{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T04:31:03Z","timestamp":1793939463664,"version":"4.8.0"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T00:00:00Z","timestamp":1717372800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T00:00:00Z","timestamp":1717372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"funder":[{"DOI":"10.13039\/100000038","name":"U.S. Department of Health & Human Services | U.S. Food and Drug Administration","doi-asserted-by":"publisher","award":["5R01FD006589"],"award-info":[{"award-number":["5R01FD006589"]}],"id":[{"id":"10.13039\/100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["U01CA214369"],"award-info":[{"award-number":["U01CA214369"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Gouvernement du Canada | Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["K00CA234959"],"award-info":[{"award-number":["K00CA234959"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat. Biomed. Eng"],"DOI":"10.1038\/s41551-024-01216-4","type":"journal-article","created":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T10:07:49Z","timestamp":1717409269000},"page":"268-278","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Subcutaneous biodegradable scaffolds for restimulating the antitumour activity of pre-administered CAR-T cells"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6999-6454","authenticated-orcid":false,"given":"David K. Y.","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2775-3478","authenticated-orcid":false,"given":"Joshua M.","family":"Brockman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1959-6794","authenticated-orcid":false,"given":"Kwasi","family":"Adu-Berchie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5683-5451","authenticated-orcid":false,"given":"Yutong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9901-7782","authenticated-orcid":false,"given":"Yoav","family":"Binenbaum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2775-0173","authenticated-orcid":false,"given":"Irene","family":"de L\u00e1zaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel C.","family":"Sobral","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rea","family":"Tresa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6299-1194","authenticated-orcid":false,"given":"David J.","family":"Mooney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,3]]},"reference":[{"key":"1216_CR1","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.omtm.2016.12.006","volume":"4","author":"BL Levine","year":"2017","unstructured":"Levine, B. L., Miskin, J., Wonnacott, K. & Keir, C. Global manufacturing of CAR T cell therapy. Mol. Ther. Methods Clin. Dev. 4, 92\u2013101 (2017).","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"1216_CR2","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1038\/s41591-019-0564-6","volume":"25","author":"RG Majzner","year":"2019","unstructured":"Majzner, R. G. & Mackall, C. L. Clinical lessons learned from the first leg of the CAR T cell journey. Nat. Med. 25, 1341\u20131355 (2019).","journal-title":"Nat. Med."},{"key":"1216_CR3","doi-asserted-by":"publisher","first-page":"1166","DOI":"10.1126\/science.abc1855","volume":"371","author":"RA Hernandez-Lopez","year":"2021","unstructured":"Hernandez-Lopez, R. A. et al. T cell circuits that sense antigen density with an ultrasensitive threshold. Science 371, 1166\u20131171 (2021).","journal-title":"Science"},{"key":"1216_CR4","doi-asserted-by":"publisher","first-page":"eaan1088","DOI":"10.1126\/scisignal.aan1088","volume":"11","author":"JR James","year":"2018","unstructured":"James, J. R. Tuning ITAM multiplicity on T cell receptors can control potency and selectivity to ligand density. Sci. Signal. 11, eaan1088 (2018).","journal-title":"Sci. Signal."},{"key":"1216_CR5","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1038\/s41591-018-0290-5","volume":"25","author":"J Feucht","year":"2019","unstructured":"Feucht, J. et al. Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency. Nat. Med. 25, 82\u201388 (2019).","journal-title":"Nat. Med."},{"key":"1216_CR6","doi-asserted-by":"publisher","DOI":"10.1126\/science.aba1786","volume":"372","author":"EW Weber","year":"2021","unstructured":"Weber, E. W. et al. Transient \u2018rest\u2019 restores functionality in exhausted CAR-T cells via epigenetic remodeling. Science 372, eaba1786 (2021).","journal-title":"Science"},{"key":"1216_CR7","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1038\/s41587-019-0033-2","volume":"37","author":"Z Good","year":"2019","unstructured":"Good, Z. et al. Proliferation tracing with single-cell mass cytometry optimizes generation of stem cell memory-like T cells. Nat. Biotechnol. 37, 259\u2013266 (2019).","journal-title":"Nat. Biotechnol."},{"key":"1216_CR8","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1038\/s41586-019-1805-z","volume":"576","author":"RC Lynn","year":"2019","unstructured":"Lynn, R. C. et al. c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature 576, 293\u2013300 (2019).","journal-title":"Nature"},{"key":"1216_CR9","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1016\/j.cell.2017.01.016","volume":"168","author":"WA Lim","year":"2017","unstructured":"Lim, W. A. & June, C. H. The principles of engineering immune cells to treat cancer. Cell 168, 724\u2013740 (2017).","journal-title":"Cell"},{"key":"1216_CR10","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1038\/s41571-019-0297-y","volume":"17","author":"S Rafiq","year":"2020","unstructured":"Rafiq, S., Hackett, C. S. & Brentjens, R. J. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat. Rev. Clin. Oncol. 17, 147\u2013167 (2020).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"1216_CR11","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1038\/nature21405","volume":"543","author":"J Eyquem","year":"2017","unstructured":"Eyquem, J. et al. Targeting a CAR to the TRAC locus with CRISPR\/Cas9 enhances tumour rejection. Nature 543, 113\u2013117 (2017).","journal-title":"Nature"},{"key":"1216_CR12","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1126\/science.aav8692","volume":"365","author":"L Ma","year":"2019","unstructured":"Ma, L. et al. Enhanced CAR\u2013T cell activity against solid tumors by vaccine boosting through the chimeric receptor. Science 365, 162\u2013168 (2019).","journal-title":"Science"},{"key":"1216_CR13","doi-asserted-by":"crossref","unstructured":"Reinhard, K. et al. An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors. Science 367, 446\u2013453 (2020).","DOI":"10.1126\/science.aay5967"},{"key":"1216_CR14","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1007\/s00262-003-0485-5","volume":"53","author":"S Satthaporn","year":"2004","unstructured":"Satthaporn, S. et al. Dendritic cells are dysfunctional in patients with operable breast cancer. Cancer Immunol. Immunother. 53, 510\u2013518 (2004).","journal-title":"Cancer Immunol. Immunother."},{"key":"1216_CR15","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.molimm.2018.03.025","volume":"113","author":"J Bandola-Simon","year":"2019","unstructured":"Bandola-Simon, J. & Roche, P. A. Dysfunction of antigen processing and presentation by dendritic cells in cancer. Mol. Immunol. 113, 31\u201337 (2019).","journal-title":"Mol. Immunol."},{"key":"1216_CR16","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1038\/s41591-018-0041-7","volume":"24","author":"T Giavridis","year":"2018","unstructured":"Giavridis, T. et al. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat. Med. 24, 731\u2013738 (2018).","journal-title":"Nat. Med."},{"key":"1216_CR17","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1038\/s41551-019-0486-0","volume":"4","author":"ME Coon","year":"2020","unstructured":"Coon, M. E., Stephan, S. B., Gupta, V., Kealey, C. P. & Stephan, M. T. Nitinol thin films functionalized with CAR-T cells for the treatment of solid tumours. Nat. Biomed. Eng. 4, 195\u2013206 (2020).","journal-title":"Nat. Biomed. Eng."},{"key":"1216_CR18","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1038\/nbt.4047","volume":"36","author":"AS Cheung","year":"2018","unstructured":"Cheung, A. S., Zhang, D. K. Y., Koshy, S. T. & Mooney, D. J. Scaffolds that mimic antigen-presenting cells enable ex vivo expansion of primary T cells. Nat. Biotechnol. 36, 160\u2013169 (2018).","journal-title":"Nat. Biotechnol."},{"key":"1216_CR19","doi-asserted-by":"publisher","unstructured":"Zhang, D. K. Y., Cheung, A. S. & Mooney, D. J. Activation and expansion of human T cells using artificial antigen-presenting cell scaffolds. Nat. Protoc. https:\/\/doi.org\/10.1038\/s41596-019-0249-0 (2020).","DOI":"10.1038\/s41596-019-0249-0"},{"key":"1216_CR20","first-page":"61","volume":"33","author":"J Kim","year":"2014","unstructured":"Kim, J. et al. Injectable, spontaneously assembling, inorganic scaffolds modulate immune cells in vivo and increase vaccine efficacy. Nat. Biotechnol. 33, 61\u201369 (2014).","journal-title":"Nat. Biotechnol."},{"key":"1216_CR21","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1038\/s41563-018-0028-2","volume":"17","author":"AW Li","year":"2018","unstructured":"Li, A. W. et al. A facile approach to enhance antigen response for personalized cancer vaccination. Nat. Mater. 17, 528 (2018).","journal-title":"Nat. Mater."},{"key":"1216_CR22","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.202002448","volume":"30","author":"MO Dellacherie","year":"2020","unstructured":"Dellacherie, M. O. et al. Single-shot mesoporous silica rods scaffold for induction of humoral responses against small antigens. Adv. Funct. Mater. 30, 2002448 (2020).","journal-title":"Adv. Funct. Mater."},{"key":"1216_CR23","doi-asserted-by":"publisher","unstructured":"Deng, Q. et al. Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas. Nat. Med. https:\/\/doi.org\/10.1038\/s41591-020-1061-7 (2020).","DOI":"10.1038\/s41591-020-1061-7"},{"key":"1216_CR24","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/j.biomaterials.2016.01.026","volume":"83","author":"WA Li","year":"2016","unstructured":"Li, W. A. et al. The effect of surface modification of mesoporous silica micro-rod scaffold on immune cell activation and infiltration. Biomaterials 83, 249\u2013256 (2016).","journal-title":"Biomaterials"},{"key":"1216_CR25","doi-asserted-by":"publisher","first-page":"4817","DOI":"10.1182\/blood-2011-04-348540","volume":"118","author":"RJ Brentjens","year":"2011","unstructured":"Brentjens, R. J. et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 118, 4817\u20134828 (2011).","journal-title":"Blood"},{"key":"1216_CR26","doi-asserted-by":"publisher","first-page":"1250","DOI":"10.1038\/s41587-022-01245-x","volume":"40","author":"P Agarwalla","year":"2022","unstructured":"Agarwalla, P. et al. Bioinstructive implantable scaffolds for rapid in vivo manufacture and release of CAR-T cells. Nat. Biotechnol. 40, 1250\u20131258 (2022).","journal-title":"Nat. Biotechnol."},{"key":"1216_CR27","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36126-7","volume":"14","author":"DKY Zhang","year":"2023","unstructured":"Zhang, D. K. Y. et al. Enhancing CAR-T cell functionality in a patient-specific manner. Nat. Commun. 14, 506 (2023).","journal-title":"Nat. Commun."},{"key":"1216_CR28","doi-asserted-by":"publisher","first-page":"2965","DOI":"10.1182\/blood-2013-06-506741","volume":"122","author":"CRY Cruz","year":"2013","unstructured":"Cruz, C. R. Y. et al. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood 122, 2965\u20132973 (2013).","journal-title":"Blood"},{"key":"1216_CR29","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1126\/science.aar3246","volume":"359","author":"JT Sockolosky","year":"2018","unstructured":"Sockolosky, J. T. et al. Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes. Science 359, 1037\u20131042 (2018).","journal-title":"Science"},{"key":"1216_CR30","doi-asserted-by":"publisher","first-page":"2425","DOI":"10.1172\/JCI66375","volume":"124","author":"CA Bauer","year":"2014","unstructured":"Bauer, C. A. et al. Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction. J. Clin. Invest. 124, 2425\u20132440 (2014).","journal-title":"J. Clin. Invest."},{"key":"1216_CR31","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1073\/pnas.0408197102","volume":"102","author":"M-L Chen","year":"2005","unstructured":"Chen, M.-L. et al. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-\u03b2 signals in vivo. Proc. Natl Acad. Sci. USA 102, 419\u2013424 (2005).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1216_CR32","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1001\/jama.1994.03510360033032","volume":"271","author":"SA Rosenberg","year":"1994","unstructured":"Rosenberg, S. A. et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 271, 907\u2013913 (1994).","journal-title":"JAMA"},{"key":"1216_CR33","doi-asserted-by":"publisher","first-page":"104539","DOI":"10.1016\/j.ebiom.2023.104539","volume":"90","author":"ME Raeber","year":"2023","unstructured":"Raeber, M. E., Sahin, D., Karakus, U. & Boyman, O. A systematic review of interleukin-2-based immunotherapies in clinical trials for cancer and autoimmune diseases. EBioMedicine 90, 104539 (2023).","journal-title":"EBioMedicine"},{"key":"1216_CR34","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s40425-014-0026-0","volume":"2","author":"JP Dutcher","year":"2014","unstructured":"Dutcher, J. P. et al. High dose interleukin-2 (Aldesleukin) - expert consensus on best management practices-2014. J. Immunother. Cancer 2, 26 (2014).","journal-title":"J. Immunother. Cancer"},{"key":"1216_CR35","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abn8264","volume":"8","author":"AK Grosskopf","year":"2022","unstructured":"Grosskopf, A. K. et al. Delivery of CAR-T cells in a transient injectable stimulatory hydrogel niche improves treatment of solid tumors. Sci. Adv. 8, eabn8264 (2022).","journal-title":"Sci. Adv."}],"container-title":["Nature Biomedical Engineering"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41551-024-01216-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41551-024-01216-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41551-024-01216-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T23:03:13Z","timestamp":1740006193000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41551-024-01216-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,3]]},"references-count":35,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["1216"],"URL":"https:\/\/doi.org\/10.1038\/s41551-024-01216-4","relation":{},"ISSN":["2157-846X"],"issn-type":[{"value":"2157-846X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,3]]},"assertion":[{"value":"6 April 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 April 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 June 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"D.J.M. is an inventor in patent applications Harvard University has filed in relation to the TES technology, which has been licensed to Lyell Immunopharma (US Patent App. 18\/072,449). D.J.M. has stock in Lyell Immunopharma. D.J.M, D.K.Y.Z. and J.M.B. are listed as inventors in a patent application based on the findings of this study (WO 2023\/147185). The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}