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Tumor Resistance to Antibody-Mediated Immunotherapy and Reversal of Resistance: Rituximab as Prototype

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Resistance to Immunotherapeutic Antibodies in Cancer

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 2))

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Abstract

It took over a century to validate what Behring [153] and Ehrlich [154] have reasoned and predicted of the potential clinical use of antibody-mediated therapies against infectious diseases and cancer. However, the practical application of antibody-mediated therapies was only possible several decades later. Porter [155] and Edelman et al. [156] published the molecular structure of the immunoglobulin molecule and through the ingenuity of Kohler and Milstein they engineered the production of hybridoma cell lines capable of producing monoclonal antibodies (mAbs). Such mAbs are one of the most important and fastest growing classes of therapeutic drugs in the treatment of non-malignant and malignant diseases. The first FDA approved cancer therapeutic antibody was in 1997 for the treatment of B-Non-Hodgkin Lymphoma (B-NHL). The mAb is a chimeric anti-CD20 mAb, rituximab, which targets both non-malignant and malignant B cells. Rituximab is currently the standard therapy when used in combination with chemotherapy (CHOP). However, like other therapeutics, a subset of patients initially does not respond and a subset responding patients develops resistance to further treatments. Such patients are in an urgent need of novel therapies to reverse resistance. This review will cover rituximab as a therapeutic prototype mAb for analyses of its several modes of action on sensitive and resistant B-NHL tumor cells, its chemo-immuno-sensitizing effects and applications of various means to reverse resistance through the use of small molecule inhibitors targeting members of the constitutively overactivated survival/antiapoptotic pathways.

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Abbreviations

ADCC:

Antibody-dependent cell cytotoxicity

ARL:

AIDS-related lymphoma

CDC:

Complement-dependent cytotoxicity

CLL:

Chronic lymphositic leukemia

CTL:

Cytotoxic T lymphocyte

DLBCL:

Diffused large B cell lymphoma

Fl:

Follicular lymphoma

ITAM:

Immunotyrosine activating motif

ITIM:

Immunotyrosine inhibitory motif

NHL:

Non-Hodgkin lymphoma

NK:

Natural killer

TRAIL:

Tumor necrosis-related apoptotic-inducing ligand

YY1:

Yin Yang 1

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Acknowledgments

This work was supported by a gift from various donors and, in part, by the Jonsson Comprehensive Cancer Center at UCLA. The author acknowledges Drs. Ali R. Jazirehi, Mario I. Vega, and Stavroula Baritaki for their published research that forums and the basis of this review. The author also acknowledges the assistance of Daphne Liang, Melissa Cao, Kathy Nguyen, and Suzie Vardanyan for the preparation of the manuscript.

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No potential conflicts of interest were disclosed.

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  1. Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center at UCLA, University of California, Los Angeles, CA, 90095, USA

    Benjamin Bonavida

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    Benjamin Bonavida

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Bonavida, B. (2013). Tumor Resistance to Antibody-Mediated Immunotherapy and Reversal of Resistance: Rituximab as Prototype. In: Bonavida, B. (eds) Resistance to Immunotherapeutic Antibodies in Cancer. Resistance to Targeted Anti-Cancer Therapeutics, vol 2. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7654-2_5

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