FcγRIIaandFcγRIIIaPolymorphisms and Cetuximab Benefit in the Microscopic Disease

Sclafani, Francesco; Castro, David González de; Cunningham, David; Wilson, Sanna Hulkki; Peckitt, Clare; Capdevila, Jaume; Glimelius, Bengt; Keränen, S. Roselló; Wotherspoon, Andrew; Brown, Gina; Tait, Diana; Begum, Ruwaida; Thomas, Janet; Oates, J.; Chau, Ian

doi:10.1158/1078-0432.ccr-14-0674

Cited by 8 publications

(4 citation statements)

References 41 publications

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“…31 For cetuximab, mutations in the Kras protein-which is downstream from the EGFR receptor-can nullify the benefit from blocking the receptor, leading to persistent intracellular signaling and cellular growth. Our finding that a germline SNP in FccRIIA correlates with clinical benefit is provocative, confirms other findings, [32][33][34] and deserves additional exploration. The observed impact by this polymorphism is likely because of cetuximab (and not lapatinib) therapy given the drug's mechanism of action, and it may indicate different activation of antibody-dependent cellular cytotoxicity.…”

Section: Discussionsupporting

confidence: 87%

A phase 1 study of cetuximab and lapatinib in patients with advanced solid tumor malignancies

Deeken

Wang

Subramaniam

et al. 2015

Cancer

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Background Acquired resistance to anti-EGFR therapy may be due to EGFR-ErbB2 heterodimerization and pathway reactivation. In pre-clinical studies. inhibiting ErbB2 blocked this resistance mechanism and re-sensitized cells to anti-EGFR therapy. Cetuximab targets the EGFR receptor, whereas lapatinib inhibits both EGFR and ErbB2. We conducted a phase I trial to assess the safety, dose-limiting toxicities (DLTS), and maximum-tolerated dose (MTD) of cetuximab and lapatinib in patients with solid tumors. Methods Patients received standard weekly cetuximab with escalating lapatinib dosages of 750, 1000 or 1250mg daily in 3-week cycles. DLTs were monitored through the end of cycle 2. Pre- and post-treatment tumor biopsies and germ-line DNA were obtained for correlative studies. Results Twenty-two patients were enrolled, and 18 each were evaluable for toxicity and response. Fifty-nine percent had prior anti-EGFR therapy. Common toxicities included rash and diarrhea. No patient experienced a DLT at the highest dose level and no grade 4 toxicity was observed. Response included no CRs, 3 PRs, 9 SD, and 6 DP, for an overall response rate of 17% and a clinical benefit rate of 67%. The clinical benefit rate in patients previously treated with anti-EGFR therapy was 70%. Mean treatment duration was 4.7 cycles (range 1–14). Decreased expression of EGFR/ErbB2 pathway components after treatment correlated with response, while increased expression in PI3K, Jak/Stat, and MAPK pathways occurred in non-responders. Conclusions The combination of cetuximab and lapatinib was well tolerated, with expected toxicities and notable clinical activity, including in patients with previous anti-EGFR therapy. Further clinical study is warranted.

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Section: Discussionsupporting

confidence: 87%

A phase 1 study of cetuximab and lapatinib in patients with advanced solid tumor malignancies

Deeken

Wang

Subramaniam

et al. 2015

Cancer

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“…Awareness of the FcγR binding profile of a mAb offers an opportunity to improve upon existing monoclonal therapies, exemplified by obinutuzumab, a de-fucosylated IgG1 bio-similar of rituximab designed to bind FcγRIIIA and enhance ADCC against CD20 + cells in chronic lymphocytic leukemia (30). Human germ-line variants of FcγRs that display altered Fc binding tropism have been identified and are an important focus in the effort to understand responses to mAb therapies that rely on FcγRs for therapeutic function, like cetuximab (31), rituximab (32), trastuzumab (33), and other mAb therapies (34). …”

Section: Discussionmentioning

confidence: 99%

In vivo imaging reveals a tumor-associated macrophage–mediated resistance pathway in anti–PD-1 therapy

et al. 2017

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Monoclonal antibodies targeting the immune checkpoint Programmed Death-1 (aPD-1 mAbs) have demonstrated impressive benefits for the treatment of some cancers; yet, these drugs are not always effective and we still have a limited understanding of the mechanisms that contribute to their efficacy or lack thereof. Here we employed in vivo imaging to uncover the fate and activity of aPD-1 mAbs in real-time and at subcellular resolution in mice. We show that aPD-1 mAbs effectively bind PD-1+ tumor-infiltrating CD8+ T cells at early time-points after administration. However, this engagement is transient, as aPD-1 mAbs are captured within minutes from the T cell surface by PD-1− tumor-associated macrophages. We further show that macrophage accrual of aPD-1 mAbs depends both on the drug’s Fc domain glycan and on Fcγ-receptors (FcγRs) expressed by host myeloid cells, and extend these findings to the human setting. Finally, we demonstrate that in vivo blockade of FcγRs prior to aPD-1 mAb administration substantially prolongs aPD-1 mAb binding to tumor-infiltrating CD8+ T cells and enhances immunotherapy-induced tumor regression in mice. These investigations yield new insight into aPD-1 target engagement in vivo and identify specific Fc : FcγR interactions that can be modulated to improve checkpoint blockade therapy.

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“…The importance of ADCC for the in vivo effect of monoclonal antibodies is evident from previous studies showing loss of efficacy of these agents in FcRγ −/− mice that are deficient in activating Fc receptors [ 37 ]. In addition, FcγRIIa and FcγRIIIa gene polymorphisms have been involved in increased ADCC-related therapeutic response to cetuximab in early-stage [ 53 ] and metastatic colon cancer patients [ 54 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

miR-143 or miR-145 overexpression increases cetuximab-mediated antibody-dependent cellular cytotoxicity in human colon cancer cells

et al. 2016

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miR-143 and miR-145 are downregulated in colon cancer. Here, we tested the effect of restoring these miRNAs on sensitization to cetuximab in mutant KRAS (HCT116 and SW480) and wild-type KRAS (SW48) colon cancer cells. We evaluated cetuximab-mediated antibody-dependent cellular cytotoxicity (ADCC) and the modulation of signaling pathways involved in immune effector cell-mediated elimination of cancer cells. Stable miR-143 or miR-145 overexpression increased cell sensitivity to cetuximab, resulting in a significant increase of cetuximab-mediated ADCC independently of KRAS status. Importantly, HCT116 cells overexpressing these miRNAs triggered apoptosis in result of cetuximab-mediated ADCC, effected by peripheral blood mononuclear cells (p < 0.01). This was associated with increased apoptosis and caspase-3/7 activity, and reduced Bcl-2 protein expression (p < 0.01). In addition, caspase inhibition abrogated cetuximab-mediated ADCC in HCT116 cells overexpressing either miR-143 or miR-145 (p < 0.01). Furthermore, Bcl-2 silencing led to high level of cetuximab-mediated ADCC, compared to control siRNA (p < 0.05). Importantly, granzyme B inhibition, abrogated cetuximab-mediated ADCC, reducing caspase-3/7 activity (p < 0.01). Collectively, our data suggests that re-introduction of miR-143 or miR-145 may provide a new approach for development of therapeutic strategies to re-sensitize colon cancer cells to cetuximab by stimulating cetuximab-dependent ADCC to induce cell death.

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FcγRIIaandFcγRIIIaPolymorphisms and Cetuximab Benefit in the Microscopic Disease

Cited by 8 publications

References 41 publications

A phase 1 study of cetuximab and lapatinib in patients with advanced solid tumor malignancies

A phase 1 study of cetuximab and lapatinib in patients with advanced solid tumor malignancies

In vivo imaging reveals a tumor-associated macrophage–mediated resistance pathway in anti–PD-1 therapy

miR-143 or miR-145 overexpression increases cetuximab-mediated antibody-dependent cellular cytotoxicity in human colon cancer cells

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