Abstract
Acute myeloid leukemia (AML) patients treated with available therapies achieve remission in approximately 60% of cases, but the long-term event-free survival is less than 30%. Use of immunotherapy during remission is a potential approach to increase survival. We propose to develop cell vaccines by genetic modification of AML cells with CD80, an essential T cell costimulator that is lacking in the majority of AML cases, and GM-CSF, to induce proliferation and activation of professional antigen-presenting cells. Here, we evaluated third generation self-inactivating (SIN) lentiviral vectors, which have the potential advantage of improved safety. CD80 and GM-CSF expression by these vectors was higher than that reported with second generation vectors (Stripecke et al, Blood 2000; 96: 1317-1326). In some cases, endogenous GM-CSF expression by transduced AML cells induced phenotypic changes consistent with the maturation of leukemia blasts into antigen-presenting cells. Further, in all cases studied, GM-CSF expression was associated with higher proliferation and cell viability. Allogeneic and autologous mixed lymphocyte reactions performed with transduced irradiated AML cells expressing CD80 and/or GM-CSF demonstrated that expression of either transgene enhanced T cell activation. These pre-clinical data demonstrate the potential feasibility of third generation SIN vectors for use in AML immunotherapy.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1645-1654 |
| Number of pages | 10 |
| Journal | Leukemia |
| Volume | 16 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 2002 |
| Externally published | Yes |
Fingerprint
Keywords
- AML
- CD80
- Gene therapy
- GM-CSF
- Immunotherapy
- Lentivirus
ASJC Scopus subject areas
- Cancer Research
- Hematology
Cite this
Transduction of acute myeloid leukemia cells with third generation self-inactivating lentiviral vectors expressing CD80 and GM-CSF : Effects on proliferation, differentiation, and stimulation of allogeneic and autologous anti-leukemia immune responses. / Koya, R. C.; Kasahara, Noriyuki; Pullarkat, V.; Levine, A. M.; Stripecke, R.
In: Leukemia, Vol. 16, No. 9, 09.2002, p. 1645-1654.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Transduction of acute myeloid leukemia cells with third generation self-inactivating lentiviral vectors expressing CD80 and GM-CSF
T2 - Effects on proliferation, differentiation, and stimulation of allogeneic and autologous anti-leukemia immune responses
AU - Koya, R. C.
AU - Kasahara, Noriyuki
AU - Pullarkat, V.
AU - Levine, A. M.
AU - Stripecke, R.
PY - 2002/9
Y1 - 2002/9
N2 - Acute myeloid leukemia (AML) patients treated with available therapies achieve remission in approximately 60% of cases, but the long-term event-free survival is less than 30%. Use of immunotherapy during remission is a potential approach to increase survival. We propose to develop cell vaccines by genetic modification of AML cells with CD80, an essential T cell costimulator that is lacking in the majority of AML cases, and GM-CSF, to induce proliferation and activation of professional antigen-presenting cells. Here, we evaluated third generation self-inactivating (SIN) lentiviral vectors, which have the potential advantage of improved safety. CD80 and GM-CSF expression by these vectors was higher than that reported with second generation vectors (Stripecke et al, Blood 2000; 96: 1317-1326). In some cases, endogenous GM-CSF expression by transduced AML cells induced phenotypic changes consistent with the maturation of leukemia blasts into antigen-presenting cells. Further, in all cases studied, GM-CSF expression was associated with higher proliferation and cell viability. Allogeneic and autologous mixed lymphocyte reactions performed with transduced irradiated AML cells expressing CD80 and/or GM-CSF demonstrated that expression of either transgene enhanced T cell activation. These pre-clinical data demonstrate the potential feasibility of third generation SIN vectors for use in AML immunotherapy.
AB - Acute myeloid leukemia (AML) patients treated with available therapies achieve remission in approximately 60% of cases, but the long-term event-free survival is less than 30%. Use of immunotherapy during remission is a potential approach to increase survival. We propose to develop cell vaccines by genetic modification of AML cells with CD80, an essential T cell costimulator that is lacking in the majority of AML cases, and GM-CSF, to induce proliferation and activation of professional antigen-presenting cells. Here, we evaluated third generation self-inactivating (SIN) lentiviral vectors, which have the potential advantage of improved safety. CD80 and GM-CSF expression by these vectors was higher than that reported with second generation vectors (Stripecke et al, Blood 2000; 96: 1317-1326). In some cases, endogenous GM-CSF expression by transduced AML cells induced phenotypic changes consistent with the maturation of leukemia blasts into antigen-presenting cells. Further, in all cases studied, GM-CSF expression was associated with higher proliferation and cell viability. Allogeneic and autologous mixed lymphocyte reactions performed with transduced irradiated AML cells expressing CD80 and/or GM-CSF demonstrated that expression of either transgene enhanced T cell activation. These pre-clinical data demonstrate the potential feasibility of third generation SIN vectors for use in AML immunotherapy.
KW - AML
KW - CD80
KW - Gene therapy
KW - GM-CSF
KW - Immunotherapy
KW - Lentivirus
UR - http://www.scopus.com/inward/record.url?scp=0036738133&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036738133&partnerID=8YFLogxK
U2 - 10.1038/sj.leu.2402582
DO - 10.1038/sj.leu.2402582
M3 - Article
VL - 16
SP - 1645
EP - 1654
JO - Leukemia
JF - Leukemia
SN - 0887-6924
IS - 9
ER -