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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

Leukemia volume 16, pages 1645–1654 (2002)Cite this article

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 selfinactivating (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.

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Acknowledgements

We thank Alexandra Vieira for technical assistance, Dr Mark Hechinger for the flow cytometry analyses, Dr Luigi Naldini for providing us with the third generation SIN lentiviral system and Dr Sue Ellen Martin, Moli Chen and Byron Espina for assisting in establishment of the Leukemia Cell Bank. RS was supported by a Special Fellow Award from the Leukemia and Lymphoma Society (3002-00), by a Howard Temin Award from the National Cancer Institute (K01-CA87864-01), by a short-term habilitation fellowship from the Deutsche Forschungsgemeinschaft, by a pilot grant from the American Cancer Society (IRG 58-007-42) and a research grant from Concern Foundation. VP was supported by a pilot grant from the American Cancer Society (IRG-58-007-42).

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Authors and Affiliations

  1. Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    RC Koya, N Kasahara & R Stripecke

  2. Division of Hematology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    V Pullarkat, AM Levine & R Stripecke

  3. Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    RC Koya, N Kasahara & R Stripecke

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Koya, R., Kasahara, N., Pullarkat, V. et al. 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. Leukemia 16, 1645–1654 (2002). https://doi.org/10.1038/sj.leu.2402582

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