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Patient-derived pancreatic tumour organoids identify therapeutic responses to oncolytic adenoviruses.

ABSTRACT: BACKGROUND:Pancreatic patient-derived organoids (PDOs) are a well-established model for studying pancreatic ductal adenocarcinoma (PDAC) carcinogenesis and are potential predictors of clinical responses to chemotherapy. Oncolytic virotherapy is envisioned as a novel treatment modality for pancreatic cancer, and candidate viruses are being tested in clinical trials. Here, we explore the feasibility of using PDOs as a screening platform for the oncolytic adenovirus (OA) response. METHODS:Organoids were established from healthy pancreas and PDAC tissues and assessed for infectivity, oncoselectivity, and patient-dependent sensitivity to OA. Antitumour effects were studied in vivo in organoid xenografts. Further evaluation of oncolytic responses was conducted in organoids derived from orthotopic models or metastastic tissues. FINDINGS:Oncolytic adenoviruses display good selectivity, with replication only in organoids derived from PDAC tumours. Furthermore, responses of PDOs to a set of OAs reveal individual differences in cytotoxicity as well as in synergism with standard chemotherapy. Adenoviral cytotoxicity in PDOs is predictive of antitumour efficacy in a subcutaneous xenograft setting. Organoids from orthotopic tumours and metastases in nude mice mirror the viral preference of PDOs, indicating that PDO sensitivity to OAs could be informative about responses in both primary tumours and metastatic foci. INTERPRETATION:Our data imply that pancreatic PDOs can serve as predictive tools for screening for sensitivity to OA.

SUBMITTER: Raimondi G

PROVIDER: S-EPMC7251378 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Patient-derived pancreatic tumour organoids identify therapeutic responses to oncolytic adenoviruses.

Raimondi Giulia G Mato-Berciano Ana A Pascual-Sabater Silvia S Rovira-Rigau Maria M Cuatrecasas Miriam M Fondevila Constantino C Sánchez-Cabús Santiago S Begthel Harry H Boj Sylvia F SF Clevers Hans H Fillat Cristina C

EBioMedicine 20200524

<h4>Background</h4>Pancreatic patient-derived organoids (PDOs) are a well-established model for studying pancreatic ductal adenocarcinoma (PDAC) carcinogenesis and are potential predictors of clinical responses to chemotherapy. Oncolytic virotherapy is envisioned as a novel treatment modality for pancreatic cancer, and candidate viruses are being tested in clinical trials. Here, we explore the feasibility of using PDOs as a screening platform for the oncolytic adenovirus (OA) response.<h4>Method ...[more]

PMID: 32460166

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Project description:Background and aimsPancreatic cancer is the seventh leading cause of cancer-related deaths worldwide. Checkpoint immunotherapy has not yet shown encouraging results in pancreatic cancer possibly because of a poor immunogenicity and/or an immune suppressive microenvironment. The aim of this study was to develop patient-derived xenograft (PDX) models, compare their genetics to the original biopsies, and assess if autologous tumor-infiltrating lymphocytes (TILs) would have antitumoral activity in pancreatic cancer.MethodsWe subcutaneously transplanted tumors from 29 patients into NOG mice to generate PDX models. We established TIL cultures and injected them into PDX mice. We analyzed histology and genetics of biopsies and PDX tumors.ResultsTumor growths were confirmed in 11 of 29 transplantations. The PDX tumors histologically resembled their original biopsies, but because stromal cells in the PDX model tumors were from mouse, their gene expression differed from the original biopsies. Immune checkpoint ligands other than programmed death ligand-1 (PD-L1) were expressed in pancreatic cancers, but PD-L1 was rarely expressed. When it was expressed, it correlated with tumor take in PDX models. One of the 3 tumors that expressed PD-L1 was an adenosquamous cancer, and another had a mismatch repair deficiency. TILs were expanded from 6 tumors and were injected into NOG or human interleukin-2 transgenic-NOG mice carrying PDX tumors. Regression of tumors could be verified in human interleukin-2 transgenic-NOG mice in 3 of the 6 PDX models treated with autologous TILs, including the adenosquamous PDX model.ConclusionPDX models of pancreatic cancer can be used to learn more about tumor characteristics and biomarkers and to evaluate responses to adoptive cell therapy and combination therapies. The major benefit of the model is that modifications of T cells can be tested in an autologous humanized mouse model to gain preclinical data to support the initiation of a clinical trial.

Dataset Information

Patient-derived pancreatic tumour organoids identify therapeutic responses to oncolytic adenoviruses.

Publications

Patient-derived pancreatic tumour organoids identify therapeutic responses to oncolytic adenoviruses.

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