Understanding and circumventing resistance to anticancer monoclonal antibodies

Abstract

With the widespread use of therapeutic monoclonal antibodies in the treatment of patients with cancer, resistance to these agents has become a major issue. Preclinical models of drug action or resistance have contributed to unravel the main mechanisms of resistance, involving both tumor-associated and host related factors. However our understanding of how a monoclonal antibody destroys cancer cells in a patient and why it one day stops being effective are still far from being complete. This review focuses on the available data on mechanisms of action and resistance to rituximab and includes some additional information for other monoclonal antibodies. Innovative approaches designed to overcome resistance, such as combination immunotherapy, costimulation with cytokines or growth factors are presented.

Long-lasting antitumor protection by anti-CD20 antibody through cellular immune response

“…4,30,31 Potential factors thought to influence the efficacy of rituximab in vivo include both host-and tumor-related resistance mechanisms. 32,33 However, another important factor that might affect this is the capacity of some rituximab-treated patients to develop a long-lasting antitumor immune response.…”

Trial watch: Tumor-targeting monoclonal antibodies for oncological indications

“…Production-associated costs undoubtedly limit the number of patients to which these immunotherapeutic agents are accessible. 187 Moreover, as for many other forms of immunotherapy, 68,188,189 the insurgence of antigen loss variants may underlie the development of resistance, [190][191][192] especially when tumor-targeting mAbs block dispensable TAAs or interrupt replaceable trophic circuitries. Finally, potent mAbs (e.g., trastuzumab) as well as some BiTEs and mAb-drug conjugates are associated (in a fraction of patients) with non-negligible off-target effects, which generally require treatment discontinuation.…”

Lonely killers

“…Apoptosis is susceptible to alteration as a consequence of the modification of several cellular pathways. 26,27 However, the most obvious way to circumvent the antibody attack is the change in antigen density or distribution in the malignant cell. It has thus been suggested that a successful strategy for cancer immunotherapy should be based in the simultaneous targeting of at least two independent molecules.…”

“…26,27 ADCC and CDC effectiveness is modulated by the host polymorphism in the Fcγ receptors (FcγRs) and key components of complement, such as C1q, respectively. CDC can also be impaired through the expression by the tumor of complement inhibitor surface proteins.…”