title: Kinetics of tumor destruction by chimeric antigen receptor-modified T cells.
abstract: The use of chimeric antigen receptor (CAR)-modified T cells as a therapy for hematologic malignancies and solid tumors is becoming more widespread. However, the infusion of a T-cell product targeting a single tumor-associated antigen may lead to target antigen modulation under this selective pressure, with subsequent tumor immune escape. With the purpose of preventing this phenomenon, we have studied the impact of simultaneously targeting two distinct antigens present on tumor cells: namely mucin 1 and prostate stem cell antigen, both of which are expressed in a variety of solid tumors, including pancreatic and prostate cancer. When used individually, CAR T cells directed against either tumor antigen were able to kill target-expressing cancer cells, but tumor heterogeneity led to immune escape. As a combination therapy, we demonstrate superior antitumor effects using both CARs simultaneously, but this was nevertheless insufficient to achieve a complete response. To understand the mechanism of escape, we studied the kinetics of T-cell killing and found that the magnitude of tumor destruction depended not only on the presence of target antigens but also on the intensity of expression-a feature that could be altered by administering epigenetic modulators that upregulated target expression and enhanced CAR T-cell potency.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Usanarat
authors.initials: U
authors.lastname: Anurathapan
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Chan
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Hakeem F
authors.initials: HF
authors.lastname: Hindi
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Roopa
authors.initials: R
authors.lastname: Mucharla
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Pradip
authors.initials: P
authors.lastname: Bajgain
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Brendan C
authors.initials: BC
authors.lastname: Hayes
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Fisher
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Heslop
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Cliona M
authors.initials: CM
authors.lastname: Rooney
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Leen
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas, USA. Electronic address: jfvera@txch.org.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Vera
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D045744:Cell Line, Tumor; D064987:Cell- and Tissue-Based Therapy; D057809:HEK293 Cells; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D018396:Mucin-1 / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D018396:Mucin-1; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins