Combination Strategies to Enhance Antitumor ADCC

Abstract

The clinical efficacy of monoclonal antibodies as cancer therapeutics is largely dependent upon their ability to target the tumor and induce a functional antitumor immune response. This two-step process of ADCC utilizes the response of innate immune cells to provide antitumor cytotoxicity triggered by the interaction of the Fc portion of the antibody with the Fc receptor on the immune cell. Immunotherapeutics that target NK cells, γδ T cells, macrophages and dendritic cells can, by augmenting the function of the immune response, enhance the antitumor activity of the antibodies. Advantages of such combination strategies include: the application to multiple existing antibodies (even across multiple diseases), the feasibility (from a regulatory perspective) of combining with previously approved agents and the assurance (to physicians and trial participants) that one of the ingredients – the antitumor antibody – has proven efficacy on its own. Here we discuss current strategies, including biologic rationale and clinical results, which enhance ADCC in the following ways: strategies that increase total target–monoclonal antibody–effector binding, strategies that trigger effector cell ‘activating’ signals and strategies that block effector cell ‘inhibitory’ signals.

Gene-Modified Human α/β-T Cells Expressing a Chimeric CD16-CD3ζ Receptor as Adoptively Transferable Effector Cells for Anticancer Monoclonal Antibody Therapy

“…The central tumoricidal machinery of this strategy in vivo is ADCC executed by FcgRIII (CD16)-expressing effector cells, such as NK cells (4). In practice, however, a decline in the clinical efficacy of this treatment is often observed, and this involves both chemotherapy-induced leukopenia and NK cell exhaustion due to ADCC evoked by the applied mAb (5). Given that effector cells play important roles in ADCC, instead of escalating the dose of therapeutic mAb, replenishment of effector cells might circumvent this drawback.…”

“…In practice, as anticancer treatment proceeds, a decline in the clinical efficacy of the mAb therapy is often observed. This decline in efficacy could be attributed to the decrease in the number of active effector cells during the ADCC process from a combination of chemotherapy-induced leukopenia and NK cell exhaustion (5). As CD16-expressing effector cells play a critical role in ADCC, we hypothesized that the combined therapeutic regimen of replenishing these cells together with the specific anticancer mAb may improve cancer treatment.…”

PD-1 blockade enhances elotuzumab efficacy in mouse tumor models

“…30 The activity of tumor-targeted mAbs can be improved with mAbs that modulate adaptive immune system responses. 12,31 Programmed death receptor-1 (PD-1) is an inhibitory receptor expressed on activated T cells as well as on NK cells and other immune cells. 32 Binding of PD-1 to its ligands, PD-ligand 1 (PD-L1) and PD-L2, dampens antitumor immune responses, 33,34 allowing tumor cells to evade immunosurveillance.…”

Anti-CD20-interleukin-21 fusokine targets malignant B cells via direct apoptosis and NK-cell–dependent cytotoxicity

“…Combining immunotherapy approaches to activate NK cells and enhance ADCC has demonstrated improved therapeutic efficacy in B-cell lymphoma tumor models. 13,14 For example, combination of anti-CD137 mAb and rituximab, where the latter upregulates CD137 on NK cells, resulted in increased ADCC. 15 Combining mAbs with immunomodulatory molecules such as Toll-like receptor agonist (CpG ODN) or NK cell stimulatory NKG2D ligand or blocking Abs to NK cells' negative regulator (killer cell immunoglobulin-like receptor, KIR) have also shown promising results in preclinical studies.…”

“…[16][17][18][19] Strategies combining mAbs with cytokines stimulating effector cells have also been attempted to enhance ADCC activity. 13,[20][21][22][23] Interleukin-21 (IL-21), a member of the IL-2 cytokine family, is a potent immunostimulatory cytokine exhibiting diverse regulatory effects on NK, T, and B cells. 24,25 IL-21 possesses antitumor activity against a variety of cancers not expressing IL-21 receptor (IL-21R) through activation of the immune system.…”