Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising/recruitment
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Recently published
    • Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Recently published
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising/recruitment
  • Contact
Anti-CD19 CAR T cells with high-dose melphalan and autologous stem cell transplantation for refractory multiple myeloma
Alfred L. Garfall, … , Marcela V. Maus, Carl H. June
Alfred L. Garfall, … , Marcela V. Maus, Carl H. June
Published April 19, 2018
Citation Information: JCI Insight. 2018;3(8):e120505. https://doi.org/10.1172/jci.insight.120505.
View: Text | PDF | Corrigendum
Clinical Medicine Hematology Oncology

Anti-CD19 CAR T cells with high-dose melphalan and autologous stem cell transplantation for refractory multiple myeloma

  • Text
  • PDF
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.

Authors

Alfred L. Garfall, Edward A. Stadtmauer, Wei-Ting Hwang, Simon F. Lacey, Jan Joseph Melenhorst, Maria Krevvata, Martin P. Carroll, William H. Matsui, Qiuju Wang, Madhav V. Dhodapkar, Kavita Dhodapkar, Rituparna Das, Dan T. Vogl, Brendan M. Weiss, Adam D. Cohen, Patricia A. Mangan, Emily C. Ayers, Selene Nunez-Cruz, Irina Kulikovskaya, Megan M. Davis, Anne Lamontagne, Karen Dengel, Naseem D.S. Kerr, Regina M. Young, Donald L. Siegel, Bruce L. Levine, Michael C. Milone, Marcela V. Maus, Carl H. June

×

Figure 4

Anti-Sox2 immune responses after ASCT + CTL019.

Options: View larger image (or click on image) Download as PowerPoint
Anti-Sox2 immune responses after ASCT + CTL019.
(A) Left panel shows ant...
(A) Left panel shows anti-Sox2 antibody concentrations before and after CTL019 + ASCT as measured by ELISA in serum diluted 1:400. Subject 6 was excluded from anti-Sox2 antibody analysis due lack of post-ASCT samples. Middle panel shows serum anti-Sox2 antibody concentrations in subject 1 after dilution of serum to 1:800 (red) and 1:1,200 (green). Right panel shows serum anti–tetanus toxoid antibody concentrations before and after CTL019 + ASCT; this analysis was restricted to subjects with samples available from 4 or more time points after ASCT. Data points indicate means, and error bars indicate range, of triplicate experiments after background subtraction. (B) Percentage of T cells proliferating as assessed by CFSE dilution in response to Sox2 peptide mixes 1-2 (left) or 3-4 (right) from subjects’ PBMCs collected before ASCT or at various time points after ASCT. Results are presented for all T cells (top row), CD8+ T cells (middle row), and CD4+ T cells (bottom row), after subtraction of percentages proliferating in unstimulated (vehicle-only) cultures. Subjects 2 and 10 were excluded from this analysis due to insufficient sample. (C) Subject 1 CFSE dilution in PBMCs collected prior to ASCT (top) and at 6 (middle) and 9 (bottom) months after ASCT in response to stimulation with Sox2-derived peptide mixes (mixes 1-2 or mixes 3-4), negative control stimulation with vehicle only, CEF peptides (peptides derived from cytomegalovirus, Epstein-Barr virus, or influenza virus), or positive control stimulation with PHA. (D) Reactivity in subject 1 PBMCs obtained 12 months after ASCT against individual overlapping Sox2 peptides from mix 3.
Follow JCI Insight:
Copyright © 2021 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts