Gene and Cellular Immunotherapy for Cancer (Cancer Drug Discovery and Development)

Clinical and preclinical exploration of gene and cellular immunotherapy have seen rapid growth and interest with the development and approval of five Chimeric Antigen Receptor T-cell (CAR-T) products for lymphoma and myeloma and one Bispecific T-Cell Engager (BiTE) for acute lymphoblastic leukemia (ALL). These advances have dramatically improved the management of patients with relapsed refractory lymphoma, myeloma and leukemia. Gene and Cellular Immunotherapy for Cancer offers readers a comprehensive review of current cellular and gene-based immunotherapies. Divided into eighteen cohesive chapters, this book provides an in-depth and detailed look into cellular-based immunotherapies including CAR-T, TCR-T, TIL, Viral CTLs, NK cells in addition to T/NK cell engagers, focusing on their historical perspectives, biology, development and manufacturing, toxicities and more. Edited by two leading experts on gene and cellular immunotherapy, the book will feature chapters written by a diverse collection of recognized and up-and-coming experts and researchers in the field, providing oncologists, immunologists, researchers and clinical and basic science trainees with a bench to bedside view of the latest developments in the field. 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