Gene and Cellular Immunotherapy for Cancer

Preface
Acknowledgments
Contents
Part I: Overview
The History of Cellular Therapies
Introduction
Allogeneic Hematopoietic Cell Transplantation
Donor Lymphocyte Infusions
Chimeric Antigen Receptor T-Cells
Tumor Infiltrating Lymphocytes
T-Cell Receptor Engineered T-Cells
Viral Cytotoxic T-Lymphocytes
Natural Killer Cells
Dual-Targeting Immune Cell Engaging Therapies
References
Basics of Immunity
Innate Vs. Adaptive Immunity
The Stereotypical Immune Response to a Pathogen
Cells of the Innate Immune System
Cells of the Adaptive Immune System
T Cell Activation and Effector Functions
Basics Principles of T Cell-Mediated Immunity to Cancer and Immune Evasion
References
Part II: CAR-T
Biology of CAR-T Cells
Overall Anatomy and Design of CAR-T Cells
First, Second, and Third Generation CARs
Extracellular Antigen-Binding Domains
Hinge and Transmembrane Domain
Costimulatory Domains
Activation Domains
Next-Gen Modifications
Multi-Targeted CARs
Self- or Triggered-Assembly of CARs
Logic-Gated and Drug-Controlled CARs
Armored CARs
CAR Targets
Hematologic Malignancies
Solid Tumors
References
Cell Types Used for CAR Generation
Allogeneic CAR T-Cells
γδ T-Cells
NK Cells
NKT and iNKT Cells
iPSC
Defining the T-Cell Phenotype and CD4/CD8 Ratio
Macrophages
Neutrophils
References
Combination Therapeutics with CAR-T Cell Therapy
Introduction
Combinations that Increase CAR-T Efficacy
CAR-T Combination with Immunomodulatory Agents
Lenalidomide
Ibrutinib
PD-1 Blockade
Agonistic Anti-Costimulatory Receptor Antibodies
Oncolytic Viral Therapy
Inhibitors of the PI3K Pathway
Long-Acting Interleukin-7 Agonist (NT-I7)
Combination with Cancer Directed Therapies
Rituximab
Venetoclax
Radiation
Combination to Modulate Tumor Antigen Expression
Small Molecule g-Secretase (GS) Inhibitors
Bryostatin 1
Combination with Hematopoietic Cell Transplantation
Combinations that Decrease CAR-T Toxicity
IL-6 or IL-6R Inhibition (Tocilizumab, Siltuxumab)
GM-CSF Depletion (Lenzilumab)
IL-1 Inhibition (Anakinra)
JAK/STAT Inhibition (Ruxolitinib, Itacitinib)
Reversible CAR-T Inhibition (Dasatinib)
Endothelial Cell Protection (Defibrotide)
TNF-a Inhibition (Etanercept)
Systemic Immune System Suppression (Steroids)
PI3K Inhibition
Conclusion
References
Safety Switches Used for Cellular Therapies
Introduction
Suicide Genes for Control of GVHD
iCasp9 Suicide Gene
Administration of Allo-Depleted iCasp9 T Cells
Administration of Alloreplete iCasp9 T Cells
HSV-TK Suicide Gene
Suicide Gene Application with Gene-Redirected T Cells
Insertional Mutagenesis Risks of Gene-Modified Cellular Products
Conclusions
References
Off-the-Shelf CAR-T
Autologous Donor CAR-T
Limitation of Autologous Donor CAR-T
Allogeneic Cellular Therapy
Genetically Edited Allogeneic Donor Derived CAR-T
Off-the-Shelf “Universal” Gene-Edited CAR-T Cells for B-Cell Malignancies: Results from Clinical Trials
Clinical Experience in Acute Lymphoblastic Leukemia (ALL) Using TALEN-Edited CAR19 T Cells
Emerging Experience with Next-Generation Genome Edited CAR19 T Cells in B-Cell Malignancies
Off-the-Shelf “Universal” Gene-Edited CAR-T Cells for Indications beyond B-Cell Malignancies
Allogeneic CAR-T for the Treatment of T Cell Malignancies
Allogeneic CAR-T for the Treatment of Multiple Myeloma
Allogeneic CAR-T for the Treatment of AML
Summary
References
Manufacturing of CAR-T Cells: The Assembly Line
Introduction
CAR-T Cell Manufacturing
T Cell Collection: The Beginning
T Cell Selection: Fine-Tuning the Starting Material
T Cell Activation: Preparing T Cells for Gene Transfer and Expansion
Gene Transfer: Introduction of CARs into T Cells
Large Scale CAR-T Cell Expansion: Growing Cells to Therapeutic Dose
Cryopreservation: Enabling Storage and Long Distance Shipment
Release of CAR-T Cell Products: Obtaining the Driver’s License
Future Perspectives
References
Navigating Regulations in Gene and Cell Immunotherapy
Introduction
Regulatory Chemistry, Manufacturing, and Control (CMC) Considerations for Cellular Immunotherapies
CGTP and CGMP Requirements for Manufacturing
Reagents and Raw Materials
Cell Source Material and Donor Eligibility
Cell Bank Systems
Vector Qualification and Testing
Lot Release Testing and Product Specifications
Safety Assays
Dose
Identity
Purity
Viability
Potency
Stability
Regulatory Preclinical Considerations for Cellular Immunotherapy Products
Regulatory Clinical Considerations for Cellular Immunotherapy Products
Early-Phase Trials
Patient Population
Trial Design and Endpoints
Dose Regimen
Adverse Event Monitoring and Reporting
Long-Term Follow-Up
Treatment Discontinuation Criteria and Trial Stopping Criteria
Later Phase Clinical Trials
Interaction with FDA
Expedited Programs
Conclusions
References
Bringing CAR-T to the Clinic
Overview of the CAR-T Patient Journey
Patient Selection
CAR-T Product Selection
Approved CAR-T Cell Products in Clinical Use
Axicabtagene Ciloleucel
Tisagenlecleucel
Lisocabtagene Maraleucel
Brexucabtagene Autoleucel
Idecabtagene Vicleucel
Clinical Management of Patients Receiving CAR-T Cell Therapy
Referral and Authorization
Patient Fitness Testing
Apheresis
Bridging Therapy
Lymphodepleting Chemotherapy Prior to CAR-T Cell Infusion
Acute Monitoring after CAR-T Cell Infusion
Disease Response Evaluation and Relapse Prevention
CAR-T Cell Therapy Survivorship
Conclusion
References
CAR-T Cell Complications
Introduction
Pre-Clinical Models of CRS and Neurotoxicity
CAR T-Cell Toxicity in Clinical Studies and Correlative Studies
Cytokine Release Syndrome in Diffuse Large B-Cell Lymphoma
Cytokine Release Syndrome in B-Cell Acute Lymphoblastic Leukemia
Cytokine Release Syndrome in Mantle Cell Lymphoma
Cytokine Release Syndrome in Indolent Non-Hodgkin Lymphoma
Cytokine Release Syndrome in Multiple Myeloma
Neurotoxicity in Diffuse Large B Cell Lymphoma
Neurotoxicity in B-Cell Acute Lymphoblastic Leukemia
Neurotoxicity in Mantle Cell Lymphoma
Neurotoxicity in Indolent Non-Hodgkin Lymphoma
Neurotoxicity in Multiple Myeloma
Risk Factors and Predictors of Toxicity
Consensus CRS and Neurotoxicity Grading Systems
Definition of CRS
Grading of CRS
Definition of Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS)
Grading of ICANS
Guidelines for Management
Management of CRS
Management of ICANS
Prolonged Cytopenias and Their Management
Antimicrobial Prophylaxis During CAR T Cell Therapy
Hypogammaglobinemia and Management
Monitoring for Replication Competent Retrovirus/Lentivirus, Mutagenesis, and Secondary Malignancies
Replication Competent Virus
Insertional Mutagenesis and Development of Secondary Malignancies
Conclusion
References
Mechanisms of Resistance and Relapse After CAR-T Cell Therapy
Introduction
Tumor Evasion
Antigen Loss: Genomic and Transcriptional Modulation
Antigen Modulation: Structural
Antigen-Independent Resistance
T Cell Failure
T Cell Fitness
Product Manufacturing
CAR-T Cell Dysfunction
Next Steps
Conclusions
References
Part III: TIL
Tumor Infiltrating Lymphocytes (TIL): From Bench to Bedside
Preclinical Demonstration that Tumor Infiltrating Lymphocytes Have Therapeutic Potential
Clinical Demonstration of Tumor Responses with Lymphokine Activated Killer Cells (LAK)
Identification and Purification of Tumor-Infiltrating Lymphocytes (TIL)
Initial Clinical Trials of TIL Therapies
Role of Nonmyeloablative Conditioning and Total Body Irradiation Prior to TIL Therapy
Management of Side Effects of High Dose IL-2 Therapy
Generation of TIL Products at Clinical Scale
Clinical Trial Data in Non-melanoma Tumor Histologies
Renal Cell Carcinoma
Non-small Cell Lung Cancer
Gynecologic Malignancies
Gastrointestinal Malignancies
Malignant Gliomas
Persistence of TIL Post-Infusion
Determination of TIL Specificity
Clinical Studies of Tumor Antigen-Targeted TIL
Future Directions
Which Populations of TIL Have the Best Capacity for Therapeutic Efficacy?
What Are the Ideal Conditions for the Generation of TIL Products?
Where Does TIL Therapy Fit into the Current Clinical Landscape?
References
Part IV: TCR
T-Cell Receptor (TCR) Engineered Cells and Their Transition to the Clinic
Introduction
Tumor Infiltrating Lymphocytes
TCR Receptor
Manufacturing of TCR Gene Modified T (TCR-T) Cells
Clinical TCR Targets
MART1
gp100
CEA
NY-ESO-1
MAGE-A3
MAGE-A4
Toxicities
Strategies to Enhance TCR-T Efficacy
Conclusion
References
Part V: Viral CTLs
Viral Cytotoxic T Lymphocytes (CTLs): From Bench to Bedside
History
Generation
Multi-Viral Targeted Cells
Lymphocyte Source
Characterization of T Cells
Pre-Clinical Models
CTL Persistence
Clinical Experience
Future Directions
Accessibility
Applicability
References
Part VI: NK Cell
Biology of NK Cells and NK Cells in Clinic
Introduction
NK Cells in Cancer
Isolation, Expansion and Stimulation of NK Cells
Cytokine Induced Memory-Like (CIML) and Adaptive NK Cells
CIML NK Cells in Cancer Treatment
Overcoming Tumor Evasion of the NK Cell Response
References
Part VII: T/NK Cell Engagers
Biology and Clinical Evaluation of T/NK Cell Engagers
Introduction
Bispecific Antibody Design
Immunogenicity
Structure
Pharmacokinetics
Mechanism of Action
Antigen Selection
Tumor Antigens
Immune Cell Antigens
Clinical Translation of Bispecific Engagers
T Cell Engagers
Hematologic Malignancies
Solid Tumors
Bispecific Innate Immune Cell Engagers
Hematologic Malignancies
Solid Tumors
Alternative Delivery Methods and Adoptive Cellular Therapies
Bispecific Antibody Armed Activated T Cells
T Cells Secreting Bispecific Engagers
Alternative Delivery Methods
Challenges and Future Directions for Engager Therapy
References
Part VIII: Logistics
Roadmap for Starting an Outpatient Cellular Therapy Program
Introduction
Rationale
Barriers
Determinants and Components of a Successful Outpatient Program
Key Factors in Planning Phase
Clinical Space and Logistics of Patient Care
Workforce
Resource Utilization and Tracking
Setting up an Outpatient Cellular Therapy Center
Cellular Therapy Educational Considerations
Summary
References
Index