Effective treatment of a murine model of adult T-cell leukemia using 211At-7G7/B6 and its combination with unmodified anti-Tac (daclizumab) directed toward CD25

Abstract

IntroductionAdult T-cell leukemia (ATL) develops in a small portion of individuals infected with human T-cell lymphotrophic virus-1 (HTLV-I) and consists of an overabundance of malignant activated T cells, which are characterized by expression of the ␣ subunit of the interleukin-2 receptor (IL-2R␣; CD25) on their cell surfaces. [1][2][3][4] Presently, there is no accepted curative therapy for ATL and patients progress to death with a median survival duration of 9 months for those with acute ATL and 24 months for those with chronic ATL. 1 The observation that IL-2R␣ is not expressed by normal resting cells but is expressed by ATL cells provided the rationale for the use of monoclonal antibodies (mAbs) directed toward IL-2R␣ to deliver therapeutic agents. 5 Some partial and rare complete remissions were obtained in patients with ATL treated in clinical trials with the intact murine anti-Tac, humanized anti-Tac (daclizumab), as well as these intact antibodies armed with yttrium-90 ( 90 Y) used in an effort to develop yet more effective IL-2R␣-directed agents. 6,7 A preclinical in vivo murine model of ATL was developed by introducing leukemic cells (MET-1) from a patient with ATL into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, and new therapeutic approaches have been tested in this model before initiating human clinical trials. [8][9][10][11][12][13][14] In initial studies, antibodies to IL-2R␣ including daclizumab, murine anti-Tac, and 7G7/B6 inhibited the progression of the leukemia and prolonged survival of the leukemia-bearing mice. However, in general, cures were not achieved. 8 Therefore, more effective therapeutic approaches were required. In previous therapeutic trials, daclizumab was combined with pretargeted radioimmunotherapy in the ATL model and achieved the complementary actions of receptor-saturating doses of daclizumab to yield antibodydependent cellular cytotoxicity (ADCC) and cytokine deprivationmediated leukemic cell death along with the tumor cytoreduction provided by the radiation delivered to leukemic cell surfaces. 9,10 We also demonstrated that combining daclizumab with flavopiridol or with PS341 significantly improved therapeutic efficacy in the ATL model. 13,14 These observations suggest that for cancer therapy, the addition of 2 therapeutic agents that function via different mechanisms of action may be greater than additive in their cytotoxic action, leading to malignant cell death.In the clinical and preclinical trials, remissions have been observed using either the unmodified daclizumab monoclonal antibody at receptor-saturating doses or this antibody labeled at high specific activity with 90 Y. However, the complementary From the Metabolism Branch and the Radiation

Effective therapy of murine models of human leukemia and lymphoma with radiolabeled anti-CD30 antibody, HeFi-1

“…Radionuclides emitting ␣-particles have a high linear energy transfer (6-to 9-MeV particles) that act over 10-80 m and are effective at killing individual target cells (39). We have demonstrated that 211 At-labeled 7G7/B6, an anti-CD25 monoclonal antibody, was very effective in the treatment of murine models of leukemia (36,40). A phase I clinical trial with 213 Bi-HuM195 in the treatment of patients with relapsed and refractory acute or chronic myelogenous leukemia was reported to show promising results (41).…”

“…In the present study, we demonstrated that 211 At linked to the anti-CD30 monoclonal antibody, HeFi-1, provided effective therapy for the karpas299 leukemia model. A paradigm is emerging in monoclonal antibody-mediated treatment that therapeutic efficacy may be augmented through the use of two agents with different modes of action (30)(31)(32)(33)(34)(35)(36). In this study, we used 211 At-HeFi-1, which causes radiation damage to the tumor cells, followed by the administration of receptor-saturating doses of unmodified HeFi-1.…”

“…A paradigm is also emerging that, for cancer therapy, the addition of two therapeutic agents that function via different mechanisms may be greater than additive in their cytotoxic action, leading to malignant cell death (30)(31)(32)(33)(34)(35)(36). In our previous therapeutic trials, we demonstrated that the therapeutic efficacy of radioimmunotherapy for an adult T cell leukemia model was enhanced by the simultaneous coadministration of an anti-CD25…”

“…E-mail: tawald@helix.nih.gov. monoclonal antibody, daclizumab, at receptor-saturating doses (30,32,36).…”

Gene Expression Profiling in Non-Hodgkin Lymphomas

“…The increase in BIRC5 (survivin) expression in ATLL may play a role in cell survival by inhibiting apoptosis and is associated with resistance to chemotherapy and poor prognosis. CD25 (TAC) tends to be highly expressed in ATLL, and attempts have been made to target this using monoclonal antibody-toxin conjugates [74][75][76]. More recently, CCR4 (chemokine receptor 4) expression has been reported to be frequent in ATLL [77] and may account for the frequent infiltration of the lymphoma in skin and lymph nodes.…”