{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T08:22:07Z","timestamp":1790842927541,"version":"4.1.0"},"reference-count":26,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,7]],"date-time":"2023-01-07T00:00:00Z","timestamp":1673049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Aleta Biotherapeutics"},{"name":"Fortune Program of the Medical Faculty of the University of Cologne"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The efficacy of CD19-specific CAR T cells in the treatment of leukemia\/lymphoma relies, at least in part, on the unique properties of the particular CAR and the presence of healthy B cells that enhance the target cell lysis and cytokine secretion through repetitive stimulation. Here, we report to apply the same CAR to target solid tumors, such as ErbB2+ carcinoma. CD19 CAR T cells are redirected towards the ErbB2+ cells by a fusion protein that is composed of the herceptin-derived anti-ErbB2 scFv 4D5 linked to the CD19 exodomain. The CD19-4D5scFv engager enabled CD19 CAR T cells to recognize the ErbB2+ cancer cells and to suppress the ErbB2+ tumor growth. The primary killing capacity by the ErbB2-redirected CD19 CAR T cells was as efficient as by the ErbB2 CAR T cells, however, adding CD19+ B cells furthermore reinforced the activation of the CD19 CAR T cells, thereby improving the anti-tumor activities. The ErbB2-redirected CD19 CAR T cells, moreover, showed a 100-fold superior selectivity in targeting cancer cells versus healthy fibroblasts, which was not the case for the ErbB2 CAR T cells. The data demonstrate that the CD19 CAR T cells can be high-jacked by a CD19-scFv engager protein to attack specifically solid cancer, thereby expanding their application beyond the B cell malignancies.<\/jats:p>","DOI":"10.3390\/cells12020248","type":"journal-article","created":{"date-parts":[[2023,1,9]],"date-time":"2023-01-09T03:25:58Z","timestamp":1673234758000},"page":"248","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A CD19-Anti-ErbB2 scFv Engager Protein Enables CD19-Specific CAR T Cells to Eradicate ErbB2+ Solid Cancer"],"prefix":"10.3390","volume":"12","author":[{"given":"Andreas A.","family":"Hombach","sequence":"first","affiliation":[{"name":"Department I Internal Medicine, University Hospital Cologne, Robert-Koch-Str. 21, 50931 K\u00f6ln, Germany"},{"name":"Center for Molecular Medicine Cologne, 50937 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Ambrose","sequence":"additional","affiliation":[{"name":"Aleta Biotherapeutics Inc., Natick, MA 01760, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy","family":"Lobb","sequence":"additional","affiliation":[{"name":"Aleta Biotherapeutics Inc., Natick, MA 01760, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4573-3764","authenticated-orcid":false,"given":"Paul","family":"Rennert","sequence":"additional","affiliation":[{"name":"Aleta Biotherapeutics Inc., Natick, MA 01760, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4302-3240","authenticated-orcid":false,"given":"Hinrich","family":"Abken","sequence":"additional","affiliation":[{"name":"Leibniz Institute for Immunotherapy, Division Genetic Immunotherapy, University Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1002\/hon.2591","article-title":"CAR T-Cell Therapy: Full Speed Ahead","volume":"37","author":"Sermer","year":"2019","journal-title":"Hematol. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1035276","DOI":"10.3389\/fimmu.2022.1035276","article-title":"Current Landscape and Future Directions of Bispecific Antibodies in Cancer Immunotherapy","volume":"13","author":"Wei","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1080\/10428190902943077","article-title":"Immunotherapy of Lymphoma and Leukemia with T-Cell Engaging BiTE Antibody Blinatumomab","volume":"50","author":"Nagorsen","year":"2009","journal-title":"Leuk. Lymphoma"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"P86","DOI":"10.1186\/2051-1426-2-S3-P86","article-title":"A Phase I, First-in-Human, Open Label, Dose Escalation Study of MGD007, a Humanized GpA33 \u00d7 CD3 Dual-Affinity Re-Targeting (DART\u00ae) Protein in Patients with Relapsed\/Refractory Metastatic Colorectal Carcinoma","volume":"2","author":"Hurwitz","year":"2014","journal-title":"J. Immunother. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3611","DOI":"10.1158\/1078-0432.CCR-17-0126","article-title":"A Rationally Designed Fully Human EGFRvIII:CD3-Targeted Bispecific Antibody Redirects Human T Cells to Treat Patient-Derived Intracerebral Malignant Glioma","volume":"24","author":"Gedeon","year":"2018","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2664","DOI":"10.1158\/1535-7163.MCT-12-0042","article-title":"Regression of Human Prostate Cancer Xenografts in Mice by AMG 212\/BAY2010112, a Novel PSMA\/CD3-Bispecific BiTE Antibody Cross-Reactive with Non-Human Primate Antigens","volume":"11","author":"Friedrich","year":"2012","journal-title":"Mol. Cancer Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"eaal4291","DOI":"10.1126\/scitranslmed.aal4291","article-title":"An Anti-Glypican 3\/CD3 Bispecific T Cell-Redirecting Antibody for Treatment of Solid Tumors","volume":"9","author":"Ishiguro","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"eaat5775","DOI":"10.1126\/scitranslmed.aat5775","article-title":"Avidity-Based Binding to HER2 Results in Selective Killing of HER2-Overexpressing Cells by Anti-HER2\/CD3","volume":"10","author":"Slaga","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1038\/s41551-021-00800-2","article-title":"Rejuvenation of Tumour-Specific T Cells through Bispecific Antibodies Targeting PD-L1 on Dendritic Cells","volume":"5","author":"Liu","year":"2021","journal-title":"Nat. Biomed. Eng."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/s41586-022-04439-0","article-title":"A Trispecific Antibody Targeting HER2 and T Cells Inhibits Breast Cancer Growth via CD4 Cells","volume":"603","author":"Seung","year":"2022","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1099\/0022-1317-36-1-59","article-title":"Characteristics of a Human Cell Line Transformed by DNA from Human Adenovirus Type 5","volume":"36","author":"Graham","year":"1977","journal-title":"J. Gen. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1089\/hum.2017.126","article-title":"CD20-CD19 Bispecific CAR T Cells for the Treatment of B-Cell Malignancies","volume":"28","author":"Martyniszyn","year":"2017","journal-title":"Hum. Gene Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"595060","DOI":"10.1155\/2012\/595060","article-title":"Engineered T Cells for the Adoptive Therapy of B-Cell Chronic Lymphocytic Leukaemia","volume":"2012","author":"Koehler","year":"2012","journal-title":"Adv. Hematol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6796","DOI":"10.1158\/0008-5472.CAN-14-0079","article-title":"Efficacy of CAR T-Cell Therapy in Large Tumors Relies upon Stromal Targeting by IFN\u03b3","volume":"74","author":"Textor","year":"2014","journal-title":"Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6123","DOI":"10.4049\/jimmunol.167.11.6123","article-title":"Tumor-Specific T Cell Activation by Recombinant Immunoreceptors: CD3 Zeta Signaling and CD28 Costimulation Are Simultaneously Required for Efficient IL-2 Secretion and Can Be Integrated into One Combined CD28\/CD3 Zeta Signaling Receptor Molecule","volume":"167","author":"Hombach","year":"2001","journal-title":"J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1089\/hgtb.2017.083","article-title":"Genetic Modification of T Cells with Chimeric Antigen Receptors: A Laboratory Manual","volume":"28","author":"Kuehle","year":"2017","journal-title":"Hum. Gene Ther. Methods"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1038\/mt.2016.82","article-title":"Superior Therapeutic Index in Lymphoma Therapy: CD30(+) CD34(+) Hematopoietic Stem Cells Resist a Chimeric Antigen Receptor T-Cell Attack","volume":"24","author":"Hombach","year":"2016","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Ambrose, C., Su, L., Wu, L., Dufort, F.J., Sanford, T., Birt, A., Hackel, B.J., Hombach, A., Abken, H., and Lobb, R.R. (2021). Anti-CD19 CAR T Cells Potently Redirected to Kill Solid Tumor Cells. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0247701"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4650","DOI":"10.4049\/jimmunol.178.7.4650","article-title":"T Cell Activation by Antibody-like Immunoreceptors: The Position of the Binding Epitope within the Target Molecule Determines the Efficiency of Activation of Redirected T Cells","volume":"178","author":"Hombach","year":"2007","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/S0022-1759(12)80003-2","article-title":"Improved Short- and Long-Term XTT-Based Colorimetric Cellular Cytotoxicity Assay for Melanoma and Other Tumor Cells","volume":"147","author":"Jost","year":"1992","journal-title":"J. Immunol. Methods"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.jim.2012.06.005","article-title":"Area under the Curve as a Tool to Measure Kinetics of Tumor Growth in Experimental Animals","volume":"382","author":"Duan","year":"2012","journal-title":"J. Immunol. Methods"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/nm.3838","article-title":"4-1BB Costimulation Ameliorates T Cell Exhaustion Induced by Tonic Signaling of Chimeric Antigen Receptors","volume":"21","author":"Long","year":"2015","journal-title":"Nat. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/mt.2010.24","article-title":"Case Report of a Serious Adverse Event Following the Administration of T Cells Transduced with a Chimeric Antigen Receptor Recognizing ERBB2","volume":"18","author":"Morgan","year":"2010","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"303ra139","DOI":"10.1126\/scitranslmed.aac5415","article-title":"Chimeric Antigen Receptor T Cells Persist and Induce Sustained Remissions in Relapsed Refractory Chronic Lymphocytic Leukemia","volume":"7","author":"Porter","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1172\/JCI125423","article-title":"CD19 CAR T Cell Product and Disease Attributes Predict Leukemia Remission Durability","volume":"130","author":"Finney","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"S42","DOI":"10.1002\/ajh.25445","article-title":"Toxicities of CD19 CAR-T Cell Immunotherapy","volume":"94","author":"Hirayama","year":"2019","journal-title":"Am. J. Hematol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/2\/248\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:02:28Z","timestamp":1760119348000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/2\/248"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,7]]},"references-count":26,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["cells12020248"],"URL":"https:\/\/doi.org\/10.3390\/cells12020248","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,7]]}}}