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Resistance to Checkpoint Blockade Inhibitors and Immunomodulatory Drugs

  • Anthony N. AudinoEmail author
  • Mitchell S. Cairo
Chapter
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 21)

Abstract

Cancer therapy has evolved from surgery and radiation to multi-agent chemotherapy, and although we have seen decreased mortality and increased cure rates, most of this therapy has continued to focus on the tumor itself, and not on the tumor microenvironment. Various cells within the tumor microenvironment have been implicated in leading to resistance to immune therapy. Through a complex system of steps, T-cells become activated after presentation of a specific antigen. Because continuous T-cell activation can lead to lymphoproliferation and unwanted autoimmunity, the human T-cell immune system has evolved into a process of checks-and-balances, referred to as immune checkpoints, that allows for co-inhibitory receptors to inhibit T-cell activation. Through the use of check point inhibitors, we have seen patients with cancers refractory to multiple treatments have durable responses, and in some, long term remissions. Some of the most studied inhibitors include Programmed Cell Death Protein 1 (PD-1) and Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4), although more have been identified. As we continue to explore possible treatment options for cancer, we must also be diligent in preemptively investigating how and why some patients will become resistant to these treatments, and what, if any, actions can be taken to circumvent this resistance.

Keywords

Checkpoint blockade inhibitors, PD-1, CTLA-4 Lymphoma Resistance 

Abbreviations

APC

Antigen Presenting Cells

ASCT

Autologous Stem Cell Transplant

BV

Brentuximab Vedotin

CAF

Cancer Associated Fibroblasts

COG

Children’s Oncology Group

CTLA-4

Cytotoxic T-Lymphocyte Associated Antigen-4

FDA

Food and Drug Administration

HL

Hodgkin Lymphoma

HSC

Hematopoietic Stem Cells

ICAM

Intracellular Activation Motifs

ICOS+

Inducible Costimulatory

IDO

Indoleamine 2, 3-Droxygenase

ITAM

Immunoreceptor Tyrosine Based Activation Motifs

LAG-3

Lymphocyte Activation Gene 3

MDSC

Myeloid Derived Suppressor Cells

MHC

Major Histocompatibility Complex

MHC I

Major Histocompatibility Complex Class I

MHC II

Major Histocompatibility Complex Class II

NSCLC

Non-small Cell Lung Cancer

ORR

Objective Response Rate

OS

Overall Survival

PD-1

Programmed Cell Death Protein 1

PD-L1

Programmed Cell Death Ligand 1

PD-L2

Programmed Cell Death Ligand 2

PFS

Progressive Free Survival

R/R

Relapsed/Refractory

TAM

Tumor Associated Macrophages

TCR

T-Cell Receptors

TIM-3

T-cell Immunoglobulin Mucin 3

Treg

Regulatory T-cells

Notes

Acknowledgement

This work was supported in part from the Pediatric Cancer Research Foundation and St. Baldrick’s Foundation. The authors would like to thank Virginia Davenport, RN and Erin Morris, RN in their assistance in the preparation of this manuscript.

Disclosure of Conflict of Interest

No potential conflicts of interest were disclosed.

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Pediatric Hematology/Oncology/BMT, Nationwide Children’s HospitalThe Ohio State UniversityColumbusUSA
  2. 2.Departments of Pediatrics, Medicine, Pathology, Microbiology and Immunology, Cell Biology and AnatomyNew York Medical CollegeValhallaUSA

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