Chimeric antigen receptor (CAR) T cells targeting a pathogenic MHC class II:peptide complex modulate the progression of autoimmune diabetes

Abstract

A primary initiating epitope in the NOD mouse model of Type 1 Diabetes (T1D) lies between residues 9 and 23 of the insulin B chain. The B:9-23 peptide can bind to the NOD MHC class II molecule (I-A) in multiple registers, but only one, (register 3, R3), creates complexes able to stimulate the majority of pathogenic B:9-23-specific CD4 T cells. Previously we generated a monoclonal antibody (mAb287) that targets this critical I-A-B:9-23(R3) complex. When given weekly to pre-diabetic mice at either early or late stages of disease, mAb287 was able to delay or prevent T1D in the treated animals. Although the precise mechanism of action of mAb287 remains unclear, we hypothesized that it may involve deletion of antigen presenting cells (APCs) bearing the pathogenic IA-B:9-23(R3) complexes, and that this process might be rendered more efficient by re-directing cytotoxic T cells using a mAb287 chimeric antigen receptor (287-CAR). As anticipated, 287-CAR T cells secreted IFN-γ in response to stimulation by I-A-B:9-23(R3) complexes expressed on artificial APCs, but not I-A loaded with other peptides, and killed the presenting cells in vitro. A single infusion of 287-CAR CD8 T cells to young (5 week old) NOD mice significantly delayed the onset of overt hyperglycemia compared to untreated animals (p = 0.022). None of the 287-CAR CD8 T cell treated mice developed diabetes before 18 weeks of age, while 29% of control-CAR T cell treated mice (p = 0.044) and 52% of the un-treated mice (p = 0.0001) had developed T1D by this time. However, the protection provided by 287-CAR CD8 T cells declined with time, and no significant difference in overall incidence by 30 weeks between the 3 groups was observed. Mechanistic studies indicated that the adoptively transferred 287-CAR T cells selectively homed to pancreatic lymph nodes, and in some animals could persist for at least 1-2 weeks post-transfer, but were essentially undetectable 10-15 weeks later. Our study demonstrates that CAR T cells specific for a pathogenic MHC class II:peptide complex can be effective in vivo, but that a single infusion of the current iteration can only delay, but not prevent, the development of T1D. Future studies should therefore be directed towards optimizing strategies designed to improve the longevity of the transferred cells.

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

“…In the future, it is conceivable that engineered T cells may also be used to target also infectious diseases [41] or facilitate the induction of tolerance in transplanted recipient and individual suffering of autoimmune diseases [96,349]. It was shown that the engineering of natural Treg cells or co-transduction of T cells with specific TCRs and FoxP3 can generate Treg cells that were able to suppress arthritis in different models or mitigate autoimmunity [350,351].…”

Targeting the MHC Ligandome by Use of TCR-Like Antibodies

“…Importantly, there was no indication of global immune suppression. The precise mode of action of mAb287 remains unclear, but the authors speculate that selective deletion of target APCs, which in addition to presenting the B:9–23 insulin epitope also present other epitopes, could lead to an overall depletion of pMHCs [81,133]. Another possible explanation for the observed effect could be induction of specific CD4 suppressor cells in line with earlier observations using pan-MHCII mAbs [134].…”

“…Recently, the potential of CAR T cells as a treatment strategy for autoimmunity was explored in diabetic NOD mice. Here, CAR T cells were constructed based on mAb287 and were shown to delay onset of disease, as had been observed by the parent mAb [81,133]. Notably, whereas the parent mAb relied on weekly injections, the CAR T cells were administered once and still showed efficacy [81].…”

Chimeric Antigen Receptor Based Therapy as a Potential Approach in Autoimmune Diseases: How Close Are We to the Treatment?

“…No engineered-T cells were detected in the treated mice, showing a limited lifespan of CAR-T cells. Taken together, these CAR-modified T cells could effectively kill APCs presenting I-Ag7:B:R3 complexes, signifying that APCs expressing the pathogenic T cell epitope are associated with autoimmunity and can be prevented by genetically modified-T cells (111). Table 2 shows further comprehensive details of CAR T-based treatment in the studies mentioned above.…”