Anti-CD19 CAR T cells with high-dose melphalan and autologous stem cell transplantation for refractory multiple myeloma
Top Cited Papers
Open Access
- 19 April 2018
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
Abstract
BACKGROUND. Multiple myeloma is usually fatal due to serial relapses that become progressively refractory to therapy. CD19 is typically absent on the dominant multiple myeloma cell population but may be present on minor subsets with unique myeloma-propagating properties. To target myeloma-propagating cells, we clinically evaluated autologous T cells transduced with a chimeric antigen receptor (CAR) against CD19 (CTL019). METHODS. Subjects received CTL019 following salvage high-dose melphalan and autologous stem cell transplantation (ASCT). All subjects had relapsed/refractory multiple myeloma and had previously undergone ASCT with less than 1 year progression-free survival (PFS). RESULTS. ASCT + CTL019 was safe and feasible, with most toxicity attributable to ASCT and no severe cytokine release syndrome. Two of 10 subjects exhibited significantly longer PFS after ASCT + CTL019 compared with prior ASCT (479 vs. 181 days; 249 vs. 127 days). Correlates of favorable clinical outcome included peak CTL019 frequency in bone marrow and emergence of humoral and cellular immune responses against the stem-cell antigen Sox2. Ex vivo treatment of primary myeloma samples with a combination of CTL019 and CAR T cells against the plasma cell antigen BCMA reliably inhibited myeloma colony formation in vitro, whereas treatment with either CAR alone inhibited colony formation inconsistently. CONCLUSION. CTL019 may improve duration of response to standard multiple myeloma therapies by targeting and precipitating secondary immune responses against myeloma-propagating cells. TRIAL REGISTRATION. Clinicaltrials.gov identifier NCT02135406. FUNDING. Novartis, NIH, Conquer Cancer Foundation.Keywords
Funding Information
- Novartis (N/A)
- National Institutes of Health (K12CA076931,T32CA009615,K08CA166039,R01CA174951,K24CA198315)
- Conquer Cancer Foundation (Career Development Award (to Dr. Maus), Career Development Award (to Dr. Garfall))
This publication has 72 references indexed in Scilit:
- Salvage Second Hematopoietic Cell Transplantation in MyelomaTransplantation and Cellular Therapy, 2013
- Combination immunotherapy using adoptive T-cell transfer and tumor antigen vaccination on the basis of hTERT and survivin after ASCT for myelomaBlood, 2011
- Transfer of influenza vaccine–primed costimulated autologous T cells after stem cell transplantation for multiple myeloma leads to reconstitution of influenza immunity: results of a randomized clinical trialBlood, 2011
- Identification of translocation products but not K-RAS mutations in memory B cells from patients with multiple myelomaHaematologica, 2010
- Rapid Immune Recovery and Graft-versus-Host Disease–like Engraftment Syndrome following Adoptive Transfer of Costimulated Autologous T CellsClinical Cancer Research, 2009
- A monoclonal gammopathy precedes multiple myeloma in most patientsBlood, 2009
- Clonogenic Multiple Myeloma Progenitors, Stem Cell Properties, and Drug ResistanceCancer Research, 2008
- Frequent and specific immunity to the embryonal stem cell–associated antigen SOX2 in patients with monoclonal gammopathyThe Journal of Experimental Medicine, 2007
- Hedgehog signaling maintains a tumor stem cell compartment in multiple myelomaProceedings of the National Academy of Sciences of the United States of America, 2007
- Core Transcriptional Regulatory Circuitry in Human Embryonic Stem CellsCell, 2005