Phase 1 studies of central memory–derived CD19 CAR T–cell therapy following autologous HSCT in patients with B-cell NHL
| Autor: | Xiuli Wang, Nikita Gidwaney, Adam Norris, M. Suzette Blanchard, Wen-Chung Chang, Michael C. Jensen, Samer K. Khaled, Tanya Siddiqi, Laurence J.N. Cooper, Sandra H. Thomas, Michelle Mott, Araceli Naranjo, Christine E. Brown, Stephen J. Forman, Jamie Wagner, Leslie Popplewell, Ching Lam W Wong, Brenda Chang, Stanley R. Riddell, Lihua E. Budde, Ryan Urak, Jingying Xu |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Oncology Clinical Trials and Observations T-Lymphocytes medicine.medical_treatment Cell Count Hematopoietic stem cell transplantation Immunotherapy Adoptive Biochemistry 0302 clinical medicine immune system diseases hemic and lymphatic diseases Lymphoma Non-Hodgkin Hematopoietic Stem Cell Transplantation hemic and immune systems Hematology Middle Aged Combined Modality Therapy Cytokine release syndrome medicine.anatomical_structure 030220 oncology & carcinogenesis Female Adult medicine.medical_specialty Lymphoma B-Cell Recombinant Fusion Proteins Antigens CD19 Immunology Receptors Antigen T-Cell chemical and pharmacologic phenomena Transplantation Autologous Young Adult 03 medical and health sciences Internal medicine medicine Humans B cell Aged business.industry Cell Biology Immunotherapy medicine.disease Chimeric antigen receptor Lymphoma Transplantation 030104 developmental biology business Immunologic Memory CD8 |
| Zdroj: | Blood. 127:2980-2990 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2015-12-686725 |
| Popis: | Myeloablative autologous hematopoietic stem cell transplantation (HSCT) is a mainstay of therapy for relapsed intermediate-grade B-cell non-Hodgkin lymphoma (NHL); however, relapse rates are high. In phase 1 studies designed to improve long-term remission rates, we administered adoptive T-cell immunotherapy after HSCT, using ex vivo-expanded autologous central memory-enriched T cells (TCM) transduced with lentivirus expressing CD19-specific chimeric antigen receptors (CARs). We present results from 2 safety/feasibility studies, NHL1 and NHL2, investigating different T-cell populations and CAR constructs. Engineered TCM-derived CD19 CAR T cells were infused 2 days after HSCT at doses of 25 to 200 × 10(6) in a single infusion. In NHL1, 8 patients safely received T-cell products engineered from enriched CD8(+) TCM subsets, expressing a first-generation CD19 CAR containing only the CD3ζ endodomain (CD19R:ζ). Four of 8 patients (50%; 95% confidence interval [CI]: 16-84%) were progression free at both 1 and 2 years. In NHL2, 8 patients safely received T-cell products engineered from enriched CD4(+) and CD8(+) TCM subsets and expressing a second-generation CD19 CAR containing the CD28 and CD3ζ endodomains (CD19R:28ζ). Six of 8 patients (75%; 95% CI: 35-97%) were progression free at 1 year. The CD4(+)/CD8(+) TCM-derived CD19 CAR T cells (NHL2) exhibited improvement in expansion; however, persistence was ≤28 days, similar to that seen by others using CD28 CARs. Neither cytokine release syndrome nor delayed hematopoietic engraftment was observed in either trial. These data demonstrate the safety and feasibility of CD19 CAR TCM therapy after HSCT. Trials were registered at www.clinicaltrials.gov as #NCT01318317 and #NCT01815749. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|