title: CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients.
abstract: Targeted T cell immunotherapies using engineered T lymphocytes expressing tumor-directed chimeric antigen receptors (CARs) are designed to benefit patients with cancer. Although incorporation of costimulatory endodomains within these CARs increases the proliferation of CAR-redirected T lymphocytes, it has proven difficult to draw definitive conclusions about the specific effects of costimulatory endodomains on the expansion, persistence, and antitumor effectiveness of CAR-redirected T cells in human subjects, owing to the lack of side-by-side comparisons with T cells bearing only a single signaling domain. We therefore designed a study that allowed us to directly measure the consequences of adding a costimulatory endodomain to CAR-redirected T cells. Patients with B cell lymphomas were simultaneously infused with 2 autologous T cell products expressing CARs with the same specificity for the CD19 antigen, present on most B cell malignancies. One CAR encoded both the costimulatory CD28 and the ζ-endodomains, while the other encoded only the ζ-endodomain. CAR+ T cells containing the CD28 endodomain showed strikingly enhanced expansion and persistence compared with CAR+ T cells lacking this endodomain. These results demonstrate the superiority of CARs with dual signal domains and confirm a method of comparing CAR-modified T cells within individual patients, thereby avoiding patient-to-patient variability and accelerating the development of optimal T cell immunotherapies.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Savoldo
authors.forename: Carlos Almeida
authors.initials: CA
authors.lastname: Ramos
authors.forename: Enli
authors.initials: E
authors.lastname: Liu
authors.forename: Martha P
authors.initials: MP
authors.lastname: Mims
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.forename: George
authors.initials: G
authors.lastname: Carrum
authors.forename: Rammurti T
authors.initials: RT
authors.lastname: Kamble
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Bollard
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Gee
authors.forename: Zhuyong
authors.initials: Z
authors.lastname: Mei
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Bambi
authors.initials: B
authors.lastname: Grilley
authors.forename: Cliona M
authors.initials: CM
authors.lastname: Rooney
authors.forename: Helen E
authors.initials: HE
authors.lastname: Heslop
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
mesh_terms: D018941:Antigens, CD19 / Q000378:metabolism; D018106:CD28 Antigens / Q000378:metabolism*; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007167:Immunotherapy / Q000379:methods; D008213:Lymphocyte Activation; D008223:Lymphoma / Q000378:metabolism*; D016393:Lymphoma, B-Cell / Q000378:metabolism*; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography / Q000379:methods; D017434:Protein Structure, Tertiary; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism; D014057:Tomography, X-Ray Computed / Q000379:methods
chemical_list: D018941:Antigens, CD19; D018106:CD28 Antigens