The interleukin-2 receptor: a target for monoclonal antibody treatment of human T-cell lymphotrophic virus I-induced adult T-cell leukemia

Adult T-cell leukemia (ATL) is a malignancy of mature lymphocytes caused by the retrovirus human T-cell lymphotrophic virus-I (HTLV-I). It is an aggressive leukemia with an overall mortality rate of 50% within 5 months; no conventional chemotherapy regimen appears successful in inducing long-term disease-free survival in ATL patients. However, ATL cells constitutively express high-affinity interleukin-2 receptors (IL-2Rs) identified by the anti-Tac monoclonal antibody, whereas normal resting cells do not. To exploit this difference in receptor expression, we administered anti-Tac intravenously (IV) to 19 patients with ATL. In general the patients did not suffer untoward reactions, and in 18 of 19 cases did not have a reduction in normal formed elements of the blood. Seven patients developed remissions that were mixed (1 patient), partial (4 patients), or complete (2 patients), with partial and complete remissions lasting from 9 weeks to more than 3 years as assessed by routine hematologic tests, immunofluorescence analysis, and molecular genetic analysis of T-cell receptor gene rearrangements and of HTLV-I proviral integration. Furthermore, remission was associated with a return to normal serum calcium levels and an improvement of liver function tests. Remission was also associated in some cases with an amelioration of the profound immunodeficiency state that characterizes ATL. Thus the use of a monoclonal antibody that blocks the interaction of IL-2 with its receptor expressed on ATL cells provides a rational approach for treatment of this aggressive malignancy.

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The interleukin-2 receptor: a target for monoclonal antibody treatment of human T-cell lymphotrophic virus I-induced adult T-cell leukemia

Blood ◽

10.1182/blood.v82.6.1701.1701 ◽

1993 ◽

Vol 82 (6) ◽

pp. 1701-1712 ◽

Cited By ~ 139

Author(s):

TA Waldmann ◽

JD White ◽

CK Goldman ◽

L Top ◽

A Grant ◽

...

Keyword(s):

Monoclonal Antibody ◽

T Cell ◽

Interleukin 2 ◽

Receptor Expression ◽

Rational Approach ◽

Resting Cells ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

Human T Cell

Abstract Adult T-cell leukemia (ATL) is a malignancy of mature lymphocytes caused by the retrovirus human T-cell lymphotrophic virus-I (HTLV-I). It is an aggressive leukemia with an overall mortality rate of 50% within 5 months; no conventional chemotherapy regimen appears successful in inducing long-term disease-free survival in ATL patients. However, ATL cells constitutively express high-affinity interleukin-2 receptors (IL-2Rs) identified by the anti-Tac monoclonal antibody, whereas normal resting cells do not. To exploit this difference in receptor expression, we administered anti-Tac intravenously (IV) to 19 patients with ATL. In general the patients did not suffer untoward reactions, and in 18 of 19 cases did not have a reduction in normal formed elements of the blood. Seven patients developed remissions that were mixed (1 patient), partial (4 patients), or complete (2 patients), with partial and complete remissions lasting from 9 weeks to more than 3 years as assessed by routine hematologic tests, immunofluorescence analysis, and molecular genetic analysis of T-cell receptor gene rearrangements and of HTLV-I proviral integration. Furthermore, remission was associated with a return to normal serum calcium levels and an improvement of liver function tests. Remission was also associated in some cases with an amelioration of the profound immunodeficiency state that characterizes ATL. Thus the use of a monoclonal antibody that blocks the interaction of IL-2 with its receptor expressed on ATL cells provides a rational approach for treatment of this aggressive malignancy.

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Therapy of patients with human T-cell lymphotrophic virus I-induced adult T-cell leukemia with anti-Tac, a monoclonal antibody to the receptor for interleukin-2

Blood ◽

10.1182/blood.v72.5.1805.1805 ◽

1988 ◽

Vol 72 (5) ◽

pp. 1805-1816 ◽

Cited By ~ 111

Author(s):

TA Waldmann ◽

CK Goldman ◽

KF Bongiovanni ◽

SO Sharrow ◽

MP Davey ◽

...

Keyword(s):

Monoclonal Antibody ◽

T Cell ◽

Interleukin 2 ◽

Rational Approach ◽

Resting Cells ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Antitumor Effects ◽

Adult T Cell Leukemia ◽

Human T Cell

Abstract Human T-cell lymphotropic virus I (HTLV-I)-induced adult T-cell leukemia (ATL) cells constitutively express interleukin-2 (IL-2) receptors identified by the anti-Tac monoclonal antibody (MoAb), whereas normal resting cells do not. This observation provided the scientific basis for a trial of intravenous anti-Tac in the treatment of nine patients with ATL. The patients did not suffer untoward reactions and did not have a reduction in the normal formed elements of the blood, and only one of the nine produced antibodies to the anti-Tac MoAb. Three patients had transient mixed, partial, or complete remissions lasting from 1 to more than 8 months after anti-Tac therapy, as assessed by routine hematologic tests, immunofluorescence analysis of circulating cells, and molecular genetic analysis of HTLV-I provirus integration and of the T-cell receptor gene rearrangement. The precise mechanism of the antitumor effects is unclear; however, the use of a MoAb that prevents the interaction of IL-2 with its receptor on ATL cells provides a rational approach for the treatment of this malignancy.

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Therapy of patients with human T-cell lymphotrophic virus I-induced adult T-cell leukemia with anti-Tac, a monoclonal antibody to the receptor for interleukin-2

Blood ◽

10.1182/blood.v72.5.1805.bloodjournal7251805 ◽

1988 ◽

Vol 72 (5) ◽

pp. 1805-1816 ◽

Cited By ~ 1

Author(s):

TA Waldmann ◽

CK Goldman ◽

KF Bongiovanni ◽

SO Sharrow ◽

MP Davey ◽

...

Keyword(s):

Monoclonal Antibody ◽

T Cell ◽

Interleukin 2 ◽

Rational Approach ◽

Resting Cells ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Antitumor Effects ◽

Adult T Cell Leukemia ◽

Human T Cell

Human T-cell lymphotropic virus I (HTLV-I)-induced adult T-cell leukemia (ATL) cells constitutively express interleukin-2 (IL-2) receptors identified by the anti-Tac monoclonal antibody (MoAb), whereas normal resting cells do not. This observation provided the scientific basis for a trial of intravenous anti-Tac in the treatment of nine patients with ATL. The patients did not suffer untoward reactions and did not have a reduction in the normal formed elements of the blood, and only one of the nine produced antibodies to the anti-Tac MoAb. Three patients had transient mixed, partial, or complete remissions lasting from 1 to more than 8 months after anti-Tac therapy, as assessed by routine hematologic tests, immunofluorescence analysis of circulating cells, and molecular genetic analysis of HTLV-I provirus integration and of the T-cell receptor gene rearrangement. The precise mechanism of the antitumor effects is unclear; however, the use of a MoAb that prevents the interaction of IL-2 with its receptor on ATL cells provides a rational approach for the treatment of this malignancy.

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Radioimmunotherapy of interleukin-2R alpha-expressing adult T-cell leukemia with Yttrium-90-labeled anti-Tac [see comments]

Blood ◽

10.1182/blood.v86.11.4063.bloodjournal86114063 ◽

1995 ◽

Vol 86 (11) ◽

pp. 4063-4075 ◽

Cited By ~ 172

Author(s):

TA Waldmann ◽

JD White ◽

JA Carrasquillo ◽

JC Reynolds ◽

CH Paik ◽

...

Keyword(s):

T Cell ◽

Interleukin 2 ◽

Disease Free Survival ◽

Scientific Basis ◽

Resting Cells ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

Human T Cell ◽

Yttrium 90

Adult T-cell leukemia (ATL) is a malignancy of mature lymphocytes caused by the retrovirus human T-cell lymphotropic virus-I. It is an aggressive leukemia with a median survival time of 9 months; no chemotherapy regimen appears successful in inducing long-term disease- free survival. The scientific basis of the present study is that ATL cells express high-affinity interleukin-2 receptors identified by the anti-Tac monoclonal antibody, whereas normal resting cells do not. To exploit this difference, we administered anti-Tac armed with Yttrium-90 (90Y) to 18 patients with ATL initially (first 9 patients) in a phase I dose-escalation trial and subsequently (second group of 9 patients) in a phase II trial involving a uniform 10-mCi dose of 90Y-labeled anti- Tac. Patients undergoing a remission were permitted to receive up to eight additional doses. At the 5- to 15-mCi doses used, 9 of 16 evaluable patients responded to 90Y anti-Tac with a partial (7 patients) or complete (2 patients) remission. The responses observed represent improved efficacy in terms of length of remission when compared with previous results with unmodified anti-Tac. Clinically meaningful (> or = grade 3) toxicity was largely limited to the hematopoietic system. In conclusion, radioimmunotherapy with 90Y anti- Tac directed toward the IL-2R expressed on ATL cells may provide a useful approach for treatment of this aggressive malignancy.

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Rat lymphoid cell lines producing human T cell leukemia virus. II. Constitutive expression of rat interleukin 2 receptor.

Journal of Experimental Medicine ◽

10.1084/jem.161.5.924 ◽

1985 ◽

Vol 161 (5) ◽

pp. 924-934 ◽

Cited By ~ 14

Author(s):

J Yodoi ◽

M Okada ◽

Y Tagaya ◽

K Teshigawara ◽

K Fukui ◽

...

Keyword(s):

T Cell ◽

Cell Lines ◽

Lymphoid Cell ◽

Interleukin 2 ◽

Constitutive Expression ◽

Receptor Expression ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Human T Cell ◽

Lymphoid Cell Lines

Three rat lymphoid cell lines (TARS-1, TARL-2, and TART-1) (12) transformed by human T cell leukemia/lymphoma virus I (HTLV-I) had rearrangement of the beta chain gene of the T cell antigen receptor, and had integrated proviral DNA from HTLV-I in their genomes. As is the case with adult T cell leukemia (ATL)-derived human T cell lines transformed by HTLV-I, these rat cell lines unequivocally expressed interleukin 2 (IL-2) receptor, as determined by radiolabeled IL-2 binding. By Scatchard plot analysis, one of the cell lines, TART-1, proved to have high affinity receptors (Ka = 1.3 X 10(11)/M and 8.8 X 10(9)/M). Rat IL-2 receptor, not human IL-2 receptor, was expressed on HTLV+ rat cell lines, as demonstrated by the fact that they expressed antigens reactive with monoclonal antibodies (ART-18) against rat IL-2 receptor, but not with anti-Tac antibodies. The collective evidence indicates that the endogenous IL-2 receptor gene is activated in human and rat lymphoid cell lines with HTLV-I production. The mechanism of abnormal IL-2 receptor expression in HTLV infection is discussed.

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A monoclonal antibody detecting a novel antigen expressed in the HTLV-I- infected cells

Blood ◽

10.1182/blood.v69.2.430.430 ◽

1987 ◽

Vol 69 (2) ◽

pp. 430-436 ◽

Cited By ~ 7

Author(s):

F Tsubai ◽

Y Namba ◽

M Kohno ◽

S Hanada ◽

M Matsumoto ◽

...

Keyword(s):

Monoclonal Antibody ◽

T Cell ◽

Cell Lines ◽

Polyacrylamide Gel Electrophoresis ◽

Sodium Dodecyl ◽

Interleukin 2 ◽

Lymphocytic Leukemia ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Human T Cell

Abstract A monoclonal antibody, FTF 148, was prepared by hybridizing murine myelomal cells (NS-1) and spleen cells of BALB/c mice immunized with cultured cells derived from an adult T cell leukemia (ATL) patient (KUT- 2 cells). This monoclonal antibody reacted with all of the human T cell leukemia virus I (HTLV-I)-infected cell lines tested but did not react with other T cell lines derived from acute lymphocytic leukemia, Epstein-Barr virus-transformed B cell lines, or an erythroleukemic cell line. This monoclonal antibody was not directed to viral antigens because it reacted equally well with almost all KUT-2 and MT-1 cells, only 1% to 3% of which were ATL-associated antigen-positive. In contrast to interleukin 2 receptors expressed on both ATL cells and normal phytohemagglutinin-stimulated blasts, this antigen was not expressed on the latter cells. The antigen, mainly expressed on the cell membrane, was analyzed by metabolic labeling with 3H-leucine and surface labeling with 125I followed by cell lysis and immunoprecipitation with the FTF 148 antibody. The findings obtained by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that p50 and p74 proteins were specifically precipitated and the antigen was also different from the product of the Xs gene of HTLV-I.

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Interleukin-2 increases production and secretion of parathyroid hormone-related peptide by human T cell leukemia virus type I-infected T cells: possible role in hypercalcemia associated with adult T cell leukemia.

Endocrinology ◽

10.1210/endo.132.6.8099324 ◽

1993 ◽

Vol 132 (6) ◽

pp. 2551-2556 ◽

Cited By ~ 16

Author(s):

K Ikeda ◽

R Okazaki ◽

D Inoue ◽

H Ohno ◽

E Ogata ◽

...

Keyword(s):

T Cell ◽

Leukemia Virus ◽

Interleukin 2 ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Adult T Cell Leukemia ◽

Human T Cell ◽

T Cell Leukemia Virus

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Soluble interleukin 2 receptors in sera of Japanese patients with adult T cell leukemia mark activity of disease

Blood ◽

10.1182/blood.v71.4.1021.1021 ◽

1988 ◽

Vol 71 (4) ◽

pp. 1021-1026 ◽

Cited By ~ 65

Author(s):

N Yasuda ◽

PK Lai ◽

SH Ip ◽

PC Kung ◽

Y Hinuma ◽

...

Keyword(s):

T Cell ◽

Interleukin 2 ◽

Enzyme Linked Immunosorbent Assay ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Normal Range ◽

Cell Leukemia Virus Type ◽

Adult T Cell Leukemia ◽

Human T Cell

Abstract Serum concentrations of soluble interleukin 2 receptors (sIL 2R) were measured by an enzyme-linked immunosorbent assay (ELISA) in 30 patients with adult T cell leukemia (ATL), in 9 patients with other hematopoietic malignancies, and in 17 asymptomatic individuals seropositive for human T cell leukemia virus type I (HTLV-I). Sixty HTLV-I seronegative, age-matched controls showed a normal range of form 63.2 to 480.8 U/mL. All asymptomatic carriers of HTLV-I had sIL 2R in their sera within the normal range. sIL 2R in sera was not related to the anti-HTLV-I antibody titer. Eleven patients with acute ATL, a clinical phenotype with median survival rate of 4.4 months, had markedly elevated sIL 2R (11,100 to 99,000 U/mL), but eight patients with smoldering ATL had low sIL 2R values (less than 480.8 U/mL) comparable to controls. Eleven patients with chronic ATL had intermediate elevated levels of sIL 2R (480.8 to 37,300.0 U/mL). Serum levels of sIL 2R correlated with the number of ATL cells (r = 0.812) and CD25-positive cells (r = 0.725) circulating in the peripheral blood. Longitudinal studies performed in four patients with ATL showed significant correlation between serum concentration of sIL 2R and activity of the malignancy. These findings suggest that the level of sIL 2R in serum indicated tumor load and, possibly, prognosis.

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