Tumor antigen-targeted, monoclonal antibody-based immunotherapy: clinical response, cellular immunity, and immunoescape

Abstract

Purpose: Tumor antigen (TA) -targeted monoclonal antibodies (mAb), rituximab, trastuzumab, and cetuximab, are clinically effective for some advanced malignancies, especially in conjunction with chemotherapy and/or radiotherapy. However, these results are only seen in a subset (20% to 30%) of patients. We discuss the immunologic mechanism(s) underlying these clinical findings and their potential role in the variability in patients' clinical response.

Methods: We reviewed the evidence indicating that the effects of TA-targeted mAb-based immunotherapy are mediated not only by inhibition of signaling pathways, but also by cell-mediated cytotoxicity triggered by the infused TA-targeted mAb. We analyzed the immunologic variables that can influence the outcome of antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro and in animal model systems. We also analyzed the correlation reported between these variables and the clinical response to mAb-based immunotherapy.

Results: Of the variables that influence ADCC mediated by TA-targeted mAb, only polymorphisms of Fcγ receptors (FcγR) expressed by patients' lymphocytes were correlated with clinical efficacy. However, this correlation is not absolute and is not observed in all malignancies. Thus other variables may be responsible for the antitumor effects seen in mAb-treated patients. We discuss the evidence that triggering of TA-specific cellular immunity by TA-targeted mAb, in conjunction with immune escape mechanisms used by tumor cells, may contribute to the differential clinical responses to mAb-based immunotherapy.

Conclusion: Identification of the mechanism(s) underlying the clinical response of patients with cancer treated with TA-targeted mAb is crucial to optimizing their application in the clinic and to selecting the patients most likely to benefit from their use.

Fig 1.

Immune cellular network mediated by tumor antigen (TA) –targeted monoclonal antibodies (mAbs) in the tumor microenvironment to induce antitumor activity. Direct cell lysis of mAb-bound tumor cells overexpressing the targeted TA may occur. First, exposure of TA-positive tumor cells to TA-targeted mAbs leads to their opsonization through the binding of cetuximab to the TA epitopes expressed on tumor targets. Recognition of tumor cells opsonized with mAbs is mediated via the FcγRIII (CD16) expressed on natural killer (NK) cells and FcγRIIa on monocytes, dendritic cells (DCs), and other granulocytes.^, These effectors of innate immunity are activated in the presence of mAb-coated tumor cell targets and proceed to release perforin and granzymes, thus inducing tumor cell death (antibody-dependent cell-mediated cytotoxicity [ADCC]). The mAb-coated TAs released by dying cells in the form of immune complexes are avidly taken up by DCs, processed, and presented to T cells. This recruitment of NK cells and other FcγR-bearing immune cells occurs, liberating tumor cell products and TAs in the setting of inflammatory cytokines and chemokines. Infiltration of DCs and lymphocytes into the microenvironment may lead to uptake and processing of TAs by DCs and induction of TA-specific cellular immune responses. TGF-β, transforming growth factor β; IL-10, interleukin 10; APM, antigen processing machinery.