Expansion of Anti-Mesothelin Specific CD4+ and CD8+ T Cell Responses in Patients with Pancreatic Carcinoma

Chen, Yuan; Ayaru, Lakshmana; Mathew, Sanju; Morris, Emma; Pereira, Stephen P.; Behboudi, Shahriar

doi:10.1371/journal.pone.0088133

Cited by 25 publications

(24 citation statements)

References 44 publications

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“…(36) Significantly, no toxicities were observed in the patients. In addition to CD4+ and CD8+ T-cell responses,(38) MSLN-specific antibody immune responses(39) were observed in patients with ovarian and pancreatic cancer, confirming the immunogenicity of MSLN and further supporting the safety of its immunotherapeutic targeting.…”

Section: Msln Vaccines and Immuno-conjugatesmentioning

confidence: 76%

Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors

2016

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Chimeric antigen receptors (CARs) are synthetic receptors that target T cells to cell-surface antigens and augment T-cell function and persistence. Mesothelin is a cell-surface antigen implicated in tumor invasion, which is highly expressed in mesothelioma, lung, pancreas, breast, ovarian, and other cancers. Its low-level expression in mesothelia however commands thoughtful therapeutic interventions. Encouragingly, recent clinical trials evaluating active immunization or immune-conjugates in patients with pancreatic adenocarcinoma or mesothelioma have shown responses without toxicity. Altogether, these findings and preclinical CAR therapy models using either systemic or regional T-cell delivery argue favorably for mesothelin CAR therapy in multiple solid tumors.

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Section: Msln Vaccines and Immuno-conjugatesmentioning

confidence: 76%

Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors

2016

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“…Altogether, COA‐1, mesothelin and TERT appear to be relevant targets to eliminate oxaR CRC cells. CD4 Th1 immune responses directed against these three antigens have already been described in digestive cancer patients, but they have never been associated with oxaliplatin based treatment. In order to evaluate the frequency of COA‐1, mesothelin‐specific T‐cell responses, we sought to identify promiscuous MHC‐II restricted epitopes by using binding prediction algorithm.…”

Section: Discussionmentioning

confidence: 99%

CD4 T cells target colorectal cancer antigens upregulated by oxaliplatin

Galaine

Turco

Vauchy

et al. 2019

Intl Journal of Cancer

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Immune checkpoint blockade has proven its efficacy in hypermutated subtypes of metastatic colorectal cancers (mCRC). Immunogenic potential can also be observed with conventional chemotherapies, but this property has never been explored thoroughly in CRC patients. The CRC therapeutic arsenal includes oxaliplatin, a well-characterized platinum drug already described as immunogenic. Here, we investigated the impact of the oxaliplatin-based treatment on mCRC immunopeptidome. We demonstrated that oxaliplatin-resistant CRC cell lines overexpressed telomerase reverse transcriptase (TERT), colorectalassociated-tumor antigen-1 (COA-1) and mesothelin tumor-associated antigens. We identified new HLA class-II-restricted and promiscuous peptides derived from COA-1 and mesothelin. The two naturally processed peptides COA-1 331-345 and Meso 366-380 appear to be the most immunogenic in mCRC patients. A prospective cohort of 162 mCRC patients enabled us to explore the impact of oxaliplatin exposure on the antitumor-specific immune response. Interestingly, chemotherapy-naive mCRC patients present high immune CD4 T-cell responses directed against TERT, COA-1 and mesothelin-derived peptides. These antitumor Tcell responses were maintained after 3 months of oxaliplatin-based treatment. Altogether, these findings highlight the interest of immunostimulatory agents to improve the management of chemoresistant mCRC patients. Finally, the high frequency of immune responses targeting the new immunogenic peptides derived from COA-1 and mesothelin support their use in immunomonitoring strategies. C.T. and C.V. contributed equally to this work Additional Supporting Information may be found in the online version of this article.

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“…Short-term primary T-cell lines were generated as previously described (26). Briefly, isolated PBMC were cultured at 1.5×10 6 cells/mL in normal growth medium (NGM) consisting of RPMI 1640 (Invitrogen, Paisley, United Kingdom) supplemented with 2 mM glutamine, 1% penicillin/streptomycin (Sigma-Aldrich, St. Louis, MO), and 10% heat-inactivated FCS (BioWest, Ringmer, United Kingdom).…”

Section: Methodsmentioning

confidence: 99%

Ex Vivo PD-L1/PD-1 Pathway Blockade Reverses Dysfunction of Circulating CEA-Specific T Cells in Pancreatic Cancer Patients

Yuan

Xue

Behboudi

et al. 2017

Clinical Cancer Research

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Carcinoembryonic antigen (CEA) is a candidate target for cellular immunotherapy of pancreatic cancer (PC). In this study, we have characterised the antigen-specific function of autologous cytotoxic T lymphocytes (CTL) specific for the HLA-A2 restricted peptide, pCEA691–699, isolated from the peripheral T cell repertoire of PC patients and sought to determine if ex vivo PD-L1 & TIM3 blockade could enhance CTL function. CD8+ T cell lines were generated from peripheral blood mononuclear cells (PBMCs) of 18 HLA-A2+ patients with PC and from 15 healthy controls. In vitro peptide specific responses were evaluated by flow cytometry after staining for intracellular cytokine production and CSFE cytotoxicity assays using pancreatic cancer cell lines as targets. Cytokine secreting functional CEA691-specific CTL lines were successfully generated from 10 of 18PC patients, with two CTL lines able to recognise and kill both CEA691 peptide-loaded T2 cells and CEA+ HLA-A2+ pancreatic cancer cell lines. In the presence of ex vivo PD-L1 blockade, functional CEA691-specific CD8+ T cell responses, including IFN-γ secretion and proliferation, were enhanced and this effect was more pronounced on Ag-specific T cells isolated from tumor draining lymph nodes. These data demonstrate that CEA691-specific CTL can be readily expanded from the self-restricted T cell repertoire of PC patients and that their function can be enhanced by PD-L1 blockade.

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Expansion of Anti-Mesothelin Specific CD4+ and CD8+ T Cell Responses in Patients with Pancreatic Carcinoma

Cited by 25 publications

References 44 publications

Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors

Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors

CD4 T cells target colorectal cancer antigens upregulated by oxaliplatin

Ex Vivo PD-L1/PD-1 Pathway Blockade Reverses Dysfunction of Circulating CEA-Specific T Cells in Pancreatic Cancer Patients

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