Targeting B cell leukemia with highly specific allogeneic T cells with a public recognition motif

Abstract

The possibility that allogeneic T cells may be targeted to leukemia has important therapeutic implications. As most tumor antigens represent self-proteins, high-avidity tumor-specific T cells are largely deleted from the repertoire of the patient. In contrast, T cells from major histocompatibility complex (MHC)-mismatched donors provide naïve repertoires wherein such cells have not been systematically eliminated. Yet, evidence for peptide degeneracy or poly-specificity warrants caution in the use of foreign human leukocyte antigen (HLA) or peptide complexes as therapeutic targets. Here, we cocultured HLA-A(*)0201-negative T cells with autologous dendritic cells engineered to present HLA-A(*)0201 complexed with a peptide from the B cell antigen CD20 (CD20p). HLA-A(*)0201/CD20p pentamer-reactive CD8(+) T cells were readily obtained from all donors. The polyclonal cells showed exquisite peptide and MHC specificity, and efficiently killed HLA-A(*)0201-positive B cells, including primary chronic lymphocytic leukemia cells. The T cell receptor (TCR) sequences displayed a novel type of conservation, with extensive homology in the TCR β chain complementarity-determining region 3 and in J, but not V, region. This is surprising, as the donors were HLA disparate and their TCR repertoires are expected to show little overlap. The results demonstrate the first public recognition motif for an allogeneic HLA/peptide complex. The allo-restricted T cells or TCRs could provide graft-versus-leukemia in the absence of graft-versus-host disease.

Alloreactive cytotoxic T cells provide means to decipher the immunopeptidome and reveal a plethora of tumor-associated self-epitopes

“…The concept that cancer cells can be targeted by T cells recognizing self-peptides presented by foreign HLA was first described by Stauss and coworkers (15)(16)(17). Although these and other studies have shown that certain peptides can be specifically recognized when presented on allogeneic HLA (8,9,12,(18)(19)(20)(21)(22)(23), it seemed possible that they represented exceptions, because there is also evidence that allorestricted cells are more promiscuous with regard to peptide recognition (9,18,(24)(25)(26)(27)(28). However, when assessing reactivity to a large number of epitopes at the single-cell level, we did not find evidence suggesting that peptide recognition on foreign HLA generally has a low specificity.…”

“…Functional T-cell responses were measured as mobilization of CD107a/b (degranulation) and production of IFN-γ by flow cytometry, as described in ref. 23, following coculture with various target cells that were DNA-transfected 48 h earlier, mRNA-transfected 4-10 h earlier, or peptideloaded at 10 μM or indicated concentration for 4-12 h. CD4 pos T cells were isolated using a CD4-positive isolation kit (Dynal Biotech), whereas monocytes were isolated by elutriation centrifugation.…”

“…The CD20 mRNA expression construct was reported in ref. 23. The mRNA encoding HLA-A*02:01 or target proteins was generated as described in ref.…”

Targeting B-cell neoplasia with T-cell receptors recognizing a CD20-derived peptide on patient-specific HLA

“…42 Self-reactive T cells can be difficult to identify in the autologous T cell repertoire. 43 Moreover, allo-reactive TCRs can readily be obtained that react to self-antigens with superior affinity relative to those identified in an autologous setting. 44,45 Strong binding of re-directed T cells to the intended target is important for clinical efficacy, 11,46 but on-target and off-target binding to cells other than the intended can potentially cause hazardous toxicities, 31,[47][48][49][50][51] and reviewed in 15 .…”

Therapeutic targeting of the BCR-associated protein CD79b in a TCR-based approach is hampered by aberrant expression of CD79b

“…40 In addition, antigen-specific T cells were obtained by stimulating T cells from HLA-A2-negative donors with autologous dendritic cells (DCs) pulsed with RNA to express HLA-A2 in parallel with a variety of targeted antigens. [41][42][43] In this study, from HLA-A*0201/B*0702-negative healthy individuals, we isolated 3 T-cell clones targeting 3 distinct CD79b peptides presented in HLA-A*0201 or HLA-B*0702. CD79b-positive primary CLL, ALL, and ALL cell lines were recognized by these T-cell clones, whereas no reactivity toward nonhematopoietic tissue was detected.…”