Elimination of malignant clonogenic T cells from human bone marrow using chemoimmunoseparation with 2'-deoxycoformycin, deoxyadenosine and an immunotoxin

R. B. Montgomery, J. Kurtzberg, A. Rhinehardt-Clark, A. Haleen, Sundaram Ramakrishnan, G. A. Olsen, W. P. Peters, C. A. Smith, B. F. Haynes, L. L. Houston, R. C. Bast

Research output: Contribution to journalArticle

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Abstract

Autologous bone marrow transplantation may contribute to the treatment of several types of lymphoreticular malignancies. Recent studies have suggested that a combination of chemoseparation and immunoseparation may be more effective than either modality alone in eliminating malignant cells from human bone marrow. In this report an immunotoxin has been prepared by conjugating pokeweed antiviral protein (PAP) to the 3A1 murine monoclonal antibody that recognizes a 40 kD (CD7) determinant expressed by most T cell acute lymphoblastic leukemias and a majority of normal mature peripheral T cells. When HSB-2 T lymphoma cells were mixed with normal human bone marrow and incubated with 3A1-PAP and 100 μM chloroquine, approximately 3 logs of clonogenic T cells could be eliminated from a 20-fold excess of bone marrow. Treatment of cell mixtures with 2'deoxycoformycin (2'-dCF) and deoxyadenosine (dAdo) eliminated 2 logs of clonogenic tumor cells. The use of 3A1-PAP and chloroquine with dCF/dAdo was more effective than either single modality, eliminating up to 6 logs of HSB-2 tumor cells in optimal experiments. Anti-tumor activity of the combined treatment extended to T leukemia cells taken directly from patients. Although 3A1-PAP reduced CFU-GM by only 13% and BFU-E by 36%, the addition of 2'-dCF and dAdo was more toxic for normal marrow precursors, further reducing CFU-GM, GEMM and BFU-E as well as preventing recovery of CFU-GM in long-term bone marrow culture. Thus, the additive anti-tumor activity of chemo-separation and immunoseparation may prove useful in purging malignant T cells from bone marrow ex vivo prior to autologous transplantation, but their potential effect on reconstitution of normal marrow elements requires further evaluation.

Original languageEnglish (US)
Pages (from-to)395-402
Number of pages8
JournalBone Marrow Transplantation
Volume5
Issue number6
StatePublished - Jan 1 1990
Externally publishedYes

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Pentostatin
Immunotoxins
Bone Marrow
T-Lymphocytes
Granulocyte-Macrophage Progenitor Cells
Erythroid Precursor Cells
Autologous Transplantation
Chloroquine
Neoplasms
Myeloid Progenitor Cells
T-Cell Leukemia
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
T-Cell Lymphoma
Poisons
Bone Marrow Transplantation
Bone Marrow Cells
2'-deoxyadenosine
Therapeutics
Monoclonal Antibodies
pokeweed antiviral protein

ASJC Scopus subject areas

  • Hematology
  • Transplantation

Cite this

Elimination of malignant clonogenic T cells from human bone marrow using chemoimmunoseparation with 2'-deoxycoformycin, deoxyadenosine and an immunotoxin. / Montgomery, R. B.; Kurtzberg, J.; Rhinehardt-Clark, A.; Haleen, A.; Ramakrishnan, Sundaram; Olsen, G. A.; Peters, W. P.; Smith, C. A.; Haynes, B. F.; Houston, L. L.; Bast, R. C.

In: Bone Marrow Transplantation, Vol. 5, No. 6, 01.01.1990, p. 395-402.

Research output: Contribution to journalArticle

Montgomery, RB, Kurtzberg, J, Rhinehardt-Clark, A, Haleen, A, Ramakrishnan, S, Olsen, GA, Peters, WP, Smith, CA, Haynes, BF, Houston, LL & Bast, RC 1990, 'Elimination of malignant clonogenic T cells from human bone marrow using chemoimmunoseparation with 2'-deoxycoformycin, deoxyadenosine and an immunotoxin', Bone Marrow Transplantation, vol. 5, no. 6, pp. 395-402.
Montgomery, R. B. ; Kurtzberg, J. ; Rhinehardt-Clark, A. ; Haleen, A. ; Ramakrishnan, Sundaram ; Olsen, G. A. ; Peters, W. P. ; Smith, C. A. ; Haynes, B. F. ; Houston, L. L. ; Bast, R. C. / Elimination of malignant clonogenic T cells from human bone marrow using chemoimmunoseparation with 2'-deoxycoformycin, deoxyadenosine and an immunotoxin. In: Bone Marrow Transplantation. 1990 ; Vol. 5, No. 6. pp. 395-402.
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abstract = "Autologous bone marrow transplantation may contribute to the treatment of several types of lymphoreticular malignancies. Recent studies have suggested that a combination of chemoseparation and immunoseparation may be more effective than either modality alone in eliminating malignant cells from human bone marrow. In this report an immunotoxin has been prepared by conjugating pokeweed antiviral protein (PAP) to the 3A1 murine monoclonal antibody that recognizes a 40 kD (CD7) determinant expressed by most T cell acute lymphoblastic leukemias and a majority of normal mature peripheral T cells. When HSB-2 T lymphoma cells were mixed with normal human bone marrow and incubated with 3A1-PAP and 100 μM chloroquine, approximately 3 logs of clonogenic T cells could be eliminated from a 20-fold excess of bone marrow. Treatment of cell mixtures with 2'deoxycoformycin (2'-dCF) and deoxyadenosine (dAdo) eliminated 2 logs of clonogenic tumor cells. The use of 3A1-PAP and chloroquine with dCF/dAdo was more effective than either single modality, eliminating up to 6 logs of HSB-2 tumor cells in optimal experiments. Anti-tumor activity of the combined treatment extended to T leukemia cells taken directly from patients. Although 3A1-PAP reduced CFU-GM by only 13{\%} and BFU-E by 36{\%}, the addition of 2'-dCF and dAdo was more toxic for normal marrow precursors, further reducing CFU-GM, GEMM and BFU-E as well as preventing recovery of CFU-GM in long-term bone marrow culture. Thus, the additive anti-tumor activity of chemo-separation and immunoseparation may prove useful in purging malignant T cells from bone marrow ex vivo prior to autologous transplantation, but their potential effect on reconstitution of normal marrow elements requires further evaluation.",
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