Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning Journal Article

Authors: Pegram, H. J.; Lee, J. C.; Hayman, E. G.; Imperato, G. H.; Tedder, T. F.; Sadelain, M.; Brentjens, R. J.
Article Title: Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning
Abstract: Adoptive cell therapy with tumor-targeted T cells is a promising approach to cancer therapy. Enhanced clinical outcome using this approach requires conditioning regimens with total body irradiation, lymphodepleting chemotherapy, and/or additional cytokine support. However, the need for prior conditioning precludes optimal application of this approach to a significant number of cancer patients intolerant to these regimens. Herein, we present preclinical studies demonstrating that treatment with CD19-specific, chimeric antigen receptor (CAR)-modified T cells that are further modified to constitutively secrete IL-12 are able to safely eradicate established disease in the absence of prior conditioning. We demonstrate in a novel syngeneic tumor model that tumor elimination requires both CD4+ and CD8+ T-cell subsets, autocrine IL-12 stimulation, and subsequent IFNγ secretion by the CAR+ T cells. Importantly, IL-12-secreting, tumor-targeted T cells acquire intrinsic resistance to T regulatory cell-mediated inhibition. Based on these preclinical data, we anticipate that adoptive therapy using CAR-targeted T cells modified to secrete IL-12 will obviate or reduce the need for potentially hazardous conditioning regimens to achieve optimal antitumor responses in cancer patients. © 2012 by The American Society of Hematology.
Keywords: cancer chemotherapy; unclassified drug; human cell; nonhuman; cancer radiotherapy; cd8+ t lymphocyte; t lymphocyte; animal cell; mouse; animal experiment; animal model; cyclophosphamide; antineoplastic activity; cytotoxicity; b lymphocyte; regulatory t lymphocyte; gamma interferon; cd4+ t lymphocyte; chimeric antigen receptor; cell therapy; upregulation; tumor; cd25+ t lymphocyte; cytokine release; interleukin 12; lymphocyte antigen receptor; aplasia
Journal Title: Blood
Volume: 119
Issue: 18
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2012-05-03
Start Page: 4133
End Page: 4141
Language: English
DOI: 10.1182/blood-2011-12-400044
PROVIDER: scopus
PMCID: PMC3359735
PUBMED: 22354001
Notes: --- - "Cited By (since 1996): 2" - "Export Date: 25 June 2012" - "CODEN: BLOOA" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Renier J Brentjens
    270 Brentjens
  2. Michel W J Sadelain
    520 Sadelain
  3. Hollie Jaine Pegram
    19 Pegram
  4. James C Lee
    6 Lee
  5. Erik G Hayman
    2 Hayman