A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy

Abstract

It is assumed that anti-CTLA-4 antibodies cause tumor rejection by blocking negative signaling from B7-CTLA-4 interactions. Surprisingly, at concentrations considerably higher than plasma levels achieved by clinically effective dosing, the anti-CTLA-4 antibody Ipilimumab blocks neither B7 trans-endocytosis by CTLA-4 nor CTLA-4 binding to immobilized or cell-associated B7. Consequently, Ipilimumab does not increase B7 on dendritic cells (DCs) from either CTLA4 gene humanized (Ctla4h/h) or human CD34+ stem cell-reconstituted NSG™ mice. In Ctla4h/m mice expressing both human and mouse CTLA4 genes, anti-CTLA-4 antibodies that bind to human but not mouse CTLA-4 efficiently induce Treg depletion and Fc receptor-dependent tumor rejection. The blocking antibody L3D10 is comparable to the non-blocking Ipilimumab in causing tumor rejection. Remarkably, L3D10 progenies that lose blocking activity during humanization remain fully competent in inducing Treg depletion and tumor rejection. Anti-B7 antibodies that effectively block CD4 T cell activation and de novo CD8 T cell priming in lymphoid organs do not negatively affect the immunotherapeutic effect of Ipilimumab. Thus, clinically effective anti-CTLA-4 mAb causes tumor rejection by mechanisms that are independent of checkpoint blockade but dependent on the host Fc receptor. Our data call for a reappraisal of the CTLA-4 checkpoint blockade hypothesis and provide new insights for the next generation of safe and effective anti-CTLA-4 mAbs.

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.…”

Transfer learning between preclinical models and human tumors identifies conserved NK cell activation signature in anti-CTLA-4 responsive tumors

“…Anti-CTLA-4 causes tumor regression by enhancing T cell effector activity by blocking CTLA-4 interactions with B7 ligands (Krummel and Allison, 1996; Sutmuller et al, 2001). However, recent studies in mice suggest that anti-CTLA-4 efficacy is dependent on the depletion of CTLA-4 expressing regulatory T cells (Du et al, 2018;Simpson et al, 2013). In these models, T cell depletion is mediated by the anti-CTLA-4 antibody Fc domain that interacts with Fc receptors expressed by many immune cell types, such as NK cells.…”

“…In these models, T cell depletion is mediated by the anti-CTLA-4 antibody Fc domain that interacts with Fc receptors expressed by many immune cell types, such as NK cells. This results in the lysis of CTLA-4 expressing regulatory T cells (Tregs) through antibody-dependent cellular cytotoxicity (ADCC) (Du et al, 2018;Simpson et al, 2013). However, the importance of ADCC is also subject to debate, as several publications have shown that depletion of Tregs is not a primary mechanism of action of anti-CTLA-4 therapy in both mice and humans (Ferrara et al, 2019;Kavanagh et al, 2008;Quezada et al, 2006;Schmidt et al, 2009).…”

Domain Binding and Isotype Dictate the Activity of Anti-human OX40 Antibodies

“…Current reagents typically display an unmodified hIgG1 isotype and although safe have not delivered strong anti-tumour effects [7]. These hIgG1 reagents would be expected to deliver the Treg deleting function indicated here but to date this activity has not been shown clearly in patients, with the topic currently debated for other Treg targets such as CTLA-4 [55][56][57]. Furthermore, their deletion may not be sufficient to elicit tumour regression in most human cancers, unlike the mouse models shown here.…”