Antitumor activity of antibody against cytotoxic T lymphocyte epitope peptide of lymphocyte‐specific protein tyrosine kinase

Matsueda, Satoko; Itoh, Kyogo; Shichijo, Shigeki

doi:10.1111/cas.13522

Cited by 11 publications

(12 citation statements)

References 19 publications

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“…The results revealed that, among the vaccinated peptides, only three peptides (Lck-486, EGFR-800 and HNRPL-140) were significantly associated with OS. Although the underlying mechanisms remain unclear, it was reported that a monoclonal antibody reacting to the Lck-486 peptide exhibited an antitumor activity in a murine model with suppression of T regulatory cells at tumor sites (27). Lck (a member of the Src family of non-receptor protein tyrosine kinases expressed in both activated T lymphocytes and metastatic cancers cells with oncogenic properties in human cancers), is pivotal for T regulatory cells (Tregs) and program death-1-positive T-cell activities (26).…”

Section: Pre-vaccination Igg Post Vaccination Iggmentioning

confidence: 99%

Identification of biomarkers for personalized peptide vaccination in 2,588 cancer patients

et al. 2020

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Peptide-based cancer vaccines have failed to provide sufficient clinical benefits in order to be approved in clinical trials since the 1990s. To understand the mechanisms underlying this failure, the present study investigated biomarkers associated with the lower overall survival (OS) among 2,588 patients receiving personalized peptide vaccination (PPV). Survival data were obtained from a database of 2,588 cancer patients including 399 patients with lung, 354 with prostate and 344 with colon cancer. They entered into phase II clinical trials of PPV in which 2 to 4 of 31 warehouse peptides were selected for vaccination on an individual patient basis based on human leukocyte antigen (HLA) class IA-types and pre-existing peptide-specific IgG levels. Higher pre-vaccination neutrophil, monocyte and platelet counts, and lower pre-vaccination lymphocyte and red blood cell counts were inversely associated with OS, with higher sensitivities in the proportions of neutrophils and lymphocytes, respectively. The most potent unfavorable and favorable factors for OS were the median percentage of neutrophils (≥64.8%) or percentage of lymphocytes (≥25.1%) with correlation coefficients (R 2 ) of 0.98 and 0.92, respectively. Higher pre-vaccination levels of c-reactive protein and other inflammatory soluble factors were inversely associated with OS. Pre-vaccination peptide-specific immunity levels had no effect on OS, although lower immune boosting levels were inversely associated with OS. None of the 31 peptides was inversely associated with OS, although a few peptides were positively associated with it. On the whole, the findings of the present study suggested that pre-vaccination inflammatory signatures, but not those of post-vaccination immune induction, were associated with lower clinical benefits of PPV.

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Section: Pre-vaccination Igg Post Vaccination Iggmentioning

confidence: 99%

Identification of biomarkers for personalized peptide vaccination in 2,588 cancer patients

et al. 2020

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“…Based on these initial findings a monoclonal antibody (mAb) recognizing the LCK486–494 peptide was recently developed. The mAb showed antitumor activity in immunocompetent Balb/c mice challenged with murine Colon-26 cells and an even more potent tumor inhibition was observed when this mAb was given prior to a LCK peptide vaccination [ 90 ]. This study suggests that therapeutic strategies directed against LCK might not only show effects on tumor metastasis, but could also inhibit tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Identification of lymphocyte cell-specific protein-tyrosine kinase (LCK) as a driver for invasion and migration of oral cancer by tumor heterogeneity exploitation

et al. 2021

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Background Cancer metastases are the main cause of lethality. The five-year survival rate for patients diagnosed with advanced stage oral cancer is 30%. Hence, the identification of novel therapeutic targets is an urgent need. However, tumors are comprised of a heterogeneous collection of cells with distinct genetic and molecular profiles that can differentially promote metastasis making therapy development a challenging task. Here, we leveraged intratumoral heterogeneity in order to identify drivers of cancer cell motility that might be druggable targets for anti-metastasis therapy. Methods We used 2D migration and 3D matrigel-based invasion assays to characterize the invasive heterogeneity among and within four human oral cancer cell lines in vitro. Subsequently, we applied mRNA-sequencing to map the transcriptomes of poorly and strongly invasive subclones as well as primary tumors and matched metastasis. Results We identified SAS cells as a highly invasive oral cancer cell line. Clonal analysis of SAS yielded a panel of 20 subclones with different invasive capacities. Integrative gene expression analysis identified the Lymphocyte cell-specific protein-tyrosine kinase (LCK) as a druggable target gene associated with cancer cell invasion and metastasis. Inhibition of LCK using A-770041 or dasatinib blocked invasion of highly aggressive SAS cells. Interestingly, reduction of LCK activity increased the formation of adherens junctions and induced cell differentiation. Conclusion Analysis of invasive heterogeneity led to the discovery of LCK as an important regulator of motility in oral cancer cells. Hence, small molecule mediated inhibition of LCK could be a promising anti-metastasis therapy option for oral cancer patients.

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“…We speculated that Lck-486 peptide could thus be a suiTable representative for the evaluation of the kinetics of each peptide. This investigation was also conducted based on our previous study of a monoclonal anti-Lck-486 IgG (IgG 2b) peptide capable of inhibiting tumor growth in vivo with a suppression of tumor-infiltrating T regulatory cells in a murine model ( 18 ).…”

Section: Resultsmentioning

confidence: 99%

Immune responses of patients without cancer recurrence after a cancer vaccine over a long term

et al. 2022

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The present study aimed to clarify the humoral and cellular immune responses of patients with cancer who experienced no recurrence over a long term after receiving a cancer vaccine. The immune kinetics were investigated in response to a personalized peptide vaccination (PPV) among 44 Japanese patients without an active tumor at entry to the vaccination: Lung adenocarcinoma (n=11); colon (n=18); and breast cancer (n=15) (9, 10, 12, 8 and 5 patients with stage I, II, III and IV recurrences, respectively). The patients' immunoglobulin G (IgG) and cytotoxic T lymphocyte (CTL) activities were measured using a multiplexed Luminex assay and an interferon-γ release assay, respectively. There were no severe adverse events related to the PPV other than a grade III injection site reaction. A potent boost in IgG or CTL at the end of the 1st vaccination cycle was observed in 77% of the patients (n=84). The IgG levels were sustained throughout the follow-up period, whereas the CTL levels declined and were transient. A total of 37 of the 44 patients (84%) had no recurrence, with a median follow-up of 67.6 months (interquartile range, 45.6-82.8 months). Overall, the PPV induced long-term humoral immunity with transient cellular immunity in the majority of patients with cancer without an active tumor at their entry to the PPV.

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Antitumor activity of antibody against cytotoxic T lymphocyte epitope peptide of lymphocyte‐specific protein tyrosine kinase

Cited by 11 publications

References 19 publications

Identification of biomarkers for personalized peptide vaccination in 2,588 cancer patients

Identification of biomarkers for personalized peptide vaccination in 2,588 cancer patients

Identification of lymphocyte cell-specific protein-tyrosine kinase (LCK) as a driver for invasion and migration of oral cancer by tumor heterogeneity exploitation

Immune responses of patients without cancer recurrence after a cancer vaccine over a long term

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