Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo
By D. Sommermeyer, M. Hudecek, Paula L. Kosasih, T. Gogishvili, D. Maloney, C. Turtle, S. Riddell. Leukemia, 2015
804 citations recorded by the source corpus.
Adoptive T-cell therapy with gene-modified T cells expressing a tumor-reactive T-cell receptor or chimeric antigen receptor (CAR) is a rapidly growing field of translational medicine and has shown success in the treatment of B-cell malignancies and solid tumors. In all reported trials, patients have received T-cell products comprising random compositions of CD4+ and CD8+ naive and memory T cells, meaning that each patient received a different therapeutic agent. This variation may have influenced the efficacy of T-cell therapy, and complicates comparison of outcomes between different patients and across trials. We analyzed CD19 CAR-expressing effector T cells derived from different subsets (CD4+/CD8+ naive, central memory, effector memory). T cells derived from each of the subsets were efficiently transduced and expanded, but showed clear differences in effector function and proliferation in vitro and in vivo. Combining the most potent CD4+ and CD8+ CAR-expressing subsets, resulted in synergistic antitumor effects in vivo. We show that CAR-T-cell products generated from defined T-cell subsets can provide uniform potency compared with products derived from unselected T cells that vary in phenotypic composition. These findings have important implications for the formulation of T-cell products for adoptive therapies.
Subfields: Biomedical Engineering, Genetics, Oncology
View Paper: https://www.semanticscholar.org/paper/e143926e0bf808e5b82861241ef1632cc3166b05
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- C. Turtle
- L. Hanafi
- D. Sommermeyer
- M. Hudecek
- C. Berger
- S. Cherian
- Daniel H. Li
- S. Riddell
Citations in the corpus
- Immunotherapy of non-Hodgkin lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells (2016, methodology): “Enriched CD4 and CD8 T cell subsets were separately stimulated with anti-CD3/anti-CD28 CTS paramagnetic beads (Dynabeads) and transduced with a lentivirus encoding a CAR comprising an FMC63derived CD19-specific scFv fused to a modified immunoglobulin G4 hinge spacer, a CD28 transmembrane domain, a 4”
- CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. (2016, positive): “The clinical outcome in this patient is consistent with our preclinical observations in Raji tumor–bearing immunodeficient mice that received CAR–T cells manufactured from distinct T cell subsets, showing reduced potency when either CD8+ or CD4+ CAR–T cells were omitted from the formulated product (”