@article{8ba588437dd340cab10bbf350dfedc0e,
title = "Generation of Tumor-Reactive T Cells by Co-culture of Peripheral Blood Lymphocytes and Tumor Organoids",
abstract = "Cancer immunotherapies have shown substantial clinical activity for a subset of patients with epithelial cancers. Still, technological platforms to study cancer T-cell interactions for individual patients and understand determinants of responsiveness are presently lacking. Here, we establish and validate a platform to induce and analyze tumor-specific T cell responses to epithelial cancers in a personalized manner. We demonstrate that co-cultures of autologous tumor organoids and peripheral blood lymphocytes can be used to enrich tumor-reactive T cells from peripheral blood of patients with mismatch repair-deficient colorectal cancer and non-small-cell lung cancer. Furthermore, we demonstrate that these T cells can be used to assess the efficiency of killing of matched tumor organoids. This platform provides an unbiased strategy for the isolation of tumor-reactive T cells and provides a means by which to assess the sensitivity of tumor cells to T cell-mediated attack at the level of the individual patient. A modified patient-derived tumor organoids system allows the expansion of tumor-specific T cells from blood for personalized analysis of their anti-cancer properties.",
keywords = "adoptive cell transfer, colorectal cancer, immune checkpoint blockade, immunotherapy, microsatellite instable, mismatch repair deficient, non-small cell lung cancer, organoids, T cell",
author = "Dijkstra, \{Krijn K.\} and Cattaneo, \{Chiara M.\} and Fleur Weeber and Myriam Chalabi and \{van de Haar\}, Joris and Fanchi, \{Lorenzo F.\} and Maarten Slagter and \{van der Velden\}, \{Daphne L.\} and Sovann Kaing and Sander Kelderman and \{van Rooij\}, Nienke and \{van Leerdam\}, \{Monique E.\} and Annekatrien Depla and Smit, \{Egbert F.\} and Hartemink, \{Koen J.\} and \{de Groot\}, Rosa and Wolkers, \{Monika C.\} and Norman Sachs and Petur Snaebjornsson and Kim Monkhorst and John Haanen and Hans Clevers and Schumacher, \{Ton N.\} and Voest, \{Emile E.\}",
note = "Funding Information: H.C. is an inventor on several patents related to organoid technology. N.S. reports grants from the Netherlands Organization for Scientific Research, during the conduct of the study; others come from Vertex Pharmaceuticals Incorporated, outside the submitted work. In addition, N.S. has a patent (PCT/EP2015/077990) with royalties paid to Stichting HUB and a patent (PCT/EP2015/077988) with royalties paid to Stichting HUB. Funding Information: We thank Suzanne van der Kolk, Judith Westra, Louisa Hoes, and Luuk Schipper for help with patient inclusion. We acknowledge Martijn van Baalen, Anita Pfauth, and Frank van Diepen for assistance in flow cytometry. We thank Marjolijn Mertz, Lenny Brocks, and Bram van den Broek for help in live imaging experiments. We would like to acknowledge Dennis Peters and Ingrid Hofland from the NKI-AVL Core Facility Molecular Pathology \& Biobanking (CFMPB) for supplying NKI-AVL Biobank material and lab support. DNA sequencing was performed by Marja Nieuwland, Roel Kluin, and Ron Kerkhoven. We thank Marc van de Wetering and Hubrecht Organoid Technology (HUB) for advice on organoid cultures. We would like to thank Merus for provision of anti-PD-1. Thanks to Marije Marsman, Steven van Houtvin, Hylke Galema, and Koen Verhoef for support in technology transfer. Stef van Lieshout, Ewart de Bruijn, and Edwin Cuppen (Hartwig Medical Foundation) performed authentication of organoid lines. Thanks to Salo Ooft, Chelsea McLean, Christina Stangl, Louisa Hoes, Luuk Schipper, Maarten Ligtenberg, David Vredevoogd, Julia Boshuijzen, Wouter Scheper, Joost van den Berg, Renate de Boer, Christian Blank, and Daniel Peeper for input in the design of experiments. This work was supported by the NWO Gravitation Program (NWO; 2012-2022) (to E.E.V. on behalf of CancerGenomics.nl), a KWF grant (HUBR2014-7006) (to E.E.V.), the KWF Queen Wilhelmina Award (NKI 2013-6122) (to T.S.), and ERC AdG SENSIT (to T.S.). Funding Information: We thank Suzanne van der Kolk, Judith Westra, Louisa Hoes, and Luuk Schipper for help with patient inclusion. We acknowledge Martijn van Baalen, Anita Pfauth, and Frank van Diepen for assistance in flow cytometry. We thank Marjolijn Mertz, Lenny Brocks, and Bram van den Broek for help in live imaging experiments. We would like to acknowledge Dennis Peters and Ingrid Hofland from the NKI-AVL Core Facility Molecular Pathology \& Biobanking (CFMPB) for supplying NKI-AVL Biobank material and lab support. DNA sequencing was performed by Marja Nieuwland, Roel Kluin, and Ron Kerkhoven. We thank Marc van de Wetering and Hubrecht Organoid Technology (HUB) for advice on organoid cultures. We would like to thank Merus for provision of anti-PD-1. Thanks to Marije Marsman, Steven van Houtvin, Hylke Galema, and Koen Verhoef for support in technology transfer. Stef van Lieshout, Ewart de Bruijn, and Edwin Cuppen (Hartwig Medical Foundation) performed authentication of organoid lines. Thanks to Salo Ooft, Chelsea McLean, Christina Stangl, Louisa Hoes, Luuk Schipper, Maarten Ligtenberg, David Vredevoogd, Julia Boshuijzen, Wouter Scheper, Joost van den Berg, Renate de Boer, Christian Blank, and Daniel Peeper for input in the design of experiments. This work was supported by the NWO Gravitation Program (NWO ; 2012-2022 ) (to E.E.V. on behalf of CancerGenomics.nl), a KWF grant ( HUBR2014-7006 ) (to E.E.V.), the KWF Queen Wilhelmina Award ( NKI 2013-6122 ) (to T.S.), and ERC AdG SENSIT (to T.S.). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = sep,
day = "6",
doi = "10.1016/j.cell.2018.07.009",
language = "English",
volume = "174",
pages = "1586--1598.e12",
journal = "Cell",
issn = "0092-8674",
publisher = "Elsevier",
number = "6",
}