Three major uncertainties in the antibody therapy of cancer

Abstract

Antibodies against surface molecules of human tumors are now frequently administered in combination with strong chemotherapy, increasing therapeutic efficacy but making the task of elucidating immunological events more difficult. Experiments on genetically manipulated mice indicate that antibody efficacy is greatest when IgG antibody coating tumor cells is engaged by the Fcγ-receptors of effector cells, chiefly the monocyte/macrophage lineage. Evidence suggests lesser roles for NK cells, neutrophils, receptor-mediated cytotoxicity and complement-mediated cytotoxicity. The classical mode of killing employed by macrophages is phagocytosis, but much has to be learned about optimally activating macrophages for this task, and about any other modes of cytotoxicity used. There is renewed interest in antigenic modulation, which implies removal of therapeutic antibody linked with antigen from target-cell surfaces. It is now apparent that this removal of immune complexes can be achieved either by internalization by the target cell, or by transfer of the complexes to another cell by trogocytosis. In trials, anti-idiotype antibodies surprisingly proved therapeutically more effective than anti-CD20, despite anti-idiotype being more effectively removed from target-cell surfaces by antigenic modulation. This anomalous result might reflect the fact that persistence of anti-CD20 immune complexes in large amounts induces serious effector modulation, which paralyzes macrophage attacks on antibody-coated cells. The case for effector modulation is argued by analogy with the therapeutic suppression of autoimmune inflammation by effector modulation, achieved by infusion either of normal IgG in large amounts, or of anti-red cell IgG in relatively small amounts. ABSTRACTexamined for tumor Id. Very low levels were detected in all patients, but they all subsequently remained in remission and this has been maintained up to the time of writing; a striking example of tumor dormancy.Anti-Id therapy is now in abeyance due to the logistical difficulties involved in preparing individual antibodies for each patient. However, follicular lymphomas have been found to present an unusual glycan on their variable domains, close to the idiotypic epitopes, so there is a prospect that, for these tumors, an antibody of good affinity aimed at the glycan could be an effective single substitute for multiple anti-Id preparations.

Intercellular transfer of HLA‐G: its potential in cancer immunology

“…Tumor cells are populations with high heterogeneity. Trogocytic exchanges of membrane patches containing cell‐surface proteins between surrounding tumor cells in vivo are relevant to the phenotypic and functional properties of the host cells . A study by LeMaoult et al .…”

“…Trogocytic exchanges of membrane patches containing cell-surface proteins between surrounding tumor cells in vivo are relevant to the phenotypic and functional properties of the host cells. 43 A study by LeMaoult et al 30 demonstrated that haematological tumor cell lines can uptake HLA-G molecules from either allogeneic or autologous donors. In that study, the trogocytic capability of tumor cells from haematological malignancy patients ex vivo and in ten haematological tumor cell lines in vitro was investigated.…”

The immunoglobulin G1 N-glycan composition affects binding to each low affinity Fc γ receptor

“…The FcgRs bind mAb-coated tissues through the IgG crystallizable fragment (Fc) and kill the target by phagocytosis or cell-mediated cytotoxic processes. 2 Human cells express 5 activating FcgRs (CD64, the "high affinity" FcgR, and the "low affinity" FcgRs CD32A, CD32C, CD16A, CD16B) and one "low affinity" inhibitory receptor (CD32B) (Fig. 1).…”

Replication Study: The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors

“…These include variables such as cell line genetic drift (Hughes et al, 2007; Kleensang et al, 2016), circadian biological responses to therapy (Fu and Kettner, 2013), mouse strain stocks (Clayton and Collins, 2014), housing temperature in mouse facilities (Kokolus et al, 2013), and the obesity and microbiome of recipient mice (Klevorn and Teague, 2016; Macpherson and McCoy, 2015). Additionally, a differential response to immunotherapy can occur due to heterogeneity in individual tumor microenvironments (Grosso and Jure-Kunkel, 2013), which has also been observed in the clinical setting (Ascierto and Marincola, 2014; Stevenson, 2014). Whether these or other factors influence the outcomes of this study is open to hypothesizing and further investigation, which is facilitated by direct replications and transparent reporting.…”