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Resistance to Checkpoint Blockade Inhibitors and Immunomodulatory Drugs

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Resistance to Targeted Therapies in Lymphomas

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 21))

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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.

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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

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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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Authors and Affiliations

  1. Department of Pediatric Hematology/Oncology/BMT, Nationwide Children’s Hospital, The Ohio State University, Columbus, OH, USA

    Anthony N. Audino

  2. Departments of Pediatrics, Medicine, Pathology, Microbiology and Immunology, Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA

    Mitchell S. Cairo

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  1. Anthony N. Audino
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Correspondence to Anthony N. Audino .

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Editors and Affiliations

  1. Division of Hematology/Oncology, Department of Pediatrics, University of Alabama at Birmingham Children’s Hospital of Alabama, Birmingham, AL, USA

    Ana C. Xavier

  2. Departments of Pediatrics, Medicine, Pathology, Microbiology and Immunology, Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA

    Mitchell S. Cairo

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Audino, A.N., Cairo, M.S. (2019). Resistance to Checkpoint Blockade Inhibitors and Immunomodulatory Drugs. In: Xavier, A., Cairo, M. (eds) Resistance to Targeted Therapies in Lymphomas . Resistance to Targeted Anti-Cancer Therapeutics, vol 21. Springer, Cham. https://doi.org/10.1007/978-3-030-24424-8_7

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