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

Jahn, Lorenz; Hombrink, Pleun; Hassan, Chopie; Kester, Michel G.D.; Steen, Dirk M. van der; Hagedoorn, Renate S.; Falkenburg, J.H. Frederik; Veelen, Peter A. van; Heemskerk, Mirjam H.M.

doi:10.1182/blood-2014-07-587840

Cited by 20 publications

(20 citation statements)

References 53 publications

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“…Among the T-cell clones isolated using pMHC-tetramers, only a small fraction demonstrated sufficient peptide sensitivity and strong antigen-specificity. These results reflect our previous experiences when employing pMHC-tetramers to isolate T-cell clones [20, 30, 31]. …”

Section: Discussionsupporting

confidence: 88%

“…Presentation of self-antigens in the context of allogeneic HLA (alloHLA) can induce strong antigen-specific T-cell responses as observed in HLA-mismatched hematopoietic stem cell transplantation [14, 15]. We and others have developed several approaches to generate T-cell responses towards specific antigens from which individual T-cell clones and their TCRs can be isolated [16–20]. …”

Section: Introductionmentioning

confidence: 99%

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Generation of CD20-specific TCRs for TCR gene therapy of CD20low B-cell malignancies insusceptible to CD20-targeting antibodies

et al. 2016

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Immunotherapy of B-cell leukemia and lymphoma with CD20-targeting monoclonal antibodies (mAbs) has demonstrated clinical efficacy. However, the emergence of unresponsive disease due to low or absent cell surface CD20 urges the need to develop additional strategies. In contrast to mAbs, T-cells via their T-cell receptor (TCR) can recognize not only extracellular but also intracellular antigens in the context of HLA molecules. We hypothesized that T-cells equipped with high affinity CD20-targeting TCRs would be able to recognize B-cell malignancies even in the absence of extracellular CD20. We isolated CD8+ T-cell clones binding to peptide-MHC-tetramers composed of HLA-A*02:01 and CD20-derived peptide SLFLGILSV (CD20SLF) from HLA-A*02:01neg healthy individuals to overcome tolerance towards self-antigens such as CD20. High avidity T-cell clones were identified that readily recognized and lysed primary HLA-A2pos B-cell leukemia and lymphoma in the absence of reactivity against CD20-negative but HLA-A2pos healthy hematopoietic and nonhematopoietic cells. The T-cell clone with highest avidity efficiently lysed malignant cell-lines that had insufficient extracellular CD20 to be targeted by CD20 mAbs. Transfer of this TCR installed potent CD20-specificity onto recipient T-cells and led to lysis of CD20low malignant cell-lines. Moreover, our approach facilitates the generation of an off-the-shelf TCR library with broad applicability by targeting various HLA alleles. Using the same methodology, we isolated a T-cell clone that efficiently lysed primary HLA-B*07:02pos B-cell malignancies by targeting another CD20-derived peptide. TCR gene transfer of high affinity CD20-specific TCRs can be a valuable addition to current treatment options for patients suffering from CD20low B-cell malignancies.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Generation of CD20-specific TCRs for TCR gene therapy of CD20low B-cell malignancies insusceptible to CD20-targeting antibodies

et al. 2016

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“…T-cell clone 9D4 demonstrated great peptide specificity, a feature also observed for other T-cell clones raised in an HLA-mismatched setting after allogeneic stem cell transplantation [26, 27]. In addition, other groups have reported comparable observations when inducing T-cell response across an HLA-mismatch in vitro [28–31]. …”

Section: Discussionmentioning

confidence: 52%

“…Activated CD19 + B-cells were generated by co-culturing CD19 + cells on CD40L-transduced irradiated (70 Gy) mouse-fibroblasts for 7 days in IMDM supplemented with 2 ng/ml IL-4 and 10% human serum. K562 cells expressing HLA-B7 (K562-B7) were previously described [31]. ALL cell lines were previously described [37].…”

Section: Methodsmentioning

confidence: 99%

A CD22-reactive TCR from the T-cell allorepertoire for the treatment of acute lymphoblastic leukemia by TCR gene transfer

et al. 2016

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CD22 is currently evaluated as a target-antigen for the treatment of B-cell malignancies using chimeric antigen receptor (CAR)-engineered T-cells or monoclonal antibodies (mAbs). CAR- and mAbs-based immunotherapies have been successfully applied targeting other antigens, however, occurrence of refractory disease to these interventions urges the identification of additional strategies. Here, we identified a TCR recognizing the CD22-derived peptide RPFPPHIQL (CD22RPF) presented in human leukocyte antigen (HLA)-B*07:02. To overcome tolerance to self-antigens such as CD22, we exploited the immunogenicity of allogeneic HLA. CD22RPF-specific T-cell clone 9D4 was isolated from a healthy HLA-B*07:02neg individual, efficiently produced cytokines upon stimulation with primary acute lymphoblastic leukemia and healthy B-cells, but did not react towards healthy hematopoietic and nonhematopoietic cell subsets, including dendritic cells (DCs) and macrophages expressing low levels of CD22. Gene transfer of TCR-9D4 installed potent CD22-specificity onto recipient CD8+ T-cells that recognized and lysed primary B-cell leukemia. TCR-transduced T-cells spared healthy CD22neg hematopoietic cell subsets but weakly lysed CD22low-expressing DCs and macrophages. CD22-specific TCR-engineered T-cells could form an additional immunotherapeutic strategy with a complementary role to CAR- and antibody-based interventions in the treatment of B-cell malignancies. However, CD22 expression on non-B-cells may limit the attractiveness of CD22 as target-antigen in cellular immunotherapy.

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“…The data have been deposited in NCBI's Gene Expression Omnibus (27) and are accessible through GEO Series accession number GSE76340 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc¼GSE76340). For quantitative RT-PCR, RNA isolation, cDNA synthesis and qPCR were performed as described previously (28). ITGB2 expression was measured using forward primer 5 0 -CTCTCTCAGGAGTGCACGAA-3 0 and reverse primer 5 0 -CCCTGTGAAGTTCAGCTTCTG-3 0 for the normal ITGB2 transcript and forward primer 5 0 -CAGCAGCTG-CCGGGAATG-3 0 and reverse primer 5 0 -CTCAGTCCGAGGACA-GACGG-3 0 for the alternative ITGB2 transcript.…”

Section: Microarray Gene Expression and Qpcr Analysismentioning

confidence: 99%

Integrated Whole Genome and Transcriptome Analysis Identified a Therapeutic Minor Histocompatibility Antigen in a Splice Variant of ITGB2

Pont

Lee

Meijden

et al. 2016

Clinical Cancer Research

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Purpose: In HLA-matched allogeneic hematopoietic stem cell transplantation (alloSCT), donor T cells recognizing minor histocompatibility antigens (MiHAs) can mediate desired antitumor immunity as well as undesired side effects. MiHAs with hematopoiesis-restricted expression are relevant targets to augment antitumor immunity after alloSCT without side effects. To identify therapeutic MiHAs, we analyzed the in vivo immune response in a patient with strong antitumor immunity after alloSCT. Experimental Design: T-cell clones recognizing patient, but not donor, hematopoietic cells were selected for MiHA discovery by whole genome association scanning. RNA-sequence data from the GEUVADIS project were analyzed to investigate alternative transcripts, and expression patterns were determined by microarray analysis and qPCR. T-cell reactivity was measured by cytokine release and cytotoxicity. Results: T-cell clones were isolated for two HLA-B*15:01–restricted MiHA. LB-GLE1-1V is encoded by a nonsynonymous SNP in exon 6 of GLE1. For the other MiHAs, an associating SNP in intron 3 of ITGB2 was found, but no SNP disparity was present in the normal gene transcript between patient and donor. RNA-sequence analysis identified an alternative ITGB2 transcript containing part of intron 3. qPCR demonstrated that this transcript is restricted to hematopoietic cells and SNP-positive individuals. In silico translation revealed LB-ITGB2-1 as HLA-B*15:01–binding peptide, which was validated as hematopoietic MiHA by T-cell experiments. Conclusions: Whole genome and transcriptome analysis identified LB-ITGB2-1 as MiHAs encoded by an alternative transcript. Our data support the therapeutic relevance of LB-ITGB2-1 and illustrate the value of RNA-sequence analysis for discovery of immune targets encoded by alternative transcripts. Clin Cancer Res; 22(16); 4185–96. ©2016 AACR.

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

Abstract: Key Points B-cell malignancies were efficiently recognized by T cells expressing high-affinity alloHLA-restricted TCRs specific for CD79b. Aberrant expression of CD79b in non–B cells caused unwanted reactivity, rendering CD79b unsuitable for TCR-based immunotherapies.

Cited by 20 publications

References 53 publications

Generation of CD20-specific TCRs for TCR gene therapy of CD20low B-cell malignancies insusceptible to CD20-targeting antibodies

Generation of CD20-specific TCRs for TCR gene therapy of CD20low B-cell malignancies insusceptible to CD20-targeting antibodies

A CD22-reactive TCR from the T-cell allorepertoire for the treatment of acute lymphoblastic leukemia by TCR gene transfer

Integrated Whole Genome and Transcriptome Analysis Identified a Therapeutic Minor Histocompatibility Antigen in a Splice Variant of ITGB2

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