title: Design of Switchable Chimeric Antigen Receptor T Cells Targeting Breast Cancer.
abstract: Chimeric antigen receptor T (CAR-T) cells have demonstrated promising results against hematological malignancies, but have encountered significant challenges in translation to solid tumors. To overcome these hurdles, we have developed a switchable CAR-T cell platform in which the activity of the engineered cell is controlled by dosage of an antibody-based switch. Herein, we apply this approach to Her2-expressing breast cancers by engineering switch molecules through site-specific incorporation of FITC or grafting of a peptide neo-epitope (PNE) into the anti-Her2 antibody trastuzumab (clone 4D5). We demonstrate that both switch formats can be readily optimized to redirect CAR-T cells (specific for the corresponding FITC or PNE) to Her2-expressing tumor cells, and afford dose-titratable activation of CAR-T cells ex vivo and complete clearance of the tumor in rodent xenograft models. This strategy may facilitate the application of immunotherapy to solid tumors by affording comparable efficacy with improved safety owing to switch-based control of the CAR-T response.
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA, 92037, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cao
authors.affiliation: California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA, 92037, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Rodgers
authors.affiliation: California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA, 92037, USA.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA, 92037, USA.
authors.forename: Insha
authors.initials: I
authors.lastname: Ahmad
authors.affiliation: California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA, 92037, USA.
authors.forename: Eric N
authors.initials: EN
authors.lastname: Hampton
authors.affiliation: California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA, 92037, USA.
authors.forename: Jennifer S Y
authors.initials: JS
authors.lastname: Ma
authors.affiliation: California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA, 92037, USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Mazagova
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA, 92037, USA.|Present address: Daegu-Gyeongbook Medical Innovation Center, 80 Chembok-ro, Dong-gu, Daegu, 41061, Korea.
authors.forename: Sei-Hyun
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA, 92037, USA.
authors.forename: Hwa Young
authors.initials: HY
authors.lastname: Yun
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA, 92037, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Xiao
authors.affiliation: California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA, 92037, USA.
authors.forename: Pengyu
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA, 92037, USA.
authors.forename: Xiaozhou
authors.initials: X
authors.lastname: Luo
authors.affiliation: California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA, 92037, USA.
authors.forename: Reyna K V
authors.initials: RK
authors.lastname: Lim
authors.affiliation: California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA, 92037, USA.
authors.forename: Holly M
authors.initials: HM
authors.lastname: Pugh
authors.affiliation: California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA, 92037, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA, 92037, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Kazane
authors.affiliation: California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA, 92037, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Wright
authors.affiliation: California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA, 92037, USA. chkim@calibr.org.|Present address: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Korea. chkim@calibr.org.
authors.forename: Chan Hyuk
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA, 92037, USA. Schultz@scripps.edu.|California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA, 92037, USA. Schultz@scripps.edu.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.affiliation: California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA, 92037, USA. tyoung@calibr.org.
authors.forename: Travis S
authors.initials: TS
authors.lastname: Young
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005812:Genes, Switch / Q000235:genetics; D064593:Heterografts; D006801:Humans; D007167:Immunotherapy; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell; C508053:ERBB2 protein, human
keywords: Her2-expressing breast cancer; antibody switches; chimeric antigen receptors; peptide neo-epitope; unnatural amino acids