Robust Production of Merkel Cell Polyomavirus Oncogene Specific T Cells From Healthy Donors for Adoptive Transfer

Davies, Sarah; Barrett, John; Wong, Susan; Chang, Mark; Muranski, Pawel; Brownell, Isaac

doi:10.3389/fimmu.2020.592721

Cited by 10 publications

(5 citation statements)

References 57 publications

(62 reference statements)

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“…However, significant numbers of antigen-specific CD8 T cells were not observed after vaccination with ITI-3000 ( Figure 2D ). This agrees with previous studies using human PBMC and MCC tumor-infiltrating cells that demonstrate strong CD4 T cell-mediated immune responses to the LT antigen ( 16 , 24 , 42 , 43 ).…”

Section: Discussionsupporting

confidence: 92%

LAMP1 targeting of the large T antigen of Merkel cell polyomavirus results in potent CD4 T cell responses and tumor inhibition

Buchta Rosean,

Leyder,

Hamilton

et al. 2023

Front. Immunol.

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IntroductionMost cases of Merkel cell carcinoma (MCC), a rare and highly aggressive type of neuroendocrine skin cancer, are associated with Merkel cell polyomavirus (MCPyV) infection. MCPyV integrates into the host genome, resulting in expression of oncoproteins including a truncated form of the viral large T antigen (LT) in infected cells. These oncoproteins are an attractive target for a therapeutic cancer vaccine.MethodsWe designed a cancer vaccine that promotes potent, antigen-specific CD4 T cell responses to MCPyV-LT. To activate antigen-specific CD4 T cells in vivo, we utilized our nucleic acid platform, UNITE™ (UNiversal Intracellular Targeted Expression), which fuses a tumor-associated antigen with lysosomal-associated membrane protein 1 (LAMP1). This lysosomal targeting technology results in enhanced antigen presentation and potent antigen-specific T cell responses. LTS220A, encoding a mutated form of MCPyV-LT that diminishes its pro-oncogenic properties, was introduced into the UNITE™ platform.ResultsVaccination with LTS220A-UNITE™ DNA vaccine (ITI-3000) induced antigen-specific CD4 T cell responses and a strong humoral response that were sufficient to delay tumor growth of a B16F10 melanoma line expressing LTS220A. This effect was dependent on the CD4 T cells’ ability to produce IFNγ. Moreover, ITI-3000 induced a favorable tumor microenvironment (TME), including Th1-type cytokines and significantly enhanced numbers of CD4 and CD8 T cells as well as NK and NKT cells. Additionally, ITI-3000 synergized with an α-PD-1 immune checkpoint inhibitor to further slow tumor growth and enhance survival.ConclusionsThese findings strongly suggest that in pre-clinical studies, DNA vaccination with ITI-3000, using the UNITE™ platform, enhances CD4 T cell responses to MCPyV-LT that result in significant anti-tumor immune responses. These data support the initiation of a first-in-human (FIH) Phase 1 open-label study to evaluate the safety, tolerability, and immunogenicity of ITI-3000 in patients with polyomavirus-positive MCC (NCT05422781).

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Section: Discussionsupporting

confidence: 92%

LAMP1 targeting of the large T antigen of Merkel cell polyomavirus results in potent CD4 T cell responses and tumor inhibition

Buchta Rosean,

Leyder,

Hamilton

et al. 2023

Front. Immunol.

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“…Some studies have revealed that tumor infiltration by Th1 CD4+ T cells, Th2 CD4+ T cells, and Th17 CD4+ T cells can mediate regression of advanced solid tumors. 30 Thus, these evidences provide a potential mechanism of zc3h12d in tumor immune microenvironment for researchers.…”

Section: Discussionmentioning

confidence: 83%

Zc3h12d, a Novel of Hypomethylated and Immune-Related for Prognostic Marker of Lung Adenocarcinoma

Yang

Hua

et al. 2021

JIR

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Background Zc3h12d is a negative regulator which plays a crucial role in immune modulation. However, the role of zc3h12d in lung adenocarcinoma (LUAD) remains unclear. We aim to explore the prognostic of zc3h12d and investigate the relationship between zc3h12d expression and immune infiltration in LUAD. Methods TIMER site was used to analyze the expression of zc3h12d in LUAD. The zc3h12d protein levels in patient tissue samples were detected by immunohistochemistry staining assays. Meanwhile, based on UALCAN database and samples’ data from our cohort, we explored the relationship of clinicopathological features and zc3h12d expression to determine the clinical effect of zc3h12d in LUAD. Several databases including GEPIA, Kaplan–Meier plotter and our samples’ data were used to explore the prognostic value of zc3h12d in LUAD. Cox regression analysis was established to further evaluate the prognostic value of zc3h12d in LUAD. In addition, zc3h12d promoter methylation was analyzed by UALCAN database. Genetic alteration analysis was observed in the cBioPortal web. GO and KEGG analyses were conducted to elucidate the underlying mechanisms. Finally, the correlation between zc3h12d and tumor-infiltrating immune cells in LUAD was investigated by TIMER database. The B cells level was investigated by flow cytometry analysis of peripheral blood from our LUAD cohort. Results Zc3h12d expression was significantly higher in LUAD, compared with adjacent normal tissues. The clinical data from the UALCAN database demonstrated that zc3h12d expression was closely related with cancer stage and nodal metastasis. However, patient sample detection revealed that zc3h12d expression was closely related to pathological N (p = 0.0431) and grade (p = 0.004). Moreover, low zc3h12d expression was associated with poorer overall survival in LUAD. We analyzed the methylation level of zc3h12d in LUAD and found that the methylation levels of zc3h12d promoter in LUAD were significantly reduced. In addition, zc3h12d genetic alterations, including deep deletion, could be found in LUAD. GO and KEGG pathway analysis results indicated that zc3h12d has a certain value in immune infiltration. We investigated the expression of zc3h12d in tumor-immune interactions. It was found that zc3h12d might be associated with the immune infiltration and markers of infiltrating immune cells of LUAD. The results of patient sample detection confirmed that B cells level was significantly lower in the patients with low zc3h12d expression than those in the patients with high zc3h12d expression. Conclusion zc3h12d might be considered as a potential biomarker for determining prognosis and immune-related therapeutic target in LUAD.

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“…This confirmed our expectations since both donor and patient blood are screened on a regular basis. However, traces of Merkel cell polyomavirus, which does have pathogenic potential, were observed in both healthy blood donors and dialysis pools ( Figure 2 ) [ 46 , 47 ]. Furthermore, segments of rotavirus A ( Reoviridae ), a common cause of gastroenteritis in children, [ 48 ] and adenovirus (type 41/F) have been observed in plasma pools of control patients.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Human Blood Virome in Iranian Multiple Transfused Patients

Thijssen

Khamisipour

Maleki

et al. 2023

Viruses

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Blood transfusion safety is an essential element of public health. Current blood screening strategies rely on targeted techniques that could miss unknown or unexpected pathogens. Recent studies have demonstrated the presence of a viral community (virobiota/virome) in the blood of healthy individuals. Here, we characterized the blood virome in patients frequently exposed to blood transfusion by using Illumina metagenomic sequencing. The virome of these patients was compared to viruses present in healthy blood donors. A total number of 155 beta-thalassemia, 149 hemodialysis, and 100 healthy blood donors were pooled with five samples per pool. Members of the Anelloviridae and Flaviviridae family were most frequently observed. Interestingly, samples of healthy blood donors harbored traces of potentially pathogenic viruses, including adeno-, rota-, and Merkel cell polyomavirus. Viruses of the Anelloviridae family were most abundant in the blood of hemodialysis patients and displayed a higher anellovirus richness. Pegiviruses (Flaviviridae) were only observed in patient populations. An overall trend of higher eukaryotic read abundance in both patient groups was observed. This might be associated with increased exposure through blood transfusion. Overall, the findings in this study demonstrated the presence of various viruses in the blood of Iranian multiple-transfused patients and healthy blood donors.

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Robust Production of Merkel Cell Polyomavirus Oncogene Specific T Cells From Healthy Donors for Adoptive Transfer

Cited by 10 publications

References 57 publications

LAMP1 targeting of the large T antigen of Merkel cell polyomavirus results in potent CD4 T cell responses and tumor inhibition

LAMP1 targeting of the large T antigen of Merkel cell polyomavirus results in potent CD4 T cell responses and tumor inhibition

Zc3h12d, a Novel of Hypomethylated and Immune-Related for Prognostic Marker of Lung Adenocarcinoma

Characterization of the Human Blood Virome in Iranian Multiple Transfused Patients

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