CD19 targeted cord blood derived T Cells for cancer immunotherapy Meeting Abstract

Authors: Pegram, H. J.; LaRussa, V.; Brentjens, R.
Abstract Title: CD19 targeted cord blood derived T Cells for cancer immunotherapy
Meeting Title: 52nd Annual Meeting of the American Society of Hematology (ASH)
Abstract: Transplantation of unrelated umbilical cord blood (CB) derived stem cells is often used to treat adult patients with B-cell acute lymphoblastic leukemia (B-ALL). However, many patients relapse mid overall prognosis is poor. We hypothesize that additional therapy involving adoptive transfer of CB derived T cells modified to express a CD19-specific chimeric antigen receptor (CAR) could improve patient outcome following allogeneic CB transplant. To this end, we have previously demonstrated that human T cells which express the anti-CD19 19-28 zeta CAR, containing the signaling domains of the co-stimulatory CD28 receptor and CD3 zeta chain, effectively eradicate CD19(+) tumors both in vitro as well as in vivo in SCID-Beige mice. Herein, we demonstrate the ability to,effectively isolate and expand T cells from CB samples using magnetic beads coated with agonistic CD3 and CD28 antibodies (Invitrogen) and comparing subsequent T cell expansions in in vitro cultures. with varying additions of exogenous stimulatory cytokines, including IL-2, a combination of IL-2 and IL-7, IL-12 or IL-15. We demonstrate that in vitro culture in the context of exogenous IL-12 (10 ng/ml) resulted in optimal expansion of CB T cells (150-fold). In addition, expansion of T cells in the context of exogenous IL-12 resulted in a favorable phenotype for adoptive cell transfer, with T cells expressing high levels of Granzyme B and Perforin while retaining a "memory" phenotype as assessed by persistent expression of CD62L. This combination of cytotoxic and memory phenotype is optimal for adoptive cell therapy. T cells expanded in this manner were subsequently efficiently retrovirally transduced to express the 19-28 zeta CAR. The resulting CD19-specific CB derived T cells were able to specifically lyse CD19(+) tumor targets as assessed by standard Cr-51 release cytotoxicity assays. We are currently investigating the in vivo anti-tumor function of these modified cells in our previously established preclinical SCID-Beige mouse tumor model and ultimately plan to conduct a Phase 1 clinical trial with these modified T cells in patients with B-ALL undergoing CB transplant.
Keywords: adoptive cell transfer; memory phenotype; cytotoxic phenotype
Journal Title: Blood
Volume: 116
Issue: 21
Meeting Dates: 2010 Dec 4-7
Meeting Location: Orlando, FL
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2010-11-19
Start Page: 1543
Language: English
PROVIDER: biosis
PUBMED: 22276300
DOI: 10.1182/blood.V116.21.3767.3767
Notes: --- - Meeting Abstract: 3767 - 52nd Annual Meeting of the American-Society-of-Hematology (ASH) - Orlando, FL, USA - December 04 -07, 2010 - Amer Soc Hematol - "Source: Biosis"
Citation Impact
MSK Authors
  1. Renier J Brentjens
    267 Brentjens
  2. Hollie Jaine Pegram
    19 Pegram