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.
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.
Koya
R C
RC
Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Kasahara
N
N
Pullarkat
V
V
Levine
A M
AM
Stripecke
R
R
D000208:Acute Disease; D000328:Adult; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D018122:B7-1 Antigen / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D002455:Cell Division; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D005434:Flow Cytometry; D015316:Genetic Therapy; D005822:Genetic Vectors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D018122:B7-1 Antigen; D016178:Granulocyte-Macrophage Colony-Stimulating Factor