Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies

Abstract

SummaryWith the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches.

A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization

“…Whether these autoimmune reactions occur due to the loss of CTLA-4 function in conventional T cells, regulatory T cells, or both is under debate. A recent study using a humanized CTLA-4 mouse model casts doubt on the blockade of the B7s/CTLA-4 interaction using clinical-grade anti-CTLA-4 mAbs (ipilimumab) (Du et al, 2018), and numerous works during recent years suggest that the main effect of anti-CTLA-4 mAbs may be mediated by Treg depletion (Bulliard et al, 2013; Selby et al, 2013; Simpson et al, 2013, Arce Vargas et al, 2018). These results thus call for a reassessment of the “immune checkpoint blockade” concept for anti-CTLA-4 therapy.…”

Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens

“…This observation was refined by showing that the tumoricidal activity of anti-OX40 and anti-GITR mIgG2a mAbs was abrogated in mice deficient for activating FcγRs (I, III, and IV), and was independent of the inhibitory FcγR, FcγRIIB. The overexpression of OX40, GITR, and CTLA-4 by intratumoral Treg cells combined with the abundance of activating FcγR-expressing myeloid and natural killer (NK) cells effector populations supported that Treg cell depletion was by an FcγR-mediated ADCC/P mechanism (Arce Vargas et al, 2018; Bulliard et al, 2013; Ingram et al, 2018; Kim and Ashkenazi, 2013). However, despite a common requirement for activating FcγR co-engagement for the anti-tumor activity mediated by anti-CTLA-4 and anti-GITR mAbs, we observed a quantitative and kinetic difference in the extent of Treg cell depletion mediated between mIgG2a mAbs (Figure 1B).…”

“…Consistent with these preclinical results, melanoma patients exhibiting higher frequencies of FcγRIIIA + myeloid effector cells in the peripheral blood showed an increased response to ipilimumab treatment, which was attributed to ADCC/P-mediated depletion of Treg cells within the tumor microenvironment (Romano et al, 2015). Recently, others have identified that melanoma patients expressing the high-affinity FcγRIIIA-V158 polymorphism in the context of high tumor mutational burden exhibited improved clinical response rates to ipilimumab (Arce Vargas et al, 2018). This observation was interpreted as further support for the selective depletion of intratumoral Treg cells.…”

“…For instance, emerging evidence suggests that CTLA-4 promotes T cell motility by antagonizing TCR-induced zeta chain-associated protein 70 (ZAP70) microcluster formation, leading to reduced APC-T cell dwell time (Schneider et al, 2008). To date, three anti-CTLA-4 mAbs have demonstrated single-agent anti-tumor activity in patients, although the contribution of FcγR-associated mechanism(s) to the therapeutic activity of these antibodies remains controversial (Arce Vargas et al, 2018; Gombos et al, 2018; Ribas and Flaherty, 2015; Romano et al, 2015). …”

Dual PD-1 and CTLA-4 Checkpoint Blockade Promotes Antitumor Immune Responses through CD4+Foxp3− Cell–Mediated Modulation of CD103+ Dendritic Cells

“…Although CTLA-4 is also expressed on intratumoral CD8 þ T cells and potentially limits their activity through interaction with CD80/CD86 at the tumor site (17), anti-CTLA-4 also offers therapeutic benefit through the priming of antitumor T-cell responses in the draining lymph nodes (DLN). The therapeutic efficacy of anti-CTLA-4 may also be partly attributed to the depletion of CD4 þ Foxp3 þ cells, due to their constitutively high expression of CTLA-4 (18,19). These distinct mechanisms of action for anti-PD-1 and anti-CTLA-4 may partially explain the increased efficacy observed following combination therapy.…”