The main focus of this project is a clinical trial in which patients that have relapsed or persistent B-cell malignancies after allogeneic stem cell transplantation and at least one standard donor lymphocyte infusion. These patients all have extremely advanced malignancies that have proven to be resistant to all standard therapies. The project resulted in one abstract that was presented at the American Society of Blood and Marrow Transplantation and The Center for International Blood and Marrow Transplant Research tandem meeting in 2011. A manuscript describing the results of patients on this study was submitted 2 weeks ago. We are conducting a clinical trial in which patients receive infusions of allogeneic T cells that are genetically modified with a gammaretroviral vector to express a chimeric antigen receptor (CAR) that recognizes the B-cell antigen CD19. The first patient treated on this trial was a 65 year-old man with chronic lymphocytic leukemia (CLL) who relapsed after HLA-matched unrelated donor hematopoietic stem cell transplantation. Following the relapse, the patient received 4 donor lymphocyte infusions (DLIs) with a maximum CD3+ cell dose of 2.9x10e7 per kg and then a second stem cell transplant from the original donor. An objective remission of the leukemia did not occur after any of the DLIs or the second transplant. Five months after the second transplant, when his CLL was progressing, the patient received an infusion of 6.2x10e7 (1x10e6 cells per kg) allogeneic anti-CD19-CAR-transduced T cells derived from his unrelated transplant donor. Thirty-nine percent of the infused cells expressed the anti-CD19 CAR, and the cells produced interferon-gamma and IL-2 in a CD19-specific manner. The patient did not receive any other therapy in conjunction with the CAR-transduced T cells. From 6 to 12 days after the CAR-transduced T cell infusion, the patient experienced fevers, fatigue, mild hypoxemia, and intermittent mild hypotension. Increases in serum magnesium, phosphorous, and uric acid consistent with tumor lysis syndrome occurred. A decrease in cardiac left ventricular function developed, which was improving at last follow-up. The patients blood B cell count decreased from 286 cells per microliter before the CAR-transduced T cell infusion to 0 cells per microliter 26 days after the cell infusion. Before the CAR-transduced T cell infusion, CLL cells made up 80-90 percent of the patients hypercellular bone marrow. A bone marrow biopsy performed 26 days after the cell infusion showed a normocellular marrow, nearly absent B-lineage cells, and no evidence of CLL. CT scans revealed a greater than 50 percent decrease in the size of multiple lymph nodes after the CAR-transduced T cell infusion, but residual adenopathy was present. CAR-transduced cells were not detected in the patients blood by quantitative PCR during the first week after the T cell infusion, but made up 0.98 percent of blood mononuclear cells 11 days after the infusion. These results are encouraging for further development of anti-CD19-CAR-expressing T cells as a treatment for relapse after allogeneic stem cell transplantation. We have treated 9 additional patients on this clinical trial. A patient with CLL has obtained a complete remission that is ongoing 9 months after infusion of 1.5x106 CAR+ T cells/kg. Another patient with mantle cell lymphoma achieved an ongoing partial remission after infusion of anti-CD19 CAR T cells. Toxicities have been manageable in all patients and consist mainly of fevers and mild hypotension. We continue recruit more patients for this trial. We are obtaining important information on toxicity and predictors of successful therapy with each patient.
|Sabatino, Marianna; Hu, Jinhui; Sommariva, Michele et al. (2016) Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies. Blood 128:519-28|
|Kochenderfer, James N; Dudley, Mark E; Carpenter, Robert O et al. (2013) Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood 122:4129-39|
|Kochenderfer, James N; Rosenberg, Steven A (2013) Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat Rev Clin Oncol 10:267-76|
|Feldman, Steven A; Goff, Stephanie L; Xu, Hui et al. (2011) Rapid production of clinical-grade gammaretroviral vectors in expanded surface roller bottles using a ""modified"" step-filtration process for clearance of packaging cells. Hum Gene Ther 22:107-15|