Generation of anti-tumour activity by OKT3-stimulation in multiple myeloma

In vitro inhibition of autologous haemopoiesis

C. Attisano, A. Bianchi, L. Montacchini, Nadia Carlesso, S. Peola, B. Bruno, V. Roux, D. Ferrero, E. Gallo, M. Boccadoro, A. Pileri, M. Massaia

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

T cells in multiple myeloma (MM) patients are highly susceptible to activation with the anti-CD3 monoclonal antibody (mAb) OKT3. When short-term OKT3 stimulation is carried out on bone marrow mononuclear cells (BMMC), large numbers of CD3+CD25+HLA-DR+ cells are rapidly generated and autologous malignant plasma cells are killed. OKT3 may thus be exploited in autologous bone marrow transplantation (ABMT) to purge residual plasma cells and simultaneously activate T cells to induce graft-versus-leukaemia-like (GVL-like) activity upon reinfusion. However, the possible impact of ex-vivo short-term OKT3 stimulation on haematological recovery is unknown. The aim of this work was to investigate the effect of OKT3 stimulation in vitro on autologous haemopoietic progenitor cells (HPC) of MM patients. Colony formation by granulocyte-macrophage progenitor cells (granulocyte-macrophage colony-forming units, CFU-GM) was highly suppressed, although supernatants of OKT3-activated T cells contained up to 2500 pg/ml of granulocyte-macrophage colony-stimulating factor (GM-CSF). T cell depletion completely prevented this suppression. Neutralizing antibodies against TNF-α, TNF-β and IFN-γ (which are also produced by OKT3-activated MM T cells) did not prevent it, and Transwell cultures showed that cell-to-cell contact was the main mechanism involved. OKT3-activated T cells also suppressed erythroid burst-forming units (BFU-E) and CFU-GM generation from HPC responsible for long-term maintenance of in vitro myelopoiesis. When tested on normal allogeneic BM, MM supernatants of OKT3-stimulated BMMC partially suppressed the generation of day 7 CFU-GM, but had no effect on day 14 CFU-GM. These data indicate that short-term stimulation of BMMC with OKT3 can be used to generate anti-tumour effector T cells for autologous adoptive immunotherapy. It is not a feasable approach for ex-vivo purging and activation procedures in ABMT because of its potent inhibition of autologous haemopoiesis.

Original languageEnglish (US)
Pages (from-to)494-502
Number of pages9
JournalBritish Journal of Haematology
Volume87
Issue number3
StatePublished - 1994
Externally publishedYes

Fingerprint

Muromonab-CD3
Multiple Myeloma
Granulocyte-Macrophage Progenitor Cells
T-Lymphocytes
Neoplasms
Bone Marrow Cells
Erythroid Precursor Cells
Autologous Transplantation
Plasma Cells
Bone Marrow Transplantation
Stem Cells
In Vitro Techniques
Myelopoiesis
Adoptive Immunotherapy
HLA-DR Antigens
Granulocyte-Macrophage Colony-Stimulating Factor
Neutralizing Antibodies
Leukemia
Cell Culture Techniques
Cell Count

Keywords

  • Autologous bone marrow transplantation
  • CFU-GM
  • Multiple myeloma
  • OKT3
  • T cells

ASJC Scopus subject areas

  • Hematology

Cite this

Generation of anti-tumour activity by OKT3-stimulation in multiple myeloma : In vitro inhibition of autologous haemopoiesis. / Attisano, C.; Bianchi, A.; Montacchini, L.; Carlesso, Nadia; Peola, S.; Bruno, B.; Roux, V.; Ferrero, D.; Gallo, E.; Boccadoro, M.; Pileri, A.; Massaia, M.

In: British Journal of Haematology, Vol. 87, No. 3, 1994, p. 494-502.

Research output: Contribution to journalArticle

Attisano, C, Bianchi, A, Montacchini, L, Carlesso, N, Peola, S, Bruno, B, Roux, V, Ferrero, D, Gallo, E, Boccadoro, M, Pileri, A & Massaia, M 1994, 'Generation of anti-tumour activity by OKT3-stimulation in multiple myeloma: In vitro inhibition of autologous haemopoiesis', British Journal of Haematology, vol. 87, no. 3, pp. 494-502.
Attisano, C. ; Bianchi, A. ; Montacchini, L. ; Carlesso, Nadia ; Peola, S. ; Bruno, B. ; Roux, V. ; Ferrero, D. ; Gallo, E. ; Boccadoro, M. ; Pileri, A. ; Massaia, M. / Generation of anti-tumour activity by OKT3-stimulation in multiple myeloma : In vitro inhibition of autologous haemopoiesis. In: British Journal of Haematology. 1994 ; Vol. 87, No. 3. pp. 494-502.
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AU - Bianchi, A.

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AU - Carlesso, Nadia

AU - Peola, S.

AU - Bruno, B.

AU - Roux, V.

AU - Ferrero, D.

AU - Gallo, E.

AU - Boccadoro, M.

AU - Pileri, A.

AU - Massaia, M.

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N2 - T cells in multiple myeloma (MM) patients are highly susceptible to activation with the anti-CD3 monoclonal antibody (mAb) OKT3. When short-term OKT3 stimulation is carried out on bone marrow mononuclear cells (BMMC), large numbers of CD3+CD25+HLA-DR+ cells are rapidly generated and autologous malignant plasma cells are killed. OKT3 may thus be exploited in autologous bone marrow transplantation (ABMT) to purge residual plasma cells and simultaneously activate T cells to induce graft-versus-leukaemia-like (GVL-like) activity upon reinfusion. However, the possible impact of ex-vivo short-term OKT3 stimulation on haematological recovery is unknown. The aim of this work was to investigate the effect of OKT3 stimulation in vitro on autologous haemopoietic progenitor cells (HPC) of MM patients. Colony formation by granulocyte-macrophage progenitor cells (granulocyte-macrophage colony-forming units, CFU-GM) was highly suppressed, although supernatants of OKT3-activated T cells contained up to 2500 pg/ml of granulocyte-macrophage colony-stimulating factor (GM-CSF). T cell depletion completely prevented this suppression. Neutralizing antibodies against TNF-α, TNF-β and IFN-γ (which are also produced by OKT3-activated MM T cells) did not prevent it, and Transwell cultures showed that cell-to-cell contact was the main mechanism involved. OKT3-activated T cells also suppressed erythroid burst-forming units (BFU-E) and CFU-GM generation from HPC responsible for long-term maintenance of in vitro myelopoiesis. When tested on normal allogeneic BM, MM supernatants of OKT3-stimulated BMMC partially suppressed the generation of day 7 CFU-GM, but had no effect on day 14 CFU-GM. These data indicate that short-term stimulation of BMMC with OKT3 can be used to generate anti-tumour effector T cells for autologous adoptive immunotherapy. It is not a feasable approach for ex-vivo purging and activation procedures in ABMT because of its potent inhibition of autologous haemopoiesis.

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