{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T14:33:04Z","timestamp":1790087584175,"version":"4.0.1"},"posted":{"date-parts":[[2025,3,6]]},"group-title":"Oncology","reference-count":33,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T00:00:00Z","timestamp":1741219200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Oncogenic\n                  <jats:italic>KRAS<\/jats:italic>\n                  drives initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC). Here, we show that engineered exosomes with Kras\n                  <jats:sup>G12D<\/jats:sup>\n                  specific siRNA (iExoKras\n                  <jats:sup>G12D<\/jats:sup>\n                  ) reveal impressive biodistribution in pancreas with negligible toxicity in preclinical studies in mice and Rhesus macaques. Clinical testing of iExoKras\n                  <jats:sup>G12D<\/jats:sup>\n                  in the iEXPLORE (iExoKras\n                  <jats:sup>G12D<\/jats:sup>\n                  in Pancreatic Cancer) Phase I study employed a classical 3+3 dose escalation design (Phase Ia), followed by an accelerated titration design (Phase Ib) (\n                  <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT03608631\">NCT03608631<\/jats:ext-link>\n                  ). Patients with advanced metastatic disease were enrolled after failure of multiple lines of therapy. iExoKras\n                  <jats:sup>G12D<\/jats:sup>\n                  therapy was well-tolerated with no reported dose-limiting toxicity with some cases of stable disease response, and maximum tolerated infusion was not reached even at the highest dose. Downregulation of\n                  <jats:italic>\n                    KRAS\n                    <jats:sup>G12D<\/jats:sup>\n                  <\/jats:italic>\n                  DNA and suppression of phopho-Erk was documented with increased intratumoral in CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cell infiltration in patient samples upon treatment. The CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cell recruitment priming by iExoKras\n                  <jats:sup>G12D<\/jats:sup>\n                  informed on potential efficacy of immune checkpoint therapy and lead to validation testing in preclinical PDAC models. Combination therapy of iExoKras\n                  <jats:sup>G12D<\/jats:sup>\n                  and anti-CTLA-4 antibodies, but not anti-PD1, revealed robust anti-tumor efficacy via FAS mediated CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cell anti-tumor activity. This first-in-human, precision medicine clinical trial offers new insights into priming of immunotherapy by oncogenic Kras inhibitor and an opportunistic combination therapy for PDAC patients.\n                <\/jats:p>","DOI":"10.1101\/2025.03.03.25322827","type":"posted-content","created":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T07:35:06Z","timestamp":1741332906000},"source":"Crossref","is-referenced-by-count":19,"title":["KRAS\n                  <sup>G12D<\/sup>\n                  -Specific Targeting with Engineered Exosomes Reprograms the Immune Microenvironment to Enable Efficacy of Immune Checkpoint Therapy in PDAC Patients"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8514-8551","authenticated-orcid":false,"given":"Valerie S.","family":"LeBleu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8814-8004","authenticated-orcid":false,"given":"Brandon G.","family":"Smaglo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6503-6851","authenticated-orcid":false,"given":"Krishnan K.","family":"Mahadevan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1960-3032","authenticated-orcid":false,"given":"Michelle L.","family":"Kirtley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4092-4991","authenticated-orcid":false,"given":"Kathleen M.","family":"McAndrews","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6803-8844","authenticated-orcid":false,"given":"Mayela","family":"Mendt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1116-3840","authenticated-orcid":false,"given":"Sujuan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6443-3820","authenticated-orcid":false,"given":"Ana S.","family":"Maldonado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hikaru","family":"Sugimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria E.","family":"Salvatierra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa M","family":"Solis Soto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rick","family":"Finch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihai","family":"Gagea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0285-5825","authenticated-orcid":false,"given":"Adam C.","family":"Fluty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve J.","family":"Ludtke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Jack","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhinav K.","family":"Jain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gauri","family":"Varadhachary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachna T","family":"Shroff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7923-9978","authenticated-orcid":false,"given":"Anirban","family":"Maitra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Shpall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2190-547X","authenticated-orcid":false,"given":"Raghu","family":"Kalluri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shubham","family":"Pant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025031101150870000_2025.03.03.25322827v1.1","unstructured":"Society, A.C. 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