CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape

Abstract

Chimeric antigen receptors (CARs) are synthetic antigen receptors that reprogram T cell specificity, function and persistence1. Patient-derived CAR T cells have demonstrated remarkable efficacy against a range of B-cell malignancies1–3, and the results of early clinical trials suggest activity in multiple myeloma4. Despite high complete response rates, relapses occur in a large fraction of patients; some of these are antigen-negative and others are antigen-low1,2,4–9. Unlike the mechanisms that result in complete and permanent antigen loss6,8,9, those that lead to escape of antigen-low tumours remain unclear. Here, using mouse models of leukaemia, we show that CARs provoke reversible antigen loss through trogocytosis, an active process in which the target antigen is transferred to T cells, thereby decreasing target density on tumour cells and abating T cell activity by promoting fratricide T cell killing and T cell exhaustion. These mechanisms affect both CD28- and 4-1BB-based CARs, albeit differentially, depending on antigen density. These dynamic features can be offset by cooperative killing and combinatorial targeting to augment tumour responses to immunotherapy.

Functional effects of chimeric antigen receptor co-receptor signaling domains in human Tregs

“…Further characterization of CAR Tregs in mice in which they were detectable on day 7 after injection also revealed variation in the maintenance of the expected FOXP3 + phenotype, with the CD28wt-CAR Tregs having the most consistent and high proportion of FOXP3expressing cells (Figure 2F, Supplemental Figure 4C). It has been reported that one property of CAR Tconv is their ability to acquire their target antigen through a process called trogocytosis (Hamieh et al, 2019). In all samples where Myc+ CAR T cells were detected, none were HLA-A2+, suggesting that at least in this model and at this time point, we were not able to detect trogocytosis (Supplemental Figure 4D).…”

Intercellular transfer of HLA‐G: its potential in cancer immunology

“…Moreover, cancer cells using intercellular transfer of cell‐surface proteins also play critical roles in re‐shaping the tumor microenvironment to support their expansion and metastatic activity, as well as dampen antitumor immune responses . In this context, a recent study by Hamieh et al . revealed that both CD19 and CD22 expressed on NALM6 acute lymphoblastic leukaemia cells could be transferred to chimeric antigen receptor (CAR)‐T cells through the process of trogocytosis.…”

“…Moreover, cancer cells using intercellular transfer of cell-surface proteins also play critical roles in re-shaping the tumor microenvironment to support their expansion and metastatic activity, as well as dampen antitumor immune responses. 15,16 In this context, a recent study by Hamieh et al 17 revealed that both CD19 and CD22 expressed on NALM6 acute lymphoblastic leukaemia cells could be transferred to chimeric antigen receptor (CAR)-T cells through the process of trogocytosis. Consequently, the density of the target molecules CD19 and CD22 was decreased on the tumor cells, and the T-cell killing activity was abated by the fratricide and exhaustion of the T cells with molecules acquired target by trogocytosis by CAR-T cells.…”

Targeting T cell malignancies using CAR-based immunotherapy: challenges and potential solutions

“…The mechanism may be due to the expansion of a small subset of CD19-negative cancer cells or alternatively, the cells may downregulate CD19 from the cell surface in order to evade detection by CAR T cells, rendering them resistant [19,21,[34][35][36][37]. Additionally, it was recently shown that a phenomenon referred to as trogocytosis is a mechanism of antigen escape whereby the antigen is transferred to the CAR T cell [38]. It has also been shown that transduction of a single leukemic blast with an anti-CD19 CAR that was re-infused into a B-ALL patient, ultimately resulted in relapse and death of the patient [39].…”