Spontaneous Immunity Against the Receptor Tyrosine Kinase ROR1 in Patients with Chronic Lymphocytic Leukemia

Hojjat‐Farsangi, Mohammad; Jeddi-Tehrani, Mahmood; Daneshmanesh, Amir Hossein; Mozaffari, Fariba; Moshfegh, Ali; Hansson, Lotta; Razavi, Seyed Mohsen; Sharifian, Ramazan Ali; Rabbani, Hodjattallah; Österborg, Anders; Mellstedt, Håkan; Shokri, Fazel

doi:10.1371/journal.pone.0142310

Cited by 12 publications

(10 citation statements)

References 42 publications

(56 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because spontaneous pathophysiologically relevant T-cell responses against nonmutated LAAs were described for other HMs, 38,86,87 we analyzed our CML patient cohort for preexisting T-cell responses against our newly defined targets. Of note, although preexisting T-cell responses against HLA class II peptides were identified with comparable frequencies as previously described for CLL, 38 acute myeloid leukemia, 40 and multiple myeloma, 41 functional T cells targeting HLA class I antigens were only of low frequency in CML TKI patient samples.…”

Section: Discussionmentioning

confidence: 99%

The HLA ligandome landscape of chronic myeloid leukemia delineates novel T-cell epitopes for immunotherapy

Bilich

Nelde

Bichmann

et al. 2019

Blood

View full text Add to dashboard Cite

Antileukemia immunity plays an important role in disease control and maintenance of tyrosine kinase inhibitor (TKI)-free remission in chronic myeloid leukemia (CML). Thus, antigen-specific immunotherapy holds promise for strengthening immune control in CML but requires the identification of CML-associated targets. In this study, we used a mass spectrometry–based approach to identify naturally presented HLA class I– and class II–restricted peptides in primary CML samples. Comparative HLA ligandome profiling using a comprehensive dataset of different hematological benign specimens and samples from CML patients in deep molecular remission delineated a panel of novel frequently presented CML-exclusive peptides. These nonmutated target antigens are of particular relevance because our extensive data-mining approach suggests the absence of naturally presented BCR-ABL– and ABL-BCR–derived HLA-restricted peptides and the lack of frequent tumor-exclusive presentation of known cancer/testis and leukemia-associated antigens. Functional characterization revealed spontaneous T-cell responses against the newly identified CML-associated peptides in CML patient samples and their ability to induce multifunctional and cytotoxic antigen-specific T cells de novo in samples from healthy volunteers and CML patients. Thus, these antigens are prime candidates for T-cell–based immunotherapeutic approaches that may prolong TKI-free survival and even mediate cure of CML patients.

show abstract

Section: Discussionmentioning

confidence: 99%

The HLA ligandome landscape of chronic myeloid leukemia delineates novel T-cell epitopes for immunotherapy

Bilich

Nelde

Bichmann

et al. 2019

Blood

View full text Add to dashboard Cite

show abstract

“…T.J.K. 's laboratory and others showed that the receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an onco-embryonic antigen expressed on the surface of CLL cells, but not on cells of healthy adults, except a small subgroup of distinctive pro-B cells, named hematogones (15)(16)(17)(18)(19)(20). Evaluation of the CLL cells from 1,568 cases showed that levels of ROR1 varied on the leukemia cells of different patients (21).…”

mentioning

confidence: 99%

MicroRNA dysregulation to identify therapeutic target combinations for chronic lymphocytic leukemia

Rassenti

Balatti

Ghia

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Loss of is the most common genetic lesion in chronic lymphocytic leukemia (CLL), promoting overexpression of, which factors in leukemia pathogenesis. Indeed, an inhibitor of Bcl2, venetoclcax, is highly active in the treatment of patients with CLL. However, single-agent venetoclcax fails to eradicate minimal residual disease in most patients. Accordingly, we were interested in other genes that may be regulated by , which may target other drivers in CLL. We found that targets , which encodes an onco-embryonic surface protein expressed on the CLL cells of over 90% of patients, but not on virtually all normal postpartum tissues. CLL with high-level expression of ROR1 also have high-level expression of Bcl2, but low-to-negligible Moreover, CLL cases with high-level ROR1 have deletion(s) at the chromosomal location of the genes encoding (13q14) more frequently than cases with low-to-negligible ROR1, implying that deletion of may promote overexpression of , in addition to ROR1 is a receptor for Wnt5a, which can promote leukemia-cell proliferation and survival, and can be targeted by cirmtuzumab, a humanized anti-ROR1 mAb. We find that this mAb can enhance the in vitro cytotoxic activity of venetoclcax for CLL cells with high-level expression of ROR1, indicating that combining these agents, which target ROR1 and Bcl2, may have additive, if not synergistic, activity in patients with this disease.

show abstract

“…However, although numerous clinical trials reported peptidespecific T cell induction upon vaccination with non-mutated tumor antigens, no correlation with clinical activity was shown and no meaningful clinical results were achieved (4-10). Nevertheless, there are two main points that prompt us and others, despite former disappointing clinical data, to use novel technologies and methods to unravel and resolve the underlying issues and limitations of non-mutated antigen-based vaccines: (i) Several studies report on the existence of spontaneous preexisting T cell responses targeting non-mutated tumor antigens and their correlation with beneficial clinical outcome, suggesting a pathophysiological relevance of these immune responses in vivo (11)(12)(13)(14) and (ii) recent data show that immune checkpoint inhibitor-mediated T cell responses are not only targeting neoepitopes but also non-mutated tumor antigens (60)(61)(62).…”

Section: Discussionmentioning

confidence: 99%

“…Whereas a huge number of clinical studies have shown immune responses, including strong CD8 + T cell responses, to vaccines targeting non-mutated tumor antigens, so far, all performed trials failed to show meaningful clinical results (4)(5)(6)(7)(8)(9)(10). Nonetheless, several studies showed a pathophysiological relevance of these tumor antigens, correlating spontaneous, pre-existing as well as immune checkpoint inhibitor-induced T cell responses, targeting non-mutated tumor antigens with improved clinical outcome of malignancies (11)(12)(13)(14). Therefore, the usage of novel technologies and methods, to unravel and resolve the underlying issues and limitations of non-mutated antigen-based vaccines, might enable that T cell responses, induced or boosted by these vaccines, may result in clinical effectiveness in the future (15).…”

Section: Introductionmentioning

confidence: 99%

Immunopeptidomics-Guided Warehouse Design for Peptide-Based Immunotherapy in Chronic Lymphocytic Leukemia

et al. 2021

View full text Add to dashboard Cite

Antigen-specific immunotherapies, in particular peptide vaccines, depend on the recognition of naturally presented antigens derived from mutated and unmutated gene products on human leukocyte antigens, and represent a promising low-side-effect concept for cancer treatment. So far, the broad application of peptide vaccines in cancer patients is hampered by challenges of time- and cost-intensive personalized vaccine design, and the lack of neoepitopes from tumor-specific mutations, especially in low-mutational burden malignancies. In this study, we developed an immunopeptidome-guided workflow for the design of tumor-associated off-the-shelf peptide warehouses for broadly applicable personalized therapeutics. Comparative mass spectrometry-based immunopeptidome analyses of primary chronic lymphocytic leukemia (CLL) samples, as representative example of low-mutational burden tumor entities, and a dataset of benign tissue samples enabled the identification of high-frequent non-mutated CLL-associated antigens. These antigens were further shown to be recognized by pre-existing and de novo induced T cells in CLL patients and healthy volunteers, and were evaluated as pre-manufactured warehouse for the construction of personalized multi-peptide vaccines in a first clinical trial for CLL (NCT04688385). This workflow for the design of peptide warehouses is easily transferable to other tumor entities and can provide the foundation for the development of broad personalized T cell-based immunotherapy approaches.

show abstract

Spontaneous Immunity Against the Receptor Tyrosine Kinase ROR1 in Patients with Chronic Lymphocytic Leukemia

Cited by 12 publications

References 42 publications

The HLA ligandome landscape of chronic myeloid leukemia delineates novel T-cell epitopes for immunotherapy

The HLA ligandome landscape of chronic myeloid leukemia delineates novel T-cell epitopes for immunotherapy

MicroRNA dysregulation to identify therapeutic target combinations for chronic lymphocytic leukemia

Immunopeptidomics-Guided Warehouse Design for Peptide-Based Immunotherapy in Chronic Lymphocytic Leukemia

Contact Info

Product

Resources

About