{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T11:40:06Z","timestamp":1788176406332,"version":"build-2803163510"},"posted":{"date-parts":[[2025,9,21]]},"group-title":"Immunology","reference-count":83,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,21]],"date-time":"2025-09-21T00:00:00Z","timestamp":1758412800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["Catalyst Program"],"award-info":[{"award-number":["Catalyst Program"]}],"id":[{"id":"https:\/\/ror.org\/05yndxy10","id-type":"ROR","asserted-by":"publisher"}]},{"award":["T32GM141323"],"award-info":[{"award-number":["T32GM141323"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P30CA082103"],"award-info":[{"award-number":["P30CA082103"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,9,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The surface antigen landscape of acute myeloid leukemia (AML) displays significant heterogeneity and overlap with healthy hematopoietic cells. This imparts a substantial hurdle to the development of AML-targeting chimeric antigen receptor (CAR) T-cells that can avoid on- target, off-tumor toxicity. Here, we develop a dual-antigen targeting CAR-T against CD70 and the active conformation of integrin \u03b22 (aITGB2), each previously reported as promising AML targets due to minimal off-tumor expression. We show an OR-gated approach for these antigens significantly increases the proportion of AML blasts that can be targeted, in part using a novel\n                  <jats:italic>ex vivo<\/jats:italic>\n                  co-culture method to restore surface protein homeostasis following a freeze-thaw cycle. We test dual-targeting CAR-T constructs with different combinations of costimulatory domains, identifying constructs with superior anti-tumor cytotoxicity\n                  <jats:italic>in vitro<\/jats:italic>\n                  against AML cell line and patient-derived xenograft models. We further show significantly improved\n                  <jats:italic>in vivo<\/jats:italic>\n                  tumor clearance and survival for a dual-targeting CAR in murine models of AML tumor heterogeneity. Finally, we show that this dual-targeting CAR does not increase off-tumor toxicity, especially against hematopoietic stem and progenitor cells. Together, these findings demonstrate a promising clinically-translatable approach for the treatment of AML without the notable toxicity liabilities associated with other leading CAR-T targets for this disease.\n                <\/jats:p>","DOI":"10.1101\/2025.09.21.677627","type":"posted-content","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T03:00:15Z","timestamp":1758510015000},"source":"Crossref","is-referenced-by-count":1,"title":["Bicistronic CAR T-cells Against CD70 &amp; Active Integrin \u03b22 Overcome Antigen Heterogeneity and Preserve Safety in Acute Myeloid Leukemia"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0445-5654","authenticated-orcid":false,"given":"Amrik S","family":"Kang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1527-7910","authenticated-orcid":false,"given":"Haley","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremiah","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nabeel","family":"Razi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3296-3261","authenticated-orcid":false,"given":"Adila","family":"Izgutdina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3667-8097","authenticated-orcid":false,"given":"Corynn","family":"Kasap","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3456-8144","authenticated-orcid":false,"given":"Nikhil","family":"Chilakapati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Rivera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Phojanakong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Antonio Camara","family":"Serrano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Salangsang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Steri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1179-5879","authenticated-orcid":false,"given":"Aaron C","family":"Logan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8262-1190","authenticated-orcid":false,"given":"Justin","family":"Eyquem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin J","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7465-6964","authenticated-orcid":false,"given":"Arun P","family":"Wiita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025092504501090000_2025.09.21.677627v1.1","unstructured":"SEER Cancer Stat Facts: Leukemia \u2014 Acute Myeloid Leukemia (AML). 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