecific Antibodies

Hypomethylating Agents

Newer Checkpoint Inhibitors in Lymphomas

LAG-3

TIM-3

TIGIT

BTLA

CD47

Summary and Future Prospects for Checkpoint Inhibitors in Lymphomas

Must Reads

References

Section V Targeting Macrophages and sirp-α – Disrupting the “Do Not Eat Me”

14 The Role of CD47 in Lymphoma Biology and Strategies for Therapeutic Targeting

Take Home Messages

Introduction

CD47-SIRPa Biology

CD47 Structure and Expression

SIRPα Structure and Expression

Anti-Phagocytosis Signaling

Non-phagocytic Functions

Role of CD47 in Lymphoma

B-cell Lymphoma

T Cell Lymphoma (TCL)

Strategies for Therapeutic Targeting of the CD47- SIRPα Axis

Magrolimab – the First CD47 Antibody, with a Unique Dosing Strategy to Limit Anemia

Lemzoparlimab – a Second Generation Antibody with Minimal RBC Binding

TTI-621/TTI-622 – SIRPαFc Fusion Proteins with Minimal RBC Binding that Deliver Different “Eat Me” Signals

Evorpacept – A High Affinity SIRPαFc Fusion Protein Engineered for Combination Use

TG-1801 – A CD47/CD19 IgG1 Bispecific Designed for Greater Tumor Specificity

HX009 – A CD47/PD-1 Bispecific for Blockade of Innate and Adaptive Immune Checkpoints

GS-0189 – A SIRPα Antibody Designed for Improved Safety and Combination Use

Single Agent Activity in Lymphoma

Conclusions

Disclosures

Must Reads

References

15 Single Agent and Rational Combination Experiences with Anti-CD47 Targeted Drugs

Take Home Messages

Introduction

Mechanistic Basis for CD47 Targeted Therapies

Pre-clinical and Clinical Studies of CD47 Targeting Therapies

Magrolimab (Hu5F9-G4)

CC–90002

TTI-621

TTI-622

ALX148

Summary

Future Directions

Must Reads

References

Section VI EBV Directed Immunotherapies

16 Understanding the Role of EBV Infection in Lymphomagenesis

Take Home Messages

Introduction

EBV-related Lymphoid Malignancies

Types of EBV Infection and the Associated Viral Expression Profiles

Mechanism of Lymphomagenesis in EBV-associated Lymphomas

Roles of EBV Genes

Roles of Host Genes and Epigenetic Modifications

Burkitt Lymphoma

EBV-positive Diffuse Large B Cell Lymphoma, Not Otherwise Specified

Extra Nodal NK/T Cell Lymphoma, Nasal Type

Chronic Active EBV Disease

Immunological Aspects

Conclusion

Acknowledgments

Must Reads

References

17 Immunologic Therapies in Development for EBV Driven Lymphoid Malignancies

Take Home Messages

Classes of Immunologic Therapies for EBV-driven Lymphoid Malignancies

Immune Checkpoint Inhibitors

Cellular Therapies

Other Strategies – Antibodies, Antibody-drug Conjugates, HDAC Inhibitors

Relevant Preclinical Data for Novel Strategies against EBV-driven Lymphoid Malignancies

Immune Checkpoint Inhibitors

Lytic Induction Therapy

Prophylactic EBV Vaccines

Therapeutic EBV Vaccines

Cellular Therapy against EBV-associated Lymphoma

Future Directions

Must Reads

References

Section VII Exploiting Tumor Associated Antigens with Autologous T-Cells

18 The Scientific Rationale for Targeting Tumor-Associated Antigens

Take Home Messages

Introduction

The Rules of Engagement; T-cell Biology and the Recognition of Self versus Non-self

Major Histocompatibility Complex (MHC) – Associated Peptides in Lymphoproliferative Diseases

The Origin and Discovery of MHC-associated Cancer Antigens

Histocompatibility Antigens

Viral Antigens

Tumor-specific (TSA) and Associated (TAA) Antigens

T-cell Therapy; Summary of the Advantages and Disadvantages of the Different Antigen Classes

The TAA Expressed in Lymphoid Malignancies

Turning TAAs into Actionable Targets for T-cell Immunotherapy

Leveraging Naturally Occurring High Affinity/avidity TAA-specific TCR

TCR Enhancement to Target TAA

Other Considerations in TAA-directed Adoptive Immunotherapy

Conclusion

Must Reads

References

19 Clinical Experiences with TAA-T in Lymphoid Malignancies

Take Home Messages

Background

CAR-T versus TAA-T

Targeting Lymphoid-specific Antigens

Other Clinically Targeted TAAs

Combination Therapies

Manufacturing

Open Clinical Trials

Benefits and Barriers

Future Directions

Summary

Must Reads

References

Section VIII Chimeric Antigen Receptor T-Cells (CAR-T)

20 The Science of CAR-T Cell Technology

Take Home Messages

Background

T Cell Function and Dysregulation in Cancer

CAR Constructs

CAR-T Composition

T Cell Fitness for Autologous CAR-T Generation

Leukapheresed Cell Characteristics

T Cell Composition and Phenotype for Functionality

CAR-T Resistance

Tumor-induced Mechanisms of Resistance

T Cell Dysfunction

Tumor Microenvironment-induced T Cell Inhibition

T-regulatory Cells

Inhibitory Myeloid Cells

Cancer Associated Fibroblasts

Extracellular Vesicles

Allogeneic CAR-T

Collection and Manufacturing

Must Reads

References

21 The Spectrum of CAR T Assets in Development: Similarities and Differences

Take Home Messages

Introduction

Overcoming CAR T Antigen Escape

Tandem CARs

Sequential CARs

Upregulating Target Antigen Expression

Novel Approaches in CAR T-cell Engineering

Armored CARs

Targeting the TRAC Locus

Designing Third Generation CARs

Ex Vivo Manipulation of CAR T-cells

CAR T Combination Strategies

CAR T in Combination with Immune Checkpoint Inhibitors

CAR T in Combination with BTKi

CAR T in Combination with Immunomodulatory Agents

Expanding the Repertoire of CAR Antigen Targets

CAR T in Hodgkin Lymphoma

CAR T in T-cell Lymphomas

Conclusions

Must Reads

References

22 Clinical Experience with CAR-T Cells for Treatment of B-cell Lymphomas

Take Home Messages

Introduction

Clinical Trials

CD19-directed CAR-T Cells in B-Cell Lymphomas

ZUMA-1 Study

TRANSCEND

Real World Evidence

Moving CAR-T into Second Line Treatment in Large B Cell Lymphoma

ZUMA-7

TRANSFORM

BELINDA

CAR-T in Follicular Lymphoma

ZUMA-5 Axi-cel in Indolent Lymphoma

The ELARA Trial: Tisa-Cel in Relapsed/Refractory Follicular Lymphoma

Mantle Cell Lymphoma

ZUMA-2

CD19-directed CAR-T Cell Trials in Chronic Lymphocytic Leukemia (CLL)

Conclusions

Must Reads

References

23 “Off the Shelf” CAR-T/NK Cells

Take Home Messages

Introduction

General Aspects of Off-the-shelf Cellular Therapy

Gene Editing Technologies

Preventing GVHD from Allogenic Cellular Therapy

Preventing Allo Rejection of Cell Therapy

Engineering Allogeneic Cells with Synthetic Biology

Cellular Sources for Off-the-shelf Therapies

Peripheral Blood

Umbilical Cord Blood

iPSC-Derived

Off-the-shelf T Cell Therapy

Point of Care T Cell Therapy

Expanded Blood T Cell Therapies

Off-the-shelf Specific T Cells for EBV-associated Malignancies

Umbilical Cord Blood Derived T Cells

iPSC Derived T Cell Therapy

T Cell Therapies for T and NK Cell Malignancies

Non-classical T Cell Therapies

Off-the-shelf NK Cells

NK Cell Biology and Distinction from T Cells

Point-of-care Manufactured NK Cell Therapy

Memory-like NK Cell Therapy

Expanded Blood NK Cell Therapy

Umbilical Cord Blood (UCB, CB) Expanded or Differentiated NK Cells

iPSC-Differentiated NK Cell Therapy

NK Cell Line Based Therapy

Conclusions and Future Directions

Must Reads

References

24 Programming Myeloid Cells with Chimeric Antigen Receptor Myeloid-Based Therapies

Take Home Messages

Introduction

Myeloid Cells and the Lymphoma Tumor Microenvironment

Harnessing the Multi-potent Diversity of Monocytes for Immunotherapy

Harnessing Monocyte Differentiation into Dendritic Cells, Macrophages and their Associated Effector Functions

Engineering the Bridge between Innate and Adaptive Immunity to Trigger Durable Anti-Tumor Immune Responses

Engineering Phagocytosis for Tumor Killing

Engineering Myeloid Cells for Antigen Presentation

Myeloid Cell Engineering Practical Considerations

Building off of the CAR-T Foundation

Engineered Myeloid Cells and the Future of Immunotherapy

Must Reads

References

Section IX Miscellaneous Topics in Immunotherapy

25 Mechanistic Basis and Role of Immunomodulatory Drugs

Take Home Messages

Introduction

IMiDs

CELMoDs – New Generation of Immunomodulatory Drugs

Potential Neo-substrates of Immunomodulatory Drugs

PROTACS: The Ubiquitin-proteasome System-mediated Degradation of Target Proteins

Alternative Degrader Approaches to PROTACs

Antiviral PROTACs

Alternative PROTAC Modalities

Other Mechanisms of Action of IMiDs

Conclusions and Perspectives

Must Reads

References

26 Analytical Tools to Quantitate Immune Mediated Effects: What Should We Measure and How?

Take Home Messages

Introduction

The Case for Comprehensive and Unbiased Immune Profiling in Lymphoma

Biospecimens: What to Choose, How to Preserve

Cells in Suspension

Soluble Factors

Cells in Tissue Context

Overview of Immunological Assays

Analysis of Single Cells in Suspension

Fluorescence-based Flow Cytometry

Mass Cytometry

Single Cell Genomic Assays

Analysis of Soluble Factors

Single-cell Secretome Analysis

Analysis of Tissue

Bulk Analysis of Dissociated Tissue

Microregional Analysis of Intact Tissue

Single Cell Analysis of Intact Tissue

Conclusion

Must Reads

References

27 The Role of the Microbiome in Immune Response

Take Home Messages

Introduction

Genetic Influence on Host Immune-microbe Interactions

Environmental Influence on Host Immune-microbe Interactions

Innate Immune System and Microbiota

Adaptive Immune System and Microbiota

The Role of Aberrant Host Immune-microbe Relationships in Disease

Inflammatory Bowel Disease

Malignancy

Gut Microbiome in Immune-related Toxicity

Conclusion

Must Reads

References

28 Epigenetic Drugs as Modulators of Tumor Immunogenicity and Host Immune Response

Take Home Messages

Introduction

Putting Epigenetic Biology and the Drugs That Target the Epigenome in Context

The Connection Between the Epigenome and Immunome

The Role of Epigenetic Drugs on Viral Immune Response

Clinical Evidence of the Immunomodulatory Activity of Epigenetic Targeted Drugs

Conclusions and Future Directions

Acknowledgments

Must Reads

References

29 Tailoring Specific Radiographic Response Criteria for Immunologic Therapies in Lymphoma

Take Home Messages

Introduction to Lymphoma Staging and Response Assessment

Treatment Related Flare Response and Pseudoprogression

The LYRIC Criteria

PET-CT in the Time of COVID-19

Circulating Tumor DNA

Conclusions

Must Reads

References

Index

End User License Agreement

List of Tables

CHAPTER 02

Table 2.1 Strategies to improve...

CHAPTER 03

Table 3.1 Monoclonals...

Table 3.2 Bispecific...

CHAPTER 05

Table 5.1 Strategies...

Table 5.2 Clinical...

CHAPTER 06

Table 6.1 FDA approved...

CHAPTER 07

Table 7.1 FDA approval...

Table 7.2 Current CAR-T...

CHAPTER 08

Table 8.1 Summary of efficacy...

Table 8.2 Summary of key results...

CHAPTER 09

Table 9.1 Summary of the...

Table 9.2 Characteristics...

Table 9.3 Grade 3–4...

Table 9.4 Summary of the...

Table 9.5 Summary of phase...

CHAPTER 11

Table 11.1 Pharmacological features...

CHAPTER 12

Table 12.1 Emerging immune...

Table 12.2 Current clinical...

Table 12.3 Current clinical...

Table 12.4 Current clinical...

Table 12.5 Other immune...

Table 12.6 Current clinical...

CHAPTER 13

Table 13.1 Clinical results...

Table 13.2 Representative...

Table 13.3 Examples of newer...

CHAPTER 14

Table 14.1 CD47/SIRPα targeting...

CHAPTER 15

Table 15.1 Summary of select...

CHAPTER 16

Table 16.1 Representative...

Table 16.2 EBV latency...

Table 16.3 Immunodeficiency...

CHAPTER 17

Table 17.1 Pharmacological...

CHAPTER 18

Table 18.1 Methods to...

Table 18.2 MHC-associated...

Table 18.3 A non-exhaustive...

CHAPTER 19

Table 19.1 Comparison of...

Table 19.2 Results to-date...

CHAPTER 20

Table 20.1 Gene therapy...

Table 20.2 Summary of resistance...

CHAPTER 21

Table 21.1 Clinical applications...

CHAPTER 22

Table 22.1 Registrational trials...

Table 22.2 Clinical trials...

CHAPTER 23

Table 23.1 Comparison between...

Table 23.2 Selected clinical...

Table 23.3 Selected clinical...

CHAPTER 26

Table 26.1 Single cell...

Table 26.2 Multi-parameter...

CHAPTER 28

Table 28.1 A summary of clinical...

List of Illustrations

CHAPTER 06

Figure 6.1 Schematic Illustration...

Figure 6.2 Schematic of...

CHAPTER 07

Figure 7.1 Proposed CD30...

Figure 7.2 Brentuximab...

CHAPTER 09

Figure 9.1 The cross-fire...

Figure 9.2 Dose of...

Figure 9.3 Incidence...

Figure 9.4 Schematic...

CHAPTER 10

Figure 10.1 T cell and...

Figure 10.2 Multiple...

Figure 10.3 Recruitment...

CHAPTER 11

Figure 11.1 Mechanisms of...

Figure 11.2 Mechanisms of...

Figure 11.3 Interactions...

CHAPTER 12

Figure 12.1 TIM-3 Suppression...

Figure 12.2 Effects of TIM-3...

Figure 12.3 LAG-3 Inhibition...

Figure 12.4 Effects of LAG-3...

Figure 12.5 TIGIT-Mediated...

Figure 12.6 Effects of TIGIT...

CHAPTER 16

Figure 16.1 The viral gene...

Figure 16.2 Multi-stage model...

CHAPTER 18

Figure 18.1 The genetic...

Figure 18.2 Target MHC-associated...

CHAPTER 19

Figure 19.1 Comparison of...

Figure 19.2 General manufacturing...

CHAPTER 20

Figure 20.1 Schematic diagram...

Figure 20.2 Schematic diagram...

CHAPTER 22

Figure 22.1 Chimeric Antigen...

Figure 22.2 Structure of the...

Figure 22.3 Timelines of approval...

Figure 22.4 ZUMA-1...

Figure 22.5 Indirect...

Figure 22.6 Matching-Adjusted...

Figure 22.7 French DESCAR-T...

Figure 22.8 ZUMA-7 Primary...

Figure 22.9 TRANSCEND Primary...

Figure 22.10 SCHOLAR 5 study...

Figure 22.11 Axicabtagene...

Figure 22.12 ELARA: PFS and...

Figure 22.13 Outcome with...

Figure 22.14 CAR-T cell...

CHAPTER 23

Figure 23.1 Strategies to...

CHAPTER 24

Figure 24.1 Myeloid cells...

Figure 24.2 Innate signaling...

CHAPTER 25

Figure 25.1 IMiDs bind to...

Figure 25.2 Chemical structure...

Figure 25.3 Chemical structure...

Figure 25.4 PROTACs contain an...

Figure 25.5 Chemical structure...

Figure 25.6 Impact of lenalidomide...

CHAPTER 29

Figure 29.2 IR-2: Increase...

Figure 29.3 IR-3: An increase...

Figure 29.1 Indeterminate...

Guide

Cover

Title Page

Copyright Page

Table of Contents

List of Contributors

Volume Foreword

Volume Preface

Series Preface

Begin Reading

Index

End User License Agreement

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List of Contributors

Jeremy S. AbramsonMassachusetts General Hospital and Harvard Medical SchoolBoston, MA, USA

Stephen M. AnsellDivision of Hematology, Department of MedicineMayo ClinicRochester, MN, USA

Marie-France AubinUniversity Institute for Hematology-Oncology and Cell Therapy (IHOT) and Centre de recherche de l’HôpitalMaisonneuve-Rosemont-CIUSSS-EMTLUniversité de MontréalMontréal, Canada

Miriam BarnettMyeloid TherapeuticsCambridge, MA, USA

Allison M. BockDivision of HematologyDepartment of Internal Medicine Mayo ClinicMayo Clinic Comprehensive Cancer CenterRochester, MN, USA

Catherine M. BollardCenter for Cancer and Immunology ResearchChildren’s National Research InstituteChildren’s National HospitalWashington, DC, USA

Division of Blood and Marrow TransplantationChildren’s National HospitalWashington, DC, USA

Department of PediatricsThe George Washington University School ofMedicine and Health SciencesWashington DC, USA

George Washington Cancer CenterWashington DC, USA

Alessandro BroccoliIRCCS Azienda Ospedaliero-Universitaria di BolognaBologna, Italy

Istituto di Ematologia “Seràgnoli,” Dipartimento di ScienzeMediche e ChirurgicheUniversità degli StudiBologna, Italy

Ryan BucktroutWeill Cornell Medical CollegeCornell UniversityNew York, NY, USA

Timothy N. BullockProfessor of Pathology, School of MedicineUniversity of VirginiaVA, USA

Jason Yongsheng CHANDivision of Medical OncologyNational Cancer Centre Singapore, Singapore

Oncology Academic Clinical ProgramDuke-NUS Medical SchoolSingapore

Bruce D. ChesonLymphoma Research FoundationNew York, NY, USA

Center for Cancer and Blood DisordersBethesda, MD, USA

Máire A. ConradPerelman School of Medicine, Division ofGastroenterology, Hepatology, and NutritionThe Children’s Hospital of PhiladelphiaUniversity of PennsylvaniaPhiladelphia, PA, USA

Clifford M. CsizmarDepartment of MedicineMayo ClinicRochester, MN, USA

Jean-Sébastien DelisleUniversity Institute for Hematology-Oncology and CellTherapy (IHOT) and Centre de recherche de l’Hôpital Maisonneuve-Rosemont-CIUSSS-EMTLUniversité de MontréalMontréal, QC, Canada

Todd A. FehnigerStem Cell Biology and Bone MarrowTransplantation & Leukemia UnitOncology Division, Department of MedicineWashington University School of MedicineSt. Louis, MO, USA

Michele GerberMyeloid TherapeuticsCambridge, MA, USA

Daniel GettsMyeloid TherapeuticsCambridge, MA, USA

Nilanjan GhoshLevine Cancer Institute Charlotte, NC, USA

Richard C. GodbyDivision of HematologyDepartment of Internal Medicine Mayo ClinicMayo Clinic Comprehensive Cancer CenterRochester, MN, USA

John G. GribbenCentre for Haemato-OncologyBarts Cancer Institute, Queen Mary University of LondonLondon, UK

J.Erika HayduMassachusetts General Hospital and HarvardMedical SchoolBoston, MA, USA

Miriam T. JacobsStem Cell Biology and Bone Marrow Transplantation & Leukemia UnitOncology Division, Department of MedicineWashington University School of MedicineSt. Louis, MO, USA

Kallesh Danappa JayappaDivision of Hematology-OncologyTranslational Orphan Blood Cancer Research CenterProgram for T-Cell Malignancies, Department of MedicineUniversity of Virginia Comprehensive Cancer CenterVA, USA

Judith KelsenPerelman School of Medicine, Division of GastroenterologyHepatology, and NutritionThe Children’s Hospital of PhiladelphiaUniversity of PennsylvaniaPhiladelphia, PA, USA

Saad S. KenderianDivision of HematologyDepartment of Internal Medicine Mayo ClinicMayo Clinic Comprehensive Cancer CenterRochester, MN, USA

Nadia KhanCenter for Blood Disorders & Cellular TherapiesSwedish Cancer InstituteSeattle, WA, USA

Seok Jin KimDivision of Hematology-OncologySungkyunkwan University School of MedicineSamsung Medical Center, Seoul, Korea

Won Seog KimDivision of Hematology-OncologySungkyunkwan University School of MedicineSamsung Medical Center, Seoul, Korea

Hiroshi KimuraDepartment of VirologyNagoya University Graduate School of MedicineNagoya, Japan

Hannah KinoshitaCenter for Cancer and Immunology ResearchChildren’s National Research InstituteChildren’s National HospitalWashington, DC, USA

Division of Blood and Marrow TransplantationChildren’s National HospitalWashington, DC, USA

Division of Oncology, Children’s National HospitalWashington DC, USA

Mithunah KrishnamoorthySenior Scientist, Pfizer Inc.San Diego, CA, USA

Soon Thye LIMDivision of Medical OncologyNational Cancer Centre SingaporeSingapore

Oncology Academic Clinical ProgramDuke-NUS Medical SchoolSingapore

Yi LinDivision of HematologyDepartment of Internal Medicine Mayo Clinic Mayo Clinic Comprehensive Cancer CenterRochester, MN, USA

Jennifer K. LueLymphoma Service, Division of Hematological MalignanciesDepartment of Medicine, Memorial Sloan Kettering Cancer CenterNew York, NY, USA

John Sanil ManvalanDivision of Hematology-OncologyTranslational Orphan Blood Cancer Research CenterProgram for T-Cell Malignancies, Department of Medicine, University of Virginia Comprehensive Cancer CenterVA, USA

Enrica MarchiDivision of Hematology-OncologyTranslational Orphan Blood Cancer Research CenterProgram for T-Cell Malignancies, Department of MedicineUniversity of Virginia Comprehensive Cancer CenterVA, USA

Nancy D. MarinStem Cell Biology and Bone Marrow Transplantation & Leukemia UnitOncology Division, Department of MedicineWashington University School of MedicineSt. Louis, MO, USA

Siddartha MukherjeeMyeloid TherapeuticsCambridge, MA, USA

Columbia UniversityNew York, NY, USA

Takayuki MurataDepartment of Virology and ParasitologyFujita Health University School of MedicineToyoake, Japan

Swathi NamburiCenter for Blood Disorders & Cellular TherapiesSwedish Cancer InstituteSeattle, WA, USA

Owen A. O’ConnorDivision of Hematology-OncologyTranslational Orphan Blood Cancer Research CenterProgram for T-Cell MalignanciesDepartment of MedicineUniversity of Virginia Comprehensive Cancer CenterVA, USA

Choon Kiyat ONGLymphoma Genomic Translational Research LaboratoryDivision of Cellular and Molecular ResearchNational Cancer Centre SingaporeSingapore

Cancer and Stem Cell Biology, Duke-NUS Medical SchoolSingapore

Andrea OrlandoWeill Cornell Medical CollegeCornell UniversityNew York, NY, USA

Colette OwensLymphoma Service, Department of MedicineMemorial Sloan Kettering Cancer CenterNew York, NY, USA

Weill Cornell MedicineNew York, NY, USA

Ipsita PalDivision of Hematology-OncologyTranslational Orphan Blood Cancer Research CenterProgram for T-Cell Malignancies, Department of MedicineUniversity of Virginia Comprehensive Cancer CenterVA, USA

Krish PatelCenter for Blood Disorders & Cellular TherapiesSwedish Cancer InstituteSeattle, WA, USA

Kevin D. PavelkoDepartment of ImmunologyMayo ClinicRochester, MN, USA

Immune Monitoring Core LaboratoryMayo ClinicRochester, MN, USA

Barbara ProClinical Director of Lymphoma at the Herbert IrvingComprehensive Cancer Center, Columbia UniversityNew York, NY, USA

Marc-Anthony RodriguezDivision of Hematology and Medical OncologyDepartment of Medicine, Weill Cornell MedicineNew York, NY, USA

Weill Cornell Medical CollegeCornell UniversityNew York, NY, USA

Gilles SallesLymphoma Service, Department of MedicineMemorial Sloan Kettering Cancer CenterNew York, NY, USA

Weill Cornell MedicineNew York, NY, USA

Stephen J. SchusterAbramson Cancer CenterUniversity of PennsylvaniaPhiladelphia, PA, USA

Inna SerganovaWeill Cornell Medical CollegeCornell UniversityNew York, NY, USA

Eric L. SieversChief Medical OfficerBioAtla, Inc.San Diego, CA, USA

Sonali M. SmithElwood V. Jensen Professor of MedicineChief, Section of Hematology/OncologyThe University of ChicagoChicago, IL, USA

Kathleen E. SullivanPerelman School of Medicine, Division of Allergy and ImmunologyThe Children’s Hospital of PhiladelphiaUniversity of PennsylvaniaPhiladelphia, PA, USA

John M. TimmermanDivision of Hematology & OncologyUniversity of CaliforniaLos Angeles, CA, USA

Keri TonerCenter for Cancer and Immunology ResearchChildren’s National Research InstituteChildren’s National HospitalWashington, DC, USA

Division of Blood and Marrow TransplantationChildren’s National HospitalWashington, DC, USA

Division of Oncology, Children’s National HospitalWashington DC, USA

Robert A. UgerDrug Development ConsultantToronto, Canada

Jose C. VillasboasDivision of Hematology, Department of MedicineMayo ClinicRochester, MN, USA

Immune Monitoring Core LaboratoryMayo ClinicRochester, MN, USA

Michael WangPuddin Clarke Endowed ProfessorDepartment of Lymphoma and MyelomaHouston, TX, USA

George J. WeinerDirector Holden Comprehensive Cancer CenterProfessor Department of Internal MedicineUniversity of IowaIA, USA

Mark WongAssociate Director, VaxcyteSan Carlos, CA, USA

Roberta ZappasodiWeill Cornell Medical CollegeCornell UniversityNew York, NY, USA

Immunology and Microbial Pathogenesis ProgramWeill Cornell Graduate School of Medical SciencesNew York, NY, USA

Parker Institute for Cancer ImmunotherapySan Francisco, CA, USA

Alice ZhouStem Cell Biology and Bone Marrow Transplantation & Leukemia UnitOncology Division, Department of MedicineWashington University School of MedicineSt. Louis, MO, USA

Pier Luigi ZinzaniIRCCS Azienda Ospedaliero-Universitaria di BolognaBologna, Italy

Istituto di Ematologia “Seràgnoli,” Dipartimento di ScienzeMediche e ChirurgicheUniversità degli StudiBologna, Italy

Volume Foreword

Immunologically-based treatment for lymphoid malignancies has evolved dramatically in the quarter century since the human-murine chimeric monoclonal antibody, rituximab, became the first FDA-approved anticancer immunotherapy and entered routine clinical use. This agent emerged from early proof of principle work in B-cell lymphomas with anti-idiotype and, later, anti-CD20 and anti-CD19 monoclonals developed by Levy and others (Maloney et al. 1994, 1997; Meeker et al. 1985; Nadler et al. 1981). As a “naked” antibody, rituximab engaged intrinsic cytotoxic T-cell immunity and complement-based mechanisms and proved efficacious as a single agent in relapsed or refractory follicular lymphoma (McLaughlin et al. 1998) and, in short order, for other indolent B-cell malignancies. In pivotal phase 3 trials, rituximab combined with cytotoxic chemotherapy significantly improved cure rates and survival in diffuse large B-cell lymphoma, setting a standard of care which remains to this day (Coiffier et al. 2002; Habermann et al. 2006). Further progress was built upon this foundational work via the characterization of targetable surface antigens, and technologies that create chimeric and humanized antibodies with enhanced clinical activity.

Volume 2 of Precision Cancer Therapies provides a timely compendium of progress in both antibody- and cellular-based immunotherapeutics that leverage novel mechanisms of action to improve outcomes for patients with lymphoid malignancies. Broadly viewed, these include “weaponizing” monoclonal antibodies via radioimmunoconjugates and antibody-drug conjugates (ADC) that target B-cell malignancies via antigens such as CD19, CD20 or CD79b, as well as T-cell and Hodgkin lymphomas via CD30 targeting. More recently, bispecific T-cell engaging antibodies and chimeric antigen receptor-T-cells (CAR-T) have demonstrated durable responses in relapsed and refractory B-cell lymphomas, with CAR-T therapy outperforming traditional high-dose chemotherapy and autologous stem cell transplantation at first relapse of diffuse large B-cell lymphoma (Kamdar et al. 2022; Locke et al. 2022). Immune checkpoint inhibitors are firmly established for relapsed Hodgkin lymphoma, and are poised to become integrated into front-line therapy for those with advanced-stage disease (Ansell et al. 2015; Herrera et al. 2023). This Volume also explores novel targets for lymphoid malignancies such as CD47, the “don’t eat me” signal that, when blocked, therapeutically leads to phagocytosis and destruction of tumor cells.

The theme of rational therapeutic development and targeting is apparent throughout these chapters. The advances reported are built upon a deep and expanding knowledge of lymphoma biology and interactions within the tumor microenvironment, including an increased understanding of the mechanisms of treatment response and resistance. Predictive biomarkers across the many lymphoma subtypes will guide precision medicine approaches for individual patients. Until recently, curative-intent therapy for diffuse large B-cell lymphoma, the most common non-Hodgkin lymphoma entity, involved an anti-CD20 monoclonal antibody plus combination chemotherapy as noted above that cures only 50–60% of patients. Recent insights into the underlying biologic complexity of DLBCL are emerging via molecular profiling and identify unique lymphoma subtypes (Mondello and Ansell 2021; Wilson et al. 2021). These subtypes may be highly responsive to the incorporation of novel agents into current regimens, and diagnostic precision will facilitate clinical trials focused on biologically relevant entities.

How will these powerful advances improve the cure of lymphomas in the coming decade, and potentially reduce early- and late-onset treatment related toxicities? Traditional cytotoxic chemotherapy regimens will be de-escalated in intensity – or eliminated completely – in favor of immunotherapeutic agents alone or in combination with immunomodulatory agents, B-cell receptor pathway inhibitors and apoptosis-inducing agents. New metrics to determine the depth of remission will become standard, and will complement or perhaps even replace imaging-based assessments such as PET/CT scans. Highly sensitive determinations of measurable residual disease (MRD) in the peripheral blood or bone marrow will identify early disease progression and relapse, and dynamic assessment of the MRD kinetic response during induction therapy will enhance risk-adapted treatment approaches (Hoster et al. 2023; Melani et al. 2018).

The exciting progress of the past 25 years continues at an ever-accelerating pace, encompassing an array of therapeutic targets and modalities coupled with vital insights to lymphoma entities and their unique biology. It is indeed a hopeful and promising time for our patients, as is the need for ongoing international collaboration of laboratory and clinical scientists. The opportunities and dedication to progress are apparent in these pages, and provide a roadmap to continued success.

Michael E. Williams, MD, ScM, FACPByrd S. Leavell Professor of Medicine and Professor of PathologyUniversity of Virginia Comprehensive Cancer CenterUniversity of Virginia School of MedicineCharlottesville, Virginia, USA

References

Ansell, S.M., Lesokhin, A.M., Borrello, I. et al. (2015). PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma.

N Engl J Med

. 372(4): 311–319.

Coiffier, B., Lepage, E., Briere, J. et al. (2002). CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large B-cell lymphoma.

N Engl J Med

. 346(4): 235–242.

Habermann, T.M., Weller, E.A., Morrison, V.A. et al. (2006). Rituximab–CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma.

J Clin Oncol

. 24(19): 3121–3127.

Herrera, A.F., LeBlanc, M.L., Castellino, S.M. et al. (2023). SWOG S1826, a randomized study of nivolumab(N)-AVD versus brentuximab vedotin(BV)-AVD in advanced stage (AS) classic Hodgkin lymphoma (HL).

J Clin Oncol

. 41(17 Suppl.): LBA4.

Hoster, E., Delfau-Larue, M.-H., Macintyre, E. et al. (2023). Predictive value of minimal residual disease for efficacy of rituximab maintenance in mantle cell lymphoma: results from the European Mantle Cell Lymphoma Elderly Trial.

J Clin Oncol

. doi:10.1200/JCO.23.00899.

Kamdar, M., Solomon, S.R., Arnason, J. et al. (2022). Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial.

Lancet

. 399(10343): 2294–2308.

Locke, F.L., Miklos, D.B., Jacobson, C.A. et al. (2022). Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma.

N Engl J Med

. 386(7): 640–654. doi:10.1056/NEJMoa2116133.

Maloney, D.G., Grillo-López, A.J., Bodkin, D.J. et al. (1997). IDEC–C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin’s lymphoma.

J Clin Oncol

. 15(10): 3266–3274.

Maloney, D.G., Liles, T.M., Czerwinski, D.K. et al. (1994). Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC–C2B8) in patients with recurrent B-cell lymphoma.

J Clin Oncol

. 84(8): 2457–2466.

McLaughlin, P., Grillo-López, A.J., Link, B.K. et al. (1998). Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program.

J Clin Oncol

. 16(8): 2825–2833.

Meeker, T.C., Lowder, J., Maloney, D.G. et al. (1985). A clinical trial of anti-idiotype therapy for B cell malignancy.

Blood

. 65(6): 1349–1363.

Melani, C., Wilson, W.H., and Roschewski, M. (2018). Monitoring clinical outcomes in aggressive B-cell lymphoma: from imaging studies to circulating tumor DNA.

Best Pract Res Clin Haematol

. 31(3): 285–292.

Mondello, P. and Ansell, S.M. (2021). PHOENIX rises: genomic-based therapies for diffuse large B cell lymphoma.

Cancer Cell

. 39(12): 1570–1572.

Nadler, L.M., Stashenko, P., Hardy, R. et al. (1981). Characterization of a human B cell-specific antigen (B2) distinct from B1.

J Immunol

. 126(5): 1941–1947.

Wilson, W.H., Wright, G.W., Huang, D.W. et al. (2021). Effect of ibrutinib with R–CHOP chemotherapy in genetic subtypes of DLBCL.

Cancer Cell

. 39(12): 1643–1653.

Volume Preface

Cancer immunotherapy, the science of mobilizing the immune system to treat cancer, has been pursued for more than 150 years, yet it is only relatively recently that this powerful strategy has finally come of age and taken center stage in oncology. The history and background of the field is described in this Volume in Chapter 1 where we read that the concept of activating the immune system to treat cancer was initially tested in the 1860’s. Despite the attraction of the approach and anecdotal evidence of success and continued efforts, immunotherapy was nonetheless largely displaced in mainstream oncology by the advent of chemotherapy and radiotherapy. However, the specificity of the immune response and the potential to develop therapy with less toxicity continued to make immunotherapy an attractive if still somewhat elusive goal, and led to much further pre-clinical work.

The major advances that have laid the foundation for this new era of immunotherapy largely came in the last decades of last century. A major advance came with the development of monoclonal antibodies (1) for which Milstein and Köhler were awarded the Nobel prize with Niels Jerne in 1984. Not much later, advances in understanding of T cell anti-tumor biology, and genetic engineering led to the concept and design of chimeric antigen receptor (CAR) T cells (2). The process of humanization of monoclonal antibodies led to clinical success (3) and approval in 1997 of the anti-CD20 monoclonal antibody rituximab and not long thereafter, CAR T cells targeting CD19 were in clinical development (4). Increases in our knowledge of the mechanisms whereby tumor cells usurp physiologic processes in a pathological way to avoid immune recognition led to clinical development of checkpoint inhibitors to enhance anti-tumor responses (5). These clinical advances all have in common that they were built upon our increased scientific understanding of the immune system and increased bioengineering prowess.

This century has heralded the era of chemo-immunotherapy in which use of at least some form immunotherapy is considered standard of care for almost all cases of B cell lymphoma.

The challenge now is to maximally exploit the power of the immune system without unleashing unwanted auto-immune complications.

This volume on Precision Cancer Therapies focusing on immunotherapy in lymphoma is, therefore, very timely. Sections are organized around select concepts of targeting cell surface receptors, use of antibody drug conjugates, use of immune checkpoints, targeting macrophages, targeting EBV, targeting tumor associated antigens using autologous T cells, chimeric antigen receptor T cells and other approaches. The concept of the sections follows the same approach that was used for drug development in Volume 1, namely:

What is the immunological target;

What are the immune targeting agents at my disposal;

What is the data supporting their use;

How do we build upon, improve and optimize the therapy.

In this field with so much scientific advancement occurring at speed obviously leads us to question if text books such as this still have any place left in a modern world? Surely online learning is the way forward and how soon will it be before our diagnostic and therapeutic prowess is challenged by advances in artificial intelligence (AI) in medicine. However, even the most sophisticated AI systems still require learning tools and the quality of the chapters presented here assures me that this volume represents the state of the art of immunotherapy for lymphoma and the suggested reading from each chapter which ensure a solid foundation in the principles of immunotherapy for lymphoma for readers. As always, it is not just the overview of the field that each author brings, but their knowledge and perspective of where we are and where we need to go next that make this Volume so rewarding.

John G. Gribben, MD, DScHamilton Fairley Chair of Medical OncologyBarts Cancer Institute, Queen Mary University of London

References

Köhler, G. and Milstein, C. (1975). Continuous cultures of fused cells secreting antibody of predefined specificity.

Nature

256

, 495–497.

Gross, G., Waks, T. and Eshhar, Z.. (1989). Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity.

Proc Natl Acad Sci

U S A. 86:10024-8.

Maloney, D.C., Grillo-López, A.J. and Bodkin, D.J. et al. (1997). IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma.

J Clin Oncol

. 15:3266-74.

June, C.H., O’Connor, R.S., Kawalekar, O.U., et al. (2018). CAR T cell immunotherapy for human cancer.

Science

. 359:1361-1365.

Ansell S. (2021). Checkpoint blockade in lymphoma.

J Clin Oncol

. 39:525-533.

Series Preface

The pace of growth in scientific literature has been a subject for scientists who like to study bibliometric data, for decades. As early as 1951, Derek John de Solla Price, often regarded as one of the pioneers in studying rates of change in scientific literature, noted that the development of scientific information follows the law of exponential growth (de Solla Price 1951). In 1976, Price concluded that “at any time the rate of growth is proportional to the … total magnitude already achieved – the bigger a thing is, the faster it grows” (de Solla Price 1976). More recently, in 2018, Fortunato et al. concluded that “early studies discovered an exponential growth in the volume of scientific literature … a trend that continues with an average doubling period of 15 years” (Fortunato et al. 2018). Barabási and Wang suggested that if the scientific literature doubles every 15 years, “the bulk of knowledge remains always at the cutting edge” (Barabási and Wang 2021). That means, that the bulk of what a typical physician learns in undergraduate, graduate, or medical school is potentially obsolete by the time they assume responsibility for the care of patients, or that the information they rely on today was not yet in the textbooks that laid the foundation for their career.

For practicing oncologists, there in lies the problem. How does one stay abreast of these incomprehensible changes in scientific knowledge, much less understand it in a manner that can be used to help their patients. Cancer medicine has become a field where the need to appreciate basic science, and I emphasize “appreciate” not “comprehensively understand,” has become indispensable. Cancer medicine has become the place where fundamental cellular biology, pharmacology, and clinical medicine all collide, as physicians struggle to understand how they should integrate and evaluate diverse streams of information in order to arrive at the best solution for the patient sitting before them. It has become a field where translating the details of science has taken on larger and larger roles as physicians consider how to cure a disease, palliate pain, or improve the status quo, using only the information they have at their disposal.

Precision Cancer Therapies is designed to try and meet that very need. The volumes that will be produced in the series, the first two of which are devoted to the lymphoid malignancies, are developed around categories of diseases that share common themes in their pathogenesis, and, potentially, the strategies one might consider in targeting their dysregulated biology. Sections are organized around select mechanistic themes in disease biology established as being potentially important in disease pathogenies, followed by a chapter on the pharmacology of drugs identified as effective in nullifying that abnormal biology. Subsequent chapters in each section are focused on the translational aspects: how does one use the drugs at hand to alter the pathology in a therapeutically meaningful manner. Succeeding chapters highlight actual clinical data with specific drugs as both monotherapies and in “rational” combination. The sections within a volume are designed to share information using the same kind of logic a clinician might invoke in thinking about their patient. Here are some pertinent questions:

(i) What is the disease biology causing the problem?

(ii) What are the drugs at my disposal?

(iii) What is the data for the use of these drugs?

(iv) Are there ways to improve on these drugs’ efficacy by considering combination effects?

The sections take a decidedly translational approach to the problem.

With the advent of so much web-based learning and now the passion around how artificial intelligence (AI) might transform our approach, some might suggest, why another book, let alone a series of books. The answer lies in the simple fact that there is no substitute or singular surrogate that can replace your very own fund of knowledge. Perhaps the most widely recognized and touted AI approach ever to come to our attention did so in 2011, when we watched, with complete astonishment I might add, IBMs Watson beat the famed Ken Jennings and Brad Rutter in Jeopardy. Jennings and Rutter were the greatest Jeopardy champions of all time: more wins and more money than any other contestants in the history of the show. But, despite their intellectual prowess, they were no match for a computer that had intensely trained for years and “learned” how to beat Jennings and Rutter by playing simulated games against 100 of the best Jeopardy contestants ever. Yes, Watson too had to learn, and read, and assimilate years of information to compete with the human brain. While Jeopardy may be the most widely recognized and successful adventures for a room-sized computer, other forays of AI – and Watson in particular – in the field of oncology have, thus far at least, fallen short. IBM’s Watson for Oncology has been in development since 2012. It is being developed to provide state-of-the-art personalized treatment recommendations for patients with very specific kinds of malignant disease. Watson has undergone extensive “learning” at some of the most prestigious cancer centers in the world, being nurtured on the nuances of cancer medicine. Comprehensive details around the interpretation of blood tests, pathology, genetics, imaging data, and patient-oriented detail get fed into the computer. Then, the computational prowess of Watson combs through the vast medical literature we discussed above, to generate an evidence-based treatment recommendation for that specific patient. Why did Watson outperform on Jeopardy and underperform in oncology? One reason may be obvious. The state of cancer research and its impact on the practice of cancer medicine is extremely dynamic and in constant flux, at times it relies on instinct and experience, apparently making an appearance on Jeopardy look easy. Encyclopedic facts about the real world change slowly, if at all. Acknowledging that this type of AI technology is in its infancy (though most of us completed medical school, residency, and fellowship in the time Watson has been in development), the decade-long experience of Watson in cancer medicine has to date been less than flattering. The lay press has taken a decidedly negative impression of Watson’s first steps (watson-ibm-c), suggesting that while AI may have enormous appeal to the average observer, it is likely to never replace the intellectual prowess – and instinct – of that physician sitting in front of a patient. It re-enforces a centuries-old and fundamental truth, “knowledge itself is power,” at least as Sir Francis Bacon understood it.

And so, with some data in hand, and curiosity in endless supply, Precision Cancer Therapies intends to help keep physicians, scientists, health care providers, and the motivated reader stay up to date on the dynamic and every growing state of information in our fascinating profession. Sure, Watson and PubMed and Society Guidelines can aid us in our decision-making. However, there is nothing that can replace a good old-fashioned education nor the instinct of an informed practitioner of this most rewarding of crafts.

Owen A. O’Connor, MD, PhDAmerican Cancer Society Research ProfessorProfessor of MedicineUniversity of Virginia Comprehensive Cancer Center

References

Barabási, A.-L. and Wang, D. (2021).

The Science of Science

, Cambridge University Press.

de Solla Price, D.J. (1951). Quantitative Measures of the development of science.

Archives Internationales d'Histoire des Sciences

4(14): 85–93,

http://garfield.library.upenn.edu/price/pricequantitativemeasures1951.pdf

de Solla Price, D.J. (1976). General theory of bibliometric and other cumulative advantage processes.

J. Am. Soc. Inf. Sci

. 27 (5–6): 292–306.

http://garfield.library.upenn.edu/price/pricetheory1976.pdf

Fortunato, S., Bergstron, C.T., Borner, K., Evans, J.A., Helbing, D. et al. (2018) Science of science.

Science

359 (6379): eaao0185. doi: 10.1126/science.aao0185.