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Resistance to Immunotherapeutic Antibodies in Cancer pp 73–92Cite as

Understanding the Mechanisms of Resistance to Rituximab: Paving the Road for the Development of Therapeutic Strategies to Overcome Rituximab-Resistance

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

Abstract

Rituximab-resistance is an emerging challenge for both the scientific community and the practicing oncologist. Parallel to the improvement clinic outcomes, the incorporation of rituximab into the management of patients with B-cell lymphoma appears to be changing the biology of relapsed/refractory disease. At least in the patients with diffuse large B-cell lymphoma (DLBCL), previously established salvage rituximab-chemotherapy-based treatments [including high dose chemotherapy and autologous stem cell support (HDC-ASCS)] are less effective in patients failing rituximab immunochemotherapy induction. The estimated 3-year failure free survival in previously treated R-CHOP DLBCL following HDC-ASCT is only 33 %, stressing the need to: (1) understand the mechanisms responsible for rituximab-resistance, (2) identify cellular pathways playing a pivotal role in acquired resistance and (3) develop novel therapeutic strategies to overcome or circumvent rituximab-resistance in B-cell lymphoma. Pre-clinical models to study rituximab-resistance have been generated and characterized. Moreover, repeated exposure of lymphoma cells to rituximab, not only results in a decrease in rituximab anti-tumor activity, but also cross-resistance to multiple chemotherapy agents (suggesting shared pathways of resistance). Insightful information regarding the biological basis for rituximab-resistance is paving the next generation of clinical trials evaluating novel monoclonal antibodies, immunoconjugates, and/or targeted agents aimed at blocking key-regulatory proteins associated with acquired resistance. Here, we provide a general overview of the mechanisms associated with rituximab-resistance that have been identified so far and review some of the early therapeutic interventions being tested in pre-clinical models and in early clinical trials for patients with rituximab-resistant B-cell lymphoma.

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Abbreviations

ADCC:

Antibody-dependent cellular cytotoxicity

BIR:

Baculoviral IAP repeat

CARD:

Caspase activating and recruitment domain

CMC:

Complement-mediated cytotoxicity

DLBCL:

Diffuse large B-cell lymphoma

ESHAP:

Etoposide, methylprednisolone, cytarabine and cisplatin

FcγRIIA CD32:

Fcγ receptor IIA

FcR:

Fc receptors

GA101:

Obinutuzumab

HDC-ASCS:

High dose chemotherapy and autologous stem cell support

MCL:

Mantle cell lymphomas

NHL:

Non-Hodgkin lymphoma

R:

Rituximab

RING zinc-finger:

RING

RRCL:

Rituximab-resistant cell lines

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Acknowledgments

Supported by NIH grant R01 CA136907-01A1 awarded to Roswell Park Cancer Institute.

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No potential conflicts of interest were disclosed.

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  1. Departments of Immunology and Medical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Francisco J. Hernandez-Ilizaliturri & Myron S. Czuczman

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  1. Francisco J. Hernandez-Ilizaliturri
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  2. Myron S. Czuczman
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Correspondence to Myron S. Czuczman .

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  1. Molecular Genetics, University of California, Los Angeles Dept. Microbiology, Immunology &, Los Angeles, California, USA

    Benjamin Bonavida

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Hernandez-Ilizaliturri, F.J., Czuczman, M.S. (2013). Understanding the Mechanisms of Resistance to Rituximab: Paving the Road for the Development of Therapeutic Strategies to Overcome Rituximab-Resistance. 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_4

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