Targeting ADCC: A different approach to HER2 breast cancer in the immunotherapy era

Abstract

The clinical outcome of patients with human epidermal growth factor receptor 2 (HER2) amplified breast carcinoma (BC) has improved with the development of anti-HER2 targeted therapies. However, patients can experience disease recurrence after curative intent and disease progression in the metastatic setting. In the current era of evolving immunotherapy agents, the understanding of the immune response against HER2 tumor cells developed by anti-HER2 antibodies (Abs) is rapidly evolving. Trastuzumab therapy promotes Natural Killer (NK) cell activation in patients with BC overexpressing HER2, indicating that the efficacy of short-term trastuzumab monotherapy, albeit direct inhibition of HER, could also be related with antibody-dependent cell-mediated cytotoxicity (ADCC). Currently, dual HER2 blockade using trastuzumab and pertuzumab is the standard of care in early and advanced disease as this combination could confer an additive effect in ADCC. In patients with disease relapse or progression, ADCC may be hampered by several factors such as FcγRIIIa polymorphism and an immunosuppressive environment, among others. Hence, new drug development strategies are being investigated aiming to boost the ADCC response triggered by anti-HER2 therapy. In this review, we summarize these strategies and the rationale, through mAbs engineering and combinatorial strategies, focusing on clinical results and ongoing trials.

IFI16-dependent STING signaling is a crucial regulator of anti-HER2 immune response in HER2+ breast cancer

“…Trastuzumab binds to the Fcγ receptor on NK cells to elicit ADCC-mediated killing of HER2 + BC cells ( 39 ). We next investigated whether the epigenetic combination also potentiates trastuzumab-mediated ADCC efficacy by pretreating HER2 + BC cells with combined D9/ENT or EPZ/ENT before coculturing with NK cells in the presence of trastuzumab ( Fig.…”

LINC00589-dominated ceRNA networks regulate multiple chemoresistance and cancer stem cell-like properties in HER2+ breast cancer

“…(c) Activation of downstream effectors of HER2 signaling (e.g., PTEN) and alternative signaling pathways (e.g., IGF1R signaling) lead to trastuzumab resistance in breast cancer 27 . (d) Breast cancer cells have been demonstrated to escape from antibody-dependent cell-mediated cytotoxicity (ADCC) caused by trastuzumab 28 . These findings imply that trastuzumab resistance may arise from a combination of largely unknown mechanisms.…”

Defining the Emergence of New Immunotherapy Approaches in Breast Cancer: Role of Myeloid-Derived Suppressor Cells

“…NK cells release proinflammatory cytokines, such as INFɣ and TNFα, during ADCC, a mechanism known as antibody-dependent cytokine release (ADCR) [ 97 ]. The crosstalk among NK cells, tumor cells, and the pro-inflammatory environment induced by ADCC may promote other immune cell populations, which has been called the “vaccination effect” [ 98 ]. Finally, the extracellular binding of trastuzumab to HER2 leads to the inhibition of the RAS/MAPK and PI3K/AKT signaling pathways [ 94 , 99 ].…”

“…In vitro assays demonstrated that ZW25 leads to a concentration-dependent ADCC, causing lysis in 52% of HER2-expressing TNBC cell lines (0/1+). In several HER2-expressing cell lines, both activity and synergy with different chemotherapeutic agents such as taxanes, platinums, microtubule inhibitors, and DNA synthesis inhibitors have been observed [ 98 ]. Forty-two patients were enrolled in a phase I basket trial (NCT02892123) and 71% received an average of five lines of anti-HER2 treatment for metastatic disease and 20 patients had locally advanced or unresectable.…”

“…Overall, partial response rate was obtained in 33% of patients and disease control rate in 50%. The most common toxicity was grade 1–2 diarrhea and infusion reaction [ 98 , 108 ]. A clinical trial of ZW25 with palbociclib plus fulvestrant (NCT04224272) is currently ongoing.…”