Abstract
Purpose: Although modern cure rates for childhood acute lymphoblastic leukemia (ALL) exceed 80%, the outlook remains poor in patients with high-risk disease and those who relapse, especially when allogeneic hematopoietic stem cell transplantation is not feasible. Strategies to improve outcome and prevent relapse are therefore required. Immunotherapy with antigen-specific T cells can have antileukemic activity without the toxicities seen with intensive chemotherapy, and therefore represents an attractive strategy to improve the outcome of high-risk patients with ALL. We explored the feasibility of generating tumor antigen-specific T cells ex vivo from the peripheral blood of 50 patients with ALL [26 National Cancer Institute (NCI) high-risk and 24 standard-risk] receiving maintenance therapy. Experimental Design: Peripheral blood mononuclear cells were stimulated with autologous dendritic cells pulsed with complete peptide libraries of WT1, Survivin, MAGE-A3, and PRAME, antigens frequently expressed on ALL blasts. Results: T-cell lines were successfully expanded from all patients, despite low lymphocyte counts and irrespective of NCI risk group. Antigen-specificity was observed in more than 50% of patients after the initial stimulation and increased to more than 90% after three stimulations as assessed in IFN-γ-enzyme-linked immunospot (ELISpot) and 51Cr-release assays. Moreover, tumor-specific responses were observed by reduction of autologous leukemia blasts in short- and long-term coculture experiments. Conclusion: This study supports the use of immunotherapy with adoptively transferred autologous tumor antigen-specific T cells to prevent relapse and improve the prognosis of patients with high-risk ALL.
| Original language | English |
|---|---|
| Pages (from-to) | 5079-5091 |
| Number of pages | 13 |
| Journal | Clinical Cancer Research |
| Volume | 19 |
| Issue number | 18 |
| DOIs | |
| Publication status | Published - Sep 15 2013 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Generation of tumor antigen-specific T cell lines from pediatric patients with acute lymphoblastic leukemia-implications for immunotherapy. / Weber, Gerrit; Caruana, Ignazio; Rouce, Rayne H.; Barrett, A. John; Gerdemann, Ulrike; Leen, Ann M.; Rabin, Karen R.; Bollard, Catherine M.
In: Clinical Cancer Research, Vol. 19, No. 18, 15.09.2013, p. 5079-5091.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Generation of tumor antigen-specific T cell lines from pediatric patients with acute lymphoblastic leukemia-implications for immunotherapy
AU - Weber, Gerrit
AU - Caruana, Ignazio
AU - Rouce, Rayne H.
AU - Barrett, A. John
AU - Gerdemann, Ulrike
AU - Leen, Ann M.
AU - Rabin, Karen R.
AU - Bollard, Catherine M.
PY - 2013/9/15
Y1 - 2013/9/15
N2 - Purpose: Although modern cure rates for childhood acute lymphoblastic leukemia (ALL) exceed 80%, the outlook remains poor in patients with high-risk disease and those who relapse, especially when allogeneic hematopoietic stem cell transplantation is not feasible. Strategies to improve outcome and prevent relapse are therefore required. Immunotherapy with antigen-specific T cells can have antileukemic activity without the toxicities seen with intensive chemotherapy, and therefore represents an attractive strategy to improve the outcome of high-risk patients with ALL. We explored the feasibility of generating tumor antigen-specific T cells ex vivo from the peripheral blood of 50 patients with ALL [26 National Cancer Institute (NCI) high-risk and 24 standard-risk] receiving maintenance therapy. Experimental Design: Peripheral blood mononuclear cells were stimulated with autologous dendritic cells pulsed with complete peptide libraries of WT1, Survivin, MAGE-A3, and PRAME, antigens frequently expressed on ALL blasts. Results: T-cell lines were successfully expanded from all patients, despite low lymphocyte counts and irrespective of NCI risk group. Antigen-specificity was observed in more than 50% of patients after the initial stimulation and increased to more than 90% after three stimulations as assessed in IFN-γ-enzyme-linked immunospot (ELISpot) and 51Cr-release assays. Moreover, tumor-specific responses were observed by reduction of autologous leukemia blasts in short- and long-term coculture experiments. Conclusion: This study supports the use of immunotherapy with adoptively transferred autologous tumor antigen-specific T cells to prevent relapse and improve the prognosis of patients with high-risk ALL.
AB - Purpose: Although modern cure rates for childhood acute lymphoblastic leukemia (ALL) exceed 80%, the outlook remains poor in patients with high-risk disease and those who relapse, especially when allogeneic hematopoietic stem cell transplantation is not feasible. Strategies to improve outcome and prevent relapse are therefore required. Immunotherapy with antigen-specific T cells can have antileukemic activity without the toxicities seen with intensive chemotherapy, and therefore represents an attractive strategy to improve the outcome of high-risk patients with ALL. We explored the feasibility of generating tumor antigen-specific T cells ex vivo from the peripheral blood of 50 patients with ALL [26 National Cancer Institute (NCI) high-risk and 24 standard-risk] receiving maintenance therapy. Experimental Design: Peripheral blood mononuclear cells were stimulated with autologous dendritic cells pulsed with complete peptide libraries of WT1, Survivin, MAGE-A3, and PRAME, antigens frequently expressed on ALL blasts. Results: T-cell lines were successfully expanded from all patients, despite low lymphocyte counts and irrespective of NCI risk group. Antigen-specificity was observed in more than 50% of patients after the initial stimulation and increased to more than 90% after three stimulations as assessed in IFN-γ-enzyme-linked immunospot (ELISpot) and 51Cr-release assays. Moreover, tumor-specific responses were observed by reduction of autologous leukemia blasts in short- and long-term coculture experiments. Conclusion: This study supports the use of immunotherapy with adoptively transferred autologous tumor antigen-specific T cells to prevent relapse and improve the prognosis of patients with high-risk ALL.
UR - http://www.scopus.com/inward/record.url?scp=84884573470&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84884573470&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-13-0955
DO - 10.1158/1078-0432.CCR-13-0955
M3 - Article
C2 - 23838315
AN - SCOPUS:84884573470
VL - 19
SP - 5079
EP - 5091
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 18
ER -