Article

Increasing the Clinical Efficacy of NK and Antibody-Mediated Cancer Immunotherapy: Potential Predictors of Successful Clinical Outcome Based on Observations in High-Risk Neuroblastoma

Department of Human Oncology, University of Wisconsin Madison Madison, WI, USA.
Frontiers in Pharmacology 05/2012; 3:91. DOI: 10.3389/fphar.2012.00091
Source: PubMed

ABSTRACT Disease recurrence is frequent in high-risk neuroblastoma (NBL) patients even after multi-modality aggressive treatment [a combination of chemotherapy, surgical resection, local radiation therapy, autologous stem cell transplantation, and cis-retinoic acid (CRA)]. Recent clinical studies have explored the use of monoclonal antibodies (mAbs) that bind to disialoganglioside (GD(2)), highly expressed in NBL, as a means to enable immune effector cells to destroy NBL cells via antibody-dependent cell-mediated cytotoxicity (ADCC). Preclinical data indicate that ADCC can be more effective when appropriate effector cells are activated by cytokines. Clinical studies have pursued this by administering anti-GD(2) mAb in combination with ADCC-enhancing cytokines (IL2 and GM-CSF), a regimen that has demonstrated improved cancer-free survival. More recently, early clinical studies have used a fusion protein that consists of the anti-GD(2) mAb directly linked to IL2, and anti-tumor responses were seen in the Phase II setting. Analyses of genes that code for receptors that influence ADCC activity and natural killer (NK) cell function [Fc receptor (FcR), killer immunoglublin-like receptor (KIR), and KIR-ligand (KIR-L)] suggest patients with anti-tumor activity are more likely to have certain genotype profiles. Further analyses will need to be conducted to determine whether these genotypes can be used as predictive markers for favorable therapeutic outcome. In this review, we discuss factors that affect response to mAb-based tumor therapies such as hu14.18-IL2. Many of our observations have been made in the context of NBL; however, we will also include some observations made with mAbs targeting other tumor types that are consistent with results in NBL. Therefore, we hypothesize that the NBL observations discussed here may also be relevant to mAb therapy for other cancers, in which ADCC is known to play a role.

1 Follower
 · 
81 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: A CD44 blockade drives leukemic cells into differentiation and apoptosis by dislodging from the osteogenic niche. Because anti-CD49d also supports hematopoietic stem cell mobilization, we sought to determine the therapeutic efficacy of a joint CD49d/CD44 blockade. To unravel the underlying mechanism, the CD49d(-) EL4 lymphoma was transfected with CD49d or point-mutated CD49d, prohibiting phosphorylation and FAK binding; additionally, a CD44(-) Jurkat subline was transfected with murine CD44, CD44 with a point mutation in the ezrin binding site, or with cytoplasmic tail-truncated CD44. Parental and transfected EL4 and Jurkat cells were evaluated for adhesion, migration, and apoptosis susceptibility in vitro and in vivo. Ligand-binding and Ab-blocking studies revealed CD44-CD49d cooperation in vitro and in vivo in adhesion, migration, and apoptosis resistance. The cooperation depends on ligand-induced proximity such that both CD44 and CD49d get access to src, FAK, and paxillin and via lck to the MAPK pathway, with the latter also supporting antiapoptotic molecule liberation. Accordingly, synergisms were only seen in leukemia cells expressing wild-type CD44 and CD49d. Anti-CD44 together with anti-CD49d efficiently dislodged EL4-CD49d/Jurkat-CD44 in bone marrow and spleen. Dislodging was accompanied by increased apoptosis susceptibility that strengthened low-dose chemotherapy, the combined treatment most strongly interfering with metastatic settlement and being partly curative. Ab treatment also promoted NK and Ab-dependent cellular cytotoxicity activation, which affected leukemia cells independent of CD44/CD49d tail mutations. Thus, mostly owing to a blockade of joint signaling, anti-CD44 and anti-CD49d hamper leukemic cell settlement and break apoptosis resistance, which strongly supports low-dose chemotherapy.
    The Journal of Immunology 10/2013; 191(10). DOI:10.4049/jimmunol.1301543 · 5.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Molecular mimicry is fundamental to biology and transcends to many disciplines ranging from immune pathology to drug design. Structural characterization of molecular partners has provided insight into the origins and relative importance of complementarity in mimicry. Chemical complementarity is easy to understand; amino acid sequence similarity between peptides, for example, can lead to cross-reactivity triggering similar reactivity from their cognate receptors. However, conformational complementarity is difficult to decipher. Molecular mimicry of carbohydrates by peptides is often considered one of those. Extensive studies of innate and adaptive immune responses suggests the existence of carbohydrate mimicry, but the structural basis for this mimicry yields confounding details; peptides mimicking carbohydrates in some cases fail to exhibit both chemical and conformational mimicry. Deconvolution of these two types of complementarity in mimicry and its relationship to biological function can nevertheless lead to new therapeutics. Here, we discuss our experience examining the immunological aspects and implications of carbohydrate-peptide mimicry. Emphasis is placed on the rationale, the lessons learned from the methodologies to identify mimics, a perspective on the limitations of structural analysis, the biological consequences of mimicking tumor-associated carbohydrate antigens, and the notion of reverse engineering to develop carbohydrate-mimetic peptides in vaccine design strategies to induce responses to glycan antigens expressed on cancer cells.
    Frontiers in Immunology 06/2014; 5:308. DOI:10.3389/fimmu.2014.00308
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 20(S)-protopanaxadiol (PPD) is an extract of Panax quinquefolius L. The aim of this study was to investigate the effect of PPD on the antitumor activity and toxicity of cyclophosphamide (CTX) in tumor-bearing mice. C57BL/6 mice bearing Lewis lung carcinoma cells were treated with PPD (50 mg/kg) alone, CTX (20 mg/kg) alone or PPD (50 mg/kg) in combination with CTX (20 mg/kg), respectively. The results showed that PPD alone has no significant antitumor activity but synergistically enhanced the antitumor activity of CTX. PPD significantly increased the peripheral white blood cell count, bone marrow cell count, interleukin-2 and interferon-γ in CTX-treated tumor-bearing mice. The lowered levels of spleen index, splenocyte proliferation and natural killer cell activity in tumor-bearing mice following CTX treatment were also increased by PPD administration. PPD may be a beneficial supplement during CTX chemotherapy for enhancing the antitumor efficacy and reducing the toxicity of CTX.
    Experimental and therapeutic medicine 02/2013; 5(2):443-447. DOI:10.3892/etm.2012.820 · 0.94 Impact Factor

Preview (2 Sources)

Download
2 Downloads
Available from