{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T20:30:14Z","timestamp":1792701014025,"version":"4.5.0"},"reference-count":36,"publisher":"National Academy of Sciences","issue":"51","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,12,23]]},"abstract":"<jats:p>\n                    Clinical responses to CD19-directed CAR T cell therapy in B cell malignancies are strongly associated with robust CAR T cell expansion in the peripheral blood. In contrast, CAR T cells targeting solid tumors do not encounter cognate antigen in the periphery, resulting in limited expansion and subtherapeutic peak concentrations. To overcome this, we engineered dual-targeted and dual-costimulated CAR T cells (CD19\/28\u03b6-M5BB\u03b6) that recognize CD19+ B cells, thereby promoting peripheral expansion and increasing the pool of solid tumor-directed CAR T cells available for tumor infiltration without the need for lymphodepletion. In immunocompetent C57BL\/6 mouse models of pancreatic ductal adenocarcinoma and melanoma, these dual-targeted CAR T cells demonstrated enhanced peripheral expansion, improved anti-tumor efficacy, and increased survival without added dysfunction or toxicity compared to single antigen-targeted CAR T cells. We translated our findings to human CAR T cells by developing a pancreatic\/xenograft model with CD19\n                    <jats:sup>+<\/jats:sup>\n                    B cells in the periphery and again demonstrated that treatment with dual CAR T cells showed significantly enhanced tumor clearance and survival compared to single antigen-targeted CAR T cells. In conclusion, we demonstrate that dual-targeted CAR T cells boost peripheral expansion, and anti-tumor efficacy, providing a strategy for enhancing outcomes for patients treated with clinical CAR T products targeting solid tumors.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2518996122","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T20:01:02Z","timestamp":1765828862000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":7,"title":["Dual-targeted ping-pong CAR T cells: Leveraging peripheral expansion to improve solid tumor immunotherapy"],"prefix":"10.1073","volume":"122","author":[{"given":"Amanda V.","family":"Finck","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine","place":["Philadelphia"]},{"name":"Parker Institute for Cancer Immunotherapy at University of Pennsylvania","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziming","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine","place":["Philadelphia"]},{"name":"Parker Institute for Cancer Immunotherapy at University of Pennsylvania","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna","family":"Gonzales","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine","place":["Philadelphia"]},{"name":"Parker Institute for Cancer Immunotherapy at University of Pennsylvania","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nils","family":"Wellhausen","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine","place":["Philadelphia"]},{"name":"Parker Institute for Cancer Immunotherapy at University of Pennsylvania","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sof\u00eda","family":"Castelli","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine","place":["Philadelphia"]},{"name":"Parker Institute for Cancer Immunotherapy at University of Pennsylvania","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esha","family":"Banerjee","sequence":"additional","affiliation":[{"name":"Comparative Pathology Core, Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Angela","family":"Aznar","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine","place":["Philadelphia"]},{"name":"Parker Institute for Cancer Immunotherapy at University of Pennsylvania","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina M.","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine","place":["Philadelphia"]},{"name":"Parker Institute for Cancer Immunotherapy at University of Pennsylvania","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0241-3557","authenticated-orcid":false,"given":"Carl H.","family":"June","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine","place":["Philadelphia"]},{"name":"Parker Institute for Cancer Immunotherapy at University of Pennsylvania","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,12,15]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04390-6"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24065688"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omto.2023.04.003"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2023011399"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1407222"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-021-00459-7"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-062315-120245"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2016.97"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2023.06.006"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2010.24"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1158\/2767-9764.CRC-21-0154"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav8692"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aac5415"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.1.73"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2024.3891"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2020.07.017"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaz1863"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0247701"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.22"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0813101106"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.99573"},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","unstructured":"S. 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V. Finck Z. Wang L. Chen R.M. Young C. H. June Data from \u201cDual-Targeted Ping-Pong CAR T cells: Leveraging Peripheral Expansion to Improve Solid Tumor Immunotherapy.\u201d Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE307863. Deposited 11 September 2025."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2518996122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T20:01:24Z","timestamp":1765828884000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2518996122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,15]]},"references-count":36,"journal-issue":{"issue":"51","published-print":{"date-parts":[[2025,12,23]]}},"alternative-id":["10.1073\/pnas.2518996122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2518996122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,15]]},"assertion":[{"value":"2025-07-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2518996122"}}