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Strategies to Enhance Migration and Persistence of Chimeric Antigen Receptor (CAR)-T Cells into Tumors

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Defects in T Cell Trafficking and Resistance to Cancer Immunotherapy

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 9))

Abstract

Since the past few decades, immunotherapy based on the adoptive transfer of tumor-specific T-cells is providing a promising form of cancer treatment. This result has been obtained through the improvement of the methodologies used to expand ex vivo antigen-specific T cells, and through technology advancements in T-cell engineering aimed at transferring into these cells chimeric antigen receptors (CAR) or αβTCRs chains. High enthusiasm is especially directed to the CAR technology, as this confers MHC-independent antigen-specificity to T cells, thus allowing broad clinical applications. The greatest advances have been achieved in lymphoid malignancies, while the clinical benefits of CAR-T cells to solid tumors still remain uncertain. In this review we will explore two of the problems that are currently perceived as limiting the success of the clinical translation of CAR-T cells in solid tumors: namely, the recruitment and survival of tumor-specific T cells in the microenvironment.

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Abbreviations

Bcl-2:

B-cell lymphoma 2

Bcl-xL:

B-cell lymphoma-extra large

CAR:

Chimeric antigen receptor

CD:

Cluster of Differentiation

CTLA4:

Cytotoxic T-lymphocyte-associated protein 4

DPP4:

Dipeptidyl peptidase 4

ECM:

Extra cellular matrix

ERK:

Extracellular signal-regulated kinases

GD2:

Ganglioside Diasialo 2

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

Gro-α:

Growth-regulated oncogene-α

HVEM:

Herpes Virus Entry Mediator

IDO:

Indoleamine 2, 3-dioxygenase

IFN:

Interferon

IL:

Interleukin

LAG3:

Lymphocyte-activation gene 3

M2:

Macrophages type 2

MDC:

Macrophage-derived chemokine

MHC:

major histocompatibility complex

MDSC:

Myeloid derived suppressor cells

NF-kB:

Nuclear factor-kB

NKGD2:

Natural Killer Group 2D

PD1:

Programmed cell death protein 1

PD-L1/PD-L2:

Programmed death-ligand 1/2

PGs:

Proteoglycans

RANTES:

Regulated on Activation, Normal T Cell Expressed and Secreted

ROS:

Reactive oxygen species

siRNA:

Small interfering RNA

TARC:

Thymus and activation-regulated chemokine

TCR:

T cell receptor

Tregs:

Regulatory T cells

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Acknowledgements

This work was supported in part by a SCOR grant from the Leukemia and Lymphoma Society, RO1 1145564 from NHLBI, RO1CA193130 from NCI and Tier 2: Stimulus Award, Lineberger Comprehensive Cancer Center, University of North Carolina. The authors

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Authors and Affiliations

  1. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

    Yuhui Chen, Gianpietro Dotti & Barbara Savoldo

  2. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA

    Gianpietro Dotti

  3. Department of Pediatrics, University of North Carolina, Chapel Hill, NC, USA

    Barbara Savoldo

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  1. Yuhui Chen
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  2. Gianpietro Dotti
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  3. Barbara Savoldo
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Correspondence to Barbara Savoldo .

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  1. Institut Cochin INSERM, Université Paris Descartes, Paris, France

    Emmanuel Donnadieu

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Chen, Y., Dotti, G., Savoldo, B. (2016). Strategies to Enhance Migration and Persistence of Chimeric Antigen Receptor (CAR)-T Cells into Tumors. In: Donnadieu, E. (eds) Defects in T Cell Trafficking and Resistance to Cancer Immunotherapy. Resistance to Targeted Anti-Cancer Therapeutics, vol 9. Springer, Cham. https://doi.org/10.1007/978-3-319-42223-7_8

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