Anti-EGFR Targeted Monoclonal Antibody Isotype Influences Antitumor Cellular Immunity in Head and Neck Cancer Patients

Abstract

Purpose EGFR is highly overexpressed on several cancers and two targeted anti-EGFR antibodies which differ by isotype are FDA approved for clinical use. Cetuximab (IgG1 isotype) inhibits downstream signaling of EGFR and activates anti-tumor, cellular immune mechanisms. As panitumumab (IgG2 isotype) may inhibit downstream EGFR signaling similar to cetuximab, it might also induce adaptive immunity. Experimental Design We measured in vitro activation of cellular components of the innate and adaptive immune system. We also studied the in vivo activation of components of the adaptive immune system in patient specimens from two recent clinical trials using cetuximab or panitumumab. Results Both mAb primarily activate NK cells, although cetuximab is significantly more potent than panitumumab. Cetuximab-activated neutrophils mediate ADCC against HNSCC tumor cells, and interestingly, this effect was FcγRIIa and FcγRIIIa genotype dependent. Panitumumab may activate monocytes through CD32 (FcγRIIa), however monocytes activated by either mAb are not able to mediate ADCC. Cetuximab enhanced DC maturation to a greater extent than panitumumab, which was associated with improved tumor antigen cross presentation by cetuximab compared with panitumumab. This correlated with increased EGFR-specific cytotoxic CD8+ T cells in patients treated with cetuximab compared to those treated with panitumumab. Conclusions Although panitumumab effectively inhibits EGFR signaling to a similar extent as cetuximab, it is less effective at triggering anti-tumor, cellular immune mechanisms which may be crucial for effective therapy of HNSCC.

In vitro elimination of epidermal growth factor receptor‐overexpressing cancer cells by CD32A‐chimeric receptor T cells in combination with cetuximab or panitumumab

“…Unlike cetuximab (IgG1), panitumumab (IgG2) did not induce significant ADCC by NK cells, thereby limiting its applications in cell‐based cancer immunotherapy . However, panitumumab is still able to trigger ADCC by macrophages, which, with the exception of a small subset of cells, do not express CD16, but do express CD32 and CD64 .…”

Neutrophils are essential for induction of vaccine-like effects by antiviral monoclonal antibody immunotherapies

“…Moreover, passive immunotherapy with broadly neutralizing mAbs stimulated antiviral antibody responses in HIV-1-infected patients (14). Similarly, vaccine-like effects have also been documented in preclinical models of cancer immunotherapies (17)(18)(19) as well as in clinical trials using anti-CD20, anti-EGFR, or anti-HER2 mAbs (20)(21)(22)(23). Yet, neither the mechanisms at play nor the possible long-term protective consequences have been addressed in such clinical trials.…”

Current studies of immunotherapy in head and neck cancer

“…For example, radiation can induce immunogenic forms of cell death and can lead to the so‐called abscopal effect, which means that local irradiation results in regression of non‐irradiated metastasis through antitumour immune reactions. Therefore, through vaccine‐like effects, radiotherapy or chemotherapy may show synergistic effects with immunotherapy as well as monoclonal antibodies, such as cetuximab, for which immune‐mediated antibody‐dependent cellular cytotoxicity (ADCC) is suggested . At present, efficient multimodal therapies including immunotherapy are yet to be defined in both the curative and palliative settings.…”