Oncoimmunology

 

Description:

In this book, leading experts in cancer immunotherapy join forces to provide a comprehensive guide that sets out the main principles of oncoimmunology and examines the latest advances and their implications for clinical practice, focusing in particular on drugs with FDA/EMA approvals and breakthrough status. The aim is to deliver a landmark educational tool that will serve as the definitive reference for MD and PhD students while also meeting the needs of established researchers and healthcare professionals. Immunotherapy-based approaches are now inducing long-lasting clinical responses across multiple histological types of neoplasia, in previously difficult-to-treat metastatic cancers. The future challenges for oncologists are to understand and exploit the cellular and molecular components of complex immune networks, to optimize combinatorial regimens, to avoid immune-related side effects, and to plan immunomonitoring studies for biomarker discovery. The editors hope that this book will guide future and established health professionals toward the effective application of cancer immunology and immunotherapy and contribute significantly to further progress in the field.

 

 

Table of Contents:

 

1: Principles of Oncoimmunology

Part I: Fundamentals in I-O

2: The Human Tumor Microenvironment

2.1 Introduction

2.2 Cancer’s Natural History

2.3 The Tumor Immune Microenvironment

2.3.1 Tumor-Associated Macrophages

2.3.2 NK Cells

2.3.3 Dendritic Cells

2.3.4 Tertiary Lymphoid Structures

2.3.5 CD4+ and CD8+ T Cells

2.3.6 B Lymphocytes

2.3.7 Spatiotemporal Dynamics of the Tumor Immune Microenvironment

2.4 The TME Dictates Clinical Outcome for the Patients

2.4.1 T Cells

2.4.1.1 CD8+ T Cells

The “Classical” Case of CRC

The Discordant Case of ccRCC

2.4.1.2 CD4+-, Th2-, and Th17-Oriented T Cells

2.4.1.3 Regulatory T Cells (Tregs)

2.4.2 B Cells

2.4.3 Macrophages

2.4.4 New Techniques to Estimate the Immune Cell Populations in Tumors

2.5 TME as Predictors of Response to Therapy

2.5.1 First Emerging Data from Checkpoint Blockade Treated Patients

2.5.1.1 Tumor-Infiltrating Lymphocytes

2.5.2 From the Molecular to the Immune Signatures

References

3: CD8+ T Cells in Immunotherapy, Radiotherapy, and Chemotherapy

3.1 Introduction

3.2 CD8+ T Cells in Immunotherapy

3.2.1 Adoptive T-Cell Transfer

3.2.2 Checkpoint Blockade

3.2.3 Antibody-Based Targeted Therapy

3.3 CD8+ T Cells in Radiotherapy

3.3.1 Radiation Therapy Induces Immune Responses

3.3.2 CD8+ T Cells in Radiotherapy

3.4 CD8+ T in Cytotoxic Chemotherapy

3.4.1 Chemotherapeutic Agents Activate Immune Responses

3.4.2 Chemotherapy Enhances the Antitumor Function of CD8+ T Cells

3.4.3 CD8+ T Cells Sensitize Tumor Cells to Chemotherapy

3.5 Future Directions

References

4: Mutant Epitopes in Cancer

4.1 Introduction

4.2 Antigen Processing and Presentation in Cancer

4.3 Cancer Antigens and Epitopes: From Discovery to Therapeutic Application

4.4 Clinical Significance of Neoepitope-specific Immune Responses

4.5 Harnessing Basic Immunology to Improve Clinical Immunotherapeutic Approaches

References

5: The Secrets of T Cell Polarization

5.1 Introduction

5.2 Transcriptional and Epigenetic Regulation of T Cell Differentiation

5.2.1 A Network of Pioneer and Master Regulators, Transcription Factors, Governs CD4+ T Cell Diff

5.2.2 An Expression Gradient of Multiple Factors to Control the Balance Between Effector-­Like

5.2.3 ncRNAs in the Epigenetic Control of T Cell Differentiation

5.3 Metabolic State and T Lymphocyte Differentiation

5.3.1 Metabolic Reprogramming During T Cell Activation

5.3.2 Metabolic Checkpoints and Pathways Controlling T Cell Differentiation

5.3.3 Metabolic State and T Cell Differentiation

5.4 T Cell Transcriptional Plasticity

5.4.1 Cytokines, the Master Regulators of Plasticity

5.4.2 Transcriptional and Epigenetic Modulation of T Cell Plasticity

5.4.3 Metabolic Regulation of Plasticity

5.5 T Cell Differentiation Defects and Human Diseases

5.6 Concluding Thoughts

References

6: Regulatory T Cells: Their Role, Mechanism of Action, and Impact on Cancer

6.1 Introduction

6.2 Discovery of a T Cell Population that Regulates Autoimmunity

6.2.1 Suppression of Autoimmunity by CD4+ T Cells

6.2.2 Markers of Regulatory T Cells

6.2.3 Regulatory T Cell Origins: Thymus Versus Periphery

6.3 Regulatory T Cell Suppressive Mechanisms

6.3.1 Contact-Dependent Suppression of Immune Responses

6.3.2 Suppression of Immune Responses via Soluble Factors

6.3.3 Potentiation of Suppression and Survival

6.4 Relationship Between Regulatory T Cells and Cancer

6.4.1 Role of Regulatory T Cells in Suppression of Antitumor Immunity

6.4.2 Local Expansion of Regulatory T Cells in Tumors

6.4.3 Regulatory T Cell Trafficking to Tumor Tissues

6.4.4 Regulatory T Cells and Prognosis

6.5 Immunotherapeutics and Regulatory T Cells

6.5.1 Altering the Balance Between Regulation and Inflammation

6.5.2 Potential Direct Effects of Therapeutics on Regulatory T Cells

6.6 Perspectives on the Importance of Regulatory T Cells in Immuno-Oncology

References

7: Purinergic Receptors: Novel Targets for Cancer Immunotherapy

7.1 Introduction

7.2 Extracellular ATP and Adenosine in Cancer

7.3 Purinergic Receptors in Immunity and Cancer

7.3.1 Effect on Tumor Cells

7.3.1.1 ATP Sensing P2 Receptors: P2XR and P2YRs

7.3.1.2 Adenosine Generating Ecto-nucleotidases: CD39 and CD73

7.3.1.3 Adenosine Binding P1 Receptors: A1, A2a, A2b, and A3

7.3.2 Effects on Immune Cells

7.3.2.1 ATP/ADP Binding P2 Receptors

7.3.2.2 Adenosine Generating Ecto-nucleotidases: CD39 and CD73

7.3.2.3 Adenosine Binding P1 Receptors: A1, A2a, A2b, and A3

7.4 Pre-clinical Evidence for Purinergic Signaling in Cancer

7.4.1 Extracellular ATP in Cancer

7.4.1.1 Adenosine Generating Ecto-nucleotidases in Cancer Progression

7.4.2 Adenosine Receptors in Cancer Progression and Metastasis

7.5 Combination Therapies

7.6 Ongoing Clinical Trials

References

8: Plasmacytoid DC/Regulatory T Cell Interactions at the Center of an Immunosuppressive Network i

8.1 pDC Are Deficient for IFN-α Production in Primary Tumor Environment

8.1.1 pDC Are Specialized in Type-I IFN Production

8.1.2 Evidence for a Role of Type-I IFN in Cancer Immunosurveillance

8.1.3 pDCs in Breast Tumors

8.1.4 pDCs in Ovarian Tumors

8.1.5 Mechanisms Leading to TApDC Functional Defect

8.2 Treg in Breast Tumors

8.2.1 Treg Recruitment

8.2.2 pDC-Mediated Treg Expansion

8.2.2.1 Conclusion

8.2.3 Treg-Mediated Suppression

8.3 Therapeutic Strategies

8.3.1 Strategies to Neutralize Treg Function Based on pDC/Treg Interaction

8.3.1.1 TApDC Reactivation

8.3.1.2 TGF-β Neutralization

8.3.1.3 ICOS Neutralization on Treg

8.3.1.4 CD39/CD73 Axis

8.3.2 Other Strategies Based on Treg Targeting/Depletion

8.3.2.1 Blockade of Treg Cell Induction and Recruitment

8.3.2.2 Treg Depletion

8.3.2.3 Blockade of Treg Function

References

9: Cancer Immunosurveillance by Natural Killer Cells and Other Innate Lymphoid Cells

9.1 Introduction

9.2 Surface Receptors Involved in Tumor Recognition by ILCs

9.3 Cytokines and Soluble Factors that Activate ILCs

9.4 Direct Clearance of Cancer Cells by ILCs

9.5 Cross-Talk between ILCs and Other Immune Cells Resulting in Anti-Cancer Immunity

References

10: Biology of Myeloid-Derived Suppressor Cells

10.1 Introduction

10.2 Characterization of MDSCs in Mouse and Humans

10.3 Mechanism of MDSC-­Mediated Immune Suppression

10.4 Mechanisms Regulating MDSC Accumulation and Function

10.5 Relationship of MDSCs with Other Myeloid cells

10.6 Therapeutic Strategies to Target MDSCs in Cancer

References

11: Effect of Pharmaceutical Compounds on Myeloid-Derived Suppressor Cells

11.1 Introduction

11.2 Impact of Cytotoxic Chemotherapies on MDSCs

11.3 Effect of Chemotherapies on MDSCs in Human

11.4 Tyrosine Kinase Inhibitors

11.5 Other FDA-Approved Molecules with Impact on MDSCs

11.6 Drugs in Developments

11.7 Combination with Checkpoint Inhibitors

References

12: Immunogenic Stress and Death of Cancer Cells in Natural and Therapy-Induced Immunosurveillan

12.1 Introduction

12.2 Annexin A1

12.3 ATP

12.4 Calreticulin

12.5 HMGB1

12.6 Type-1 Interferons and Chemokines

12.7 Concluding Remarks and Perspective

References

13: Genetics and Immunology: Tumor-­Specific Genetic Alterations as a Target for Immune Modulat

13.1 Introduction

13.2 Hot and Cold: How to Measure the Tumor Immunity

13.3 Genetic Characteristics of the Tumor Influencing the Host’s Immune Response

13.4 Host-Specific Genetic Characteristics Determining the Tumor-Specific Immune Response

13.5 Tumor-Specific Genetic Alterations as a Target for Vaccination

13.6 Genetic Alterations of the Tumor as Predictive Biomarkers for Immune Response to Immune C

13.7 Personalized Immunotherapy: Combination of Immune Modulation Therapies

References

Part II: Breakthrough Status

14: Peptide-Based Therapeutic Cancer Vaccines

14.1 Introduction

14.2 Mode of Action of Therapeutic Cancer Vaccines

14.3 What Makes a Good Therapeutic Cancer Vaccine?

14.4 T Cell Epitope-Based Vaccination

14.5 Short Peptides Versus Long Peptides for Cancer Vaccines

14.6 Alternative Vaccination Platforms

14.7 Efficacy of SLP Vaccination Depends on Addition of a Strong Adjuvant

14.8 Clinical Efficacy of SLP Vaccines in Patients with Premalignant Disease

14.9 Clinical Efficacy of Therapeutic SLP Vaccines in Cancer Patients Requires Combination Treatm

14.10 Perspectives

References

15: Cancer Vaccines for HPV Malignancies

15.1 Introduction

15.1.1 Biology of HPV Infection

15.1.2 Systemic Immune Responses in Natural Infection

15.1.3 Tissue-Localized Immune Responses to Natural Infection

15.1.4 Preventive Vaccines

15.1.5 Therapeutic Vaccines

15.1.6 Adoptive T Cell Therapy

15.1.6.1 Mechanisms of Immune Evasion in the Tumor Microenvironment

15.1.7 Immune Checkpoint Inhibitors

15.1.8 Immunomodulatory Effects of Conventional Cancer Treatment Modalities

References

16: NK Cell-Based Therapies

16.1 NK Cell Manipulations in Therapeutic Approaches

16.1.1 Infusion of Purified Activated NK Cells

16.1.2 Gene Modification of NK Cells to Improve the Efficacy of Adoptive Immunotherapy

16.1.3 Infusion of Cytokines

16.1.4 Infusion of Tumor Antigen-­Specific Antibodies to Induce NK Cell ADCC

16.1.5 Infusion of Antibodies Directed Against Inhibitory NK Cell Receptors

16.2 Immune Checkpoint Inhibitors (ICI)

16.2.1 KIRs

16.2.2 NKG2A

16.2.3 PD1

16.2.4 LAG3

16.2.5 Tim-3

16.2.6 TIGIT

16.3 Perspectives

References

17: IDO/TDO Inhibition in Cancer

17.1 Introduction

17.2 IDO1 in Immune Escape from T-Cell Immunity

17.3 IDO1 in Inflammatory Programming: MDSC Development and Metastasis

17.4 IDO1 in Inflammatory Programming: Pathogenic Neovascularization and Metastasis

17.5 IDO2 in B-cell Inflamed States and Certain IDO1 Functions: Connections and Questions

17.6 Tryptophan Dioxygenase (TDO) in Inflammatory Programming: Immune Escape, Anoikis Resistance,

17.7 Lead Clinical Agents: Indoximod, GDC-0919, and Epacadostat

17.7.1 Indoximod

17.7.2 GDC-0919

17.7.3 Epacadostat (INCB024360)

17.8 Other IDO/TDO Inhibitor Clinical Candidates

References

Part III: FDA-EMA Approval of I-O

18: Tumor-Targeted Antibodies

18.1 Introduction

18.2 From Polyclonal to Monoclonal Antibodies

18.3 Monoclonal Antibodies, a Versatile Platform for Cancer Therapies

18.3.1 Mechanisms of Action of Tumor-Targeting Antibodies

18.3.2 Engineering of Tumor-­Targeting Monoclonal Antibodies

18.4 From Tumor-Targeting to Immune-Targeting Monoclonal Antibodies (and Back)

18.5 Bi-specific Antibodies: Tumor and Immune Targeted

18.6 Challenges and Perspectives for Tumor-Targeted Antibodies

References

19: PD1 Checkpoint Blockade in Melanoma: From Monotherapy to Combination Therapies

19.1 Malignant Melanoma

19.2 CD8+ T Cell Responses Against Melanoma

19.3 Checkpoint Control of T Cell Activation

19.4 Checkpoint Blocking Therapy

19.5 Approved Anti-PD1 Antibodies

19.6 Nivolumab

19.7 Pembrolizumab

19.8 Approved Combined Anti-PD1/Anti-CTLA-4 Combination Therapy

19.9 Biomarkers Associated with Response to Anti-PD1 Therapy

19.10 Resistance to Therapy

19.11 Perspective

References

20: Immune Checkpoint Inhibition in Lung Cancer

20.1 Introduction

20.2 Immune Checkpoint Blockade

20.3 Initial Studies with Single Agent Immune Checkpoint Inhibitors

20.4 Randomized Clinical Trials in Previously Treated Patients

20.5 First-Line Therapy

20.6 Predictors for Response to Immune Checkpoint Inhibitors

20.7 Summary

References

21: PD-1 Blockade in Renal Cell Carcinoma

21.1 Introduction

21.2 Role of PD-1 and Its Ligand in RCC

21.3 Anti-PD-1 Studies in RCC

21.3.1 Phase I

21.3.2 Phase II

21.3.3 Phase III

21.4 PD-L1 as Predictive Biomarker

21.5 Future of PD-1 Blockade in RCC

References

22: BCG and Anti-PDL-1 Ab in Bladder Cancers

22.1 Introduction

22.2 BCG

22.2.1 Current Indication of BCG

22.2.2 Mechanisms of Action

22.2.3 Mechanisms of Resistance to BCG Therapy

22.3 PD-1 and PD-L1 Inhibitors

22.3.1 Rationale for PD-1 and PD-L1 Inhibitors

22.3.2 Proof of Concept Trials with PD-1 and PD-L1 Inhibitors

22.3.3 PD-1 and PD-L1 Inhibitors Will Change the Standard of Care in Metastatic Setting

22.3.4 Can We Select the Patients Who Are More Likely to Respond to PD-1 and PD-L1 Inhibitors?

22.3.5 How Can We Increase the Number of Responders?

22.4 Perspective

References

23: PD-L1 and Other Immunological Diagnosis Tools

23.1 Introduction

23.2 PD-1/PD-L1 Blockade and the Role of PD-L1 Expression as Biomarker

23.2.1 Early Experience in Solid Tumors

23.2.2 NSCLC

23.2.3 Urogenital Malignancies (Urothelial and Renal Cell Carcinoma)

23.2.4 Melanoma

23.2.5 Virus-Associated Cancers

23.3 PD-L1 Assays

23.4 What is the Meaning of PD-L1 Expression in the Tumor Microenvironment (TME)?

23.5 Other Potential Biomarkers

23.5.1 Mutational Loads

23.5.2 Molecular Subgroups

23.5.3 CD8+ TIL

23.5.4 Gene Signatures

23.5.5 T-Cell Repertoire

23.5.6 Peripheral Blood Markers

23.6 Conclusions and Future Directions

References

24: Oncolytic Viruses: T-VEC and Others

24.1 Background

24.1.1 What Are Oncolytic Viruses?

24.1.2 History of Oncolytic Viruses

24.1.3 What Are the Characteristics of This Therapy?

24.1.4 Mechanism of Action of Oncolytic Viruses

24.1.5 Types of Oncolytic Viruses

24.2 T-VEC

24.2.1 What Is T-VEC

24.2.2 Structure and Proposed Mechanism of Action of T-VEC

24.2.3 Administration, Handling of T-VEC

24.2.4 Preclinical Studies Using T-VEC

24.2.5 Early Phase Clinical Trials

24.2.6 Phase III Clinical Trials

24.2.7 Adverse Events

24.2.8 Approved Use

24.2.9 Future of T-VEC

24.3 Other Oncolytic Viruses

24.3.1 Reovirus

24.3.2 Coxsackievirus

24.3.3 Adenovirus

24.3.4 Vaccinia Virus

24.3.5 Measles Virus

24.3.6 Poliovirus

24.3.7 Retrovirus

24.3.8 Parvovirus

References

Part IV: Developing Fields

25: Innate Immune Receptors in the Regulation of Tumor Immunity

25.1 Introduction

25.1.1 Role of TLRs in the Regulation of Tumor Development

25.1.2 Role of Cytosolic Nucleic Acid Sensors in Tumor Development

25.1.3 Role of CLRs in Tumor Development

25.1.4 Role of NLRs in Tumor Development

25.2 Concluding Remarks

References

26: Co-stimulation Agonists via CD137, OX40, GITR, and CD27 for Immunotherapy of Cancer

26.1 Immune Synapses and the Co-stimulation of Anticancer T-Cell Immune Responses

26.2 Preclinical and Clinical Experience with Antibody Agonists of Co-stimulatory Receptors of 

26.3 CD137 (4-1BB)

26.4 OX40 Co-stimulation

26.5 GITR

26.6 CD27

26.7 Future Perspectives

References

27: The Impact of the Intestinal Microbiota in Therapeutic Responses Against Cancer

27.1 Introduction

27.2 Evaluating Gut Dysbiosis in Cancer Bearers

27.3 Microbiome and Cancer Incidence

27.4 Radiotherapy and Microbiota

27.5 Cyclophosphamide and Gut Microbiota

27.6 Platinum Salts and Gut Microbiota

27.7 Gut Bacteria and the Efficacy of Immuno-oncological Compounds

27.8 Role of Intestinal Microbes in Graft-Versus-Host Disease (GVHD)

27.9 Bacteria for Therapy of Cancer: Probiotics and Others

27.10 Genetically Modified Bacteria

27.11 Microbial Products with Cancer-Modulating Properties

27.12 Future Prospects

References

28: Local Immunotherapies of Cancer

28.1 Introduction

28.2 Immunogenic Cell Death

28.3 Recruitment of Immune Infiltrate

28.4 Activation of Dendritic Cells

28.5 Modulating Immunosuppressive Cellular Compartment

References

29: Strategies to Reduce Intratumoral Regulatory T Cells

29.1 Introduction

29.1.1 Treg Characterization, in Mouse and Human

29.1.2 Basic Treg Immunosuppressive Activities

29.1.3 Prognostic Value of Treg Presence in Peripheral Blood and Tumor Microenvironment in Huma

29.1.4 Treg Recruitment into Tumor Microenvironment

29.1.5 Treg-Targeting Approaches in Cancer Therapy

29.2 Treg Depletion by Low Dose of Chemotherapy

29.3 IL-2 Receptor (IL-2R)-Induced Treg Depletion

29.3.1 Anti-CD25 Antibodies (e.g., Daclizumab and Basiliximab)

29.3.2 Denileukin Diftitox (ONTAK®)

29.3.3 Anti-CD25 Immunotoxin Antibodies

29.3.4 Emerging New Anti-CD25 Antibody Therapies

29.4 Blocking Treg Cell Trafficking into Tumors

29.4.1 CCL22–CCR4 Pathway Blockade

29.4.2 CXCR4–CXCL12 Pathway Blockade

29.5 Anti-angiogenic Therapies Targeting Regulatory T Cells

29.6 Immune Checkpoint Blockade Therapy (Anti-�CTLA-�4 Antibodies)

29.7 Agonist Antibodies Affecting Treg Immunosuppressive Activity

29.7.1 Agonist Anti-GITR Antibody

29.7.2 OX40/OX40L Agonist Agents

29.8 CD39–CD73–A2aR Pathway Blockade: An Emergent Therapy Targeting Tregs

References

30: Synergy Between Radiotherapy and Immunotherapy

30.1 Introduction

30.2 Radiation: Current Clinical Use and Local Effects

30.3 From Local to Abscopal: Radiotherapy and Systemic Tumor Control

30.4 Augmenting Local Control: Radiotherapy Effects that Promote the Effector Phase of the Antit

30.5 Inducing Abscopal Effects: Radiotherapy Effects that Promote Priming of Antitumor T Cells

30.6 A Balancing Act: Negative Regulators of Antitumor Immunity Elicited by Radiation in the Tum

30.7 Revisiting Current Treatment Protocols: Lymphopenia Induced by Local Radiotherapy

30.8 Exploiting Radiation Effects to Improve Responses to Immunotherapy

30.9 Clinical Translation of Combinations of Radiotherapy and Immunotherapy: A Work in Progres

30.10 Toward the Use of Radiation to Induce a Personalized Tumor Vaccine

References

31: Predictors of Response to Immune Checkpoint Blockade

31.1 Introduction

31.2 Hallmarks of Response to Immune Checkpoint Blockade

31.2.1 Tumor and Microenvironment

31.2.1.1 Tumor Genomics and Epigenomics

31.2.1.2 Tumor Microenvironment

31.2.2 Immunity

31.2.3 Environment

31.3 Current and Emerging Predictors of Response, Resistance, and Toxicity

31.3.1 Clinical Predictors of Response

31.3.2 Tissue-Based Predictors of Response

31.3.3 Blood-Based Predictors of Response

31.3.4 Noninvasive Predictors of Response

31.3.5 The Gut Microbiome as a Predictive Biomarker

31.3.6 Predictors of Toxicity

31.4 Static Versus Dynamic Assessment of Systemic and Antitumor Immunity

31.5 Building Predictors into Clinical Trials and Standard of Care Therapy

31.6 Summary and Conclusions

References

Part V: Changes in Clinical Practice

32: Immune Therapies in Phase 1 Trials

32.1 Introduction

32.2 Antibodies Targeting Immune Checkpoints

32.2.1 Dose-Limiting Toxicities and MTD Definition

32.2.1.1 Safety and MTD Definition

32.2.1.2 Dosing Schedule

32.2.2 Safety Profile and Toxicity Management

32.2.3 Pharmacokinetic and Pharmacodynamic Assessments

32.2.3.1 Pharmacokinetics

32.2.3.2 Pharmacodynamics

32.2.4 Patient Eligibility

32.2.5 Patient Selection and Personalized Immune Therapy

32.2.6 Response and Efficacy Assessment

32.2.7 Trial Design: The “Phase 1 Registration” Trials

32.3 Other Immune Therapies and Their Specificities: Selected Examples

32.3.1 Blinatumomab

32.3.2 Talimogene Laherparepvec (T-VEC)

32.3.3 CAR-T Cell Therapy

32.4 Combinations

32.5 Conclusion and Practical Considerations

References

33: Side Effects of Cancer Immunotherapy with Checkpoint Inhibitors

33.1 Introduction

33.2 Incidence of Immune-­Related Adverse Events

33.3 Timing of Immune-Related Adverse Event Onset

33.4 General Considerations

33.5 Organ-Specific Immune-�Related Adverse Events

33.5.1 Cutaneous Toxicity

33.5.2 Gastrointestinal Toxicity

33.5.3 Endocrine Toxicity

33.5.3.1 Thyroid Toxicity

33.5.3.2 Hypophysitis

33.5.4 Hepatic Toxicity

33.5.5 Pulmonary Toxicity

33.5.6 Renal Toxicity

33.5.7 Neurological Toxicity

33.5.8 Rheumatological Toxicity

33.5.9 Cardiotoxicity

33.5.10 Pancreatic Toxicity

33.5.11 Ocular Toxicity

33.5.12 Hematological Toxicity

33.6 Pre-Existing Autoimmunity

33.7 Immunologic Biomarkers

References

34: Melanoma: Immunotherapy in Advanced Melanoma and in the Adjuvant Setting

34.1 Cytokines in Melanoma

34.1.1 Interferon-Alpha

34.1.2 Interleukin-2

34.1.3 Tumor Necrosis Factor: Alpha (TNF)

34.1.4 Breaking Tolerance with Immune Checkpoint Inhibitors

34.2 Anti-CTLA4

34.2.1 Results in Advanced Melanoma Patients

34.2.2 Biomarker

34.2.3 Adjuvant Therapy in Melanoma and the Recent Approval of Ipilimumab

34.2.3.1 Prolonged Relapse Free and Overall Survival with Ipilimumab

34.2.4 Highest Benefit in Ulcerated Melanoma

34.2.4.1 Toxicity and Quality of Life

34.3 Combination Therapies with Ipilimumab

34.4 Chemotherapy

34.5 Antiangiogenic Agents

34.6 Cytokines (IL2, IFN-Alpha, GM-CSF)

34.7 Vaccines

34.8 BRAF and MEK Inhibitors

34.9 Anti-PD1 and Anti-PDL1

34.10 Nivolumab in adjuvant setting for melanoma resected stage IIIB/C-IV

34.11 Anti-PD1 Plus Anti-CTLA4 Combination Therapy

34.12 Other Combination Therapies: Anti-PD1 Will Be the Backbone

References

35: Immunotherapy for Prostate Cancer: An Evolving Landscape

35.1 Introduction

35.2 Immune Checkpoint Blockade

35.3 Cancer Vaccines

35.4 Adoptive Cellular Therapy

35.5 Antitumor Antibodies

35.6 Summary

References

36: Challenges of Oncoimmunology for Ovarian and Breast Cancers

36.1 Tumor Microenvironment and Therapeutic Targets of Ovarian and Breast Cancers

36.1.1 Tumor-Infiltrating Lymphocytes

36.1.2 Cancer-Associated Fibroblasts

36.1.3 Tumor-Associated Macrophages

36.2 Oncoimmunology Challenges in Ovarian Cancer

36.2.1 Therapeutic Approaches to Enhance Tumor Antigen Recognition

36.2.1.1 Vaccines

36.2.1.2 Innate Immune Activators

36.2.2 Therapeutic Approaches that Enhance T Cell Activation

36.2.2.1 Cytokines

36.2.2.2 Immune Checkpoint Blockade

36.2.2.3 Adoptive T Cell Therapies

36.2.3 Therapeutic Approaches that Block Other Axes of Immune Inhibition

36.2.4 Monoclonal Antibodies

36.3 Oncoimmunology Challenges in Breast Cancer

36.3.1 Vaccines

36.3.2 Immune Checkpoints

36.3.2.1 Luminal Breast Cancers

36.3.2.2 Triple-Negative Breast Cancer

36.3.2.3 Future Directions in Breast Cancer

References

37: Challenges in Colorectal Cancer: From Vaccines to Macrophage Repolarization

37.1 The Immune System in the Colon and in Colorectal Cancer

37.2 Immune Cells in Metastatic Colorectal Cancer: Factors for Prognosis and Therapy

37.3 Measuring the Microenvironment: Quantification of Immune Cells in Tissues

37.4 Immune Cells in Metastatic Colorectal Cancer: Prognostic and Predictive Implications

37.5 Primary Tumor and Metastases: Two Different Worlds

37.6 Immune Cells and Therapy: Immunogenic Cell Death and Beyond

37.7 Myeloid Immune Cells in the Microenvironment: Plasticity and Immunosuppression

37.8 Checkpoint Inhibition and Other Signaling Cascades

37.9 Cytokines and Chemokines in the Microenvironment

37.10 Clinical Strategies for Immunotherapy of Colorectal Cancer

37.11 Vaccination and Dendritic Cell Therapy: Retargeting the Immune System

37.12 Therapeutic Use of Cytokines

37.13 Adoptive T Cell Therapy and Genetically Modified T Cell Therapy

37.14 Checkpoint Inhibition in Colorectal Cancer

37.15 Modulation of the Innate Immune System

37.16 Summary

37.17 Outlook and Future Directions

References

38: Current Status of Immuno-­Oncology in Hematologic Cancers

38.1 Introduction

38.2 Direct Targeting of Cellular Surface Antigens

38.2.1 The Famous CD20 Story

38.2.2 Targeting Molecules Other than CD20

38.2.2.1 Alemtuzumab

38.2.2.2 Gemtuzumab Ozogamicin

38.2.3 Newer Target of Interest

38.2.3.1 Brentuximab Vedotin

38.2.3.2 Daratumumab

38.2.3.3 Elotuzumab

38.2.3.4 Bispecific T-Cell Engagers

38.3 Blinatumomab: A New Hope in Relapsed/Refractory ALL

38.4 BiTe for Non-ALL Hematological Malignancies

38.5 Immune Checkpoint Inhibitors (or Activators)

38.6 Checkpoint Blockade in Other Hematological Malignancies

38.6.1 Non-Hodgkin Lymphomas (NHL)

38.6.2 Multiple Myeloma

38.6.3 Myeloid Malignancies

38.7 Future Directions

References

39: Immunotherapy of Gliomas

39.1 Introduction

39.2 Defining Appropriate Antigens

39.3 Neoepitopes in Gliomas

39.4 Checkpoint Inhibitors in Glioma

39.5 T Cell Therapy

39.6 Targeting the Immune Microenvironment in Gliomas

References

40: Assessing T Cell Receptor Affinity and Avidity Against Tumor Antigens

40.1 T Cell-Based Therapies Against Malignant Disease

40.2 Defining T Cell Functional Avidity and TCR Binding Affinity and Avidity

40.3 Tumor-Specific T Cell Responses Are Mediated by TCRs of Low Binding Affinity/Avidity

40.4 Optimization of TCR-pMHC Binding Affinity/Avidity Against Cancer Cells

40.5 TCR-pMHC Binding and Kinetic Measurements

40.6 Relationship Between TCR-­pMHC Binding Parameters and CD8 T Cell Potency

40.7 Conclusive Remarks

References

41: Immune Monitoring of Blood and Tumor Microenvironment

41.1 Introduction

41.2 Flow Cytometry and Protein Expression Analysis

41.2.1 Flow Cytometry

41.2.2 Protein Arrays

41.2.3 Cytokine Analysis

41.2.4 Bioinformatics Support for Data Analysis

41.3 Further Assays to Monitor T Cell Functions

41.3.1 Analyzing Cell-Mediated Cytotoxicity

41.3.2 The ELISpot Technique for Assaying Cytokine- and Interferon-Producing Cells

41.3.3 Intracellular Cytokine Staining

41.4 Multiplexed Immunohistochemistry (IHC) Assays

41.5 High-Throughput Techniques

41.6 Validation of Assays, Biomarkers for Clinical Use, and Integration of Big Data

References

42: Toward Engineered Cells as Transformational and Broadly Available Medicines for the Treatmen

42.1 Vision for and History of CAR T Cell and TCR T Cell Medicines

42.2 Sources for TCRs/CARs

42.3 The Challenge of Identifying Suitable Targets for CAR T Cell and TCR T Cell Approaches

42.4 Nonclinical Development

42.5 Gene-Engineered T Cell Therapy: Clinical Development

42.5.1 Chimeric Antigen Receptor T Cell Therapy

42.5.2 T Cell Receptor-Transduced T Cells

42.5.2.1 Targeting NY-ESO-1

Other Clinical TCR Targets

42.6 Clinical Safety Considerations

42.7 The Challenge to Maximize Safety and Efficacy for CAR T Cell and TCR T Cell Medicines

42.8 The Challenge of Achieving Maximum Access for CAR T Cell and TCR T Cell Medicines

42.9 Conclusions and Future Perspective

References

Part VI: Concluding Remarks

43: Concluding Remarks

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An aparitie	14-12-17
Autor	Laurence Zitvogel; Guido Kroemer
Dimensiuni	18.03 x 4.57 x 25.65 cm
Editura	Springer
Format	Hardcover
ISBN	9783319624303
Limba	Engleza
Nr pag	724