Dose-finding study of anti-CD25 antibody for targeting regulatory T cells in locoregional immunotherapy of malignant effusion.
Effects of low-dose anti-CD25 antibody on targeting regulatory T (Treg) cells in vitro and in vivo were investigated. Human-mouse chimeric anti-CD25 monoclonal antibody basiliximab was administered into the effusion cavity, followed by locoregional immunotherapy using OK-432 on day 7. Peripheral blood mononuclear cells and effusion lymphocytes (ELs) were collected before and after the basiliximab administration and subjected to further investigations. Surface phenotypes, IFN-gamma production, cytotoxic activity and foxp3 expression of ELs were assessed by flow cytometry, ELISA, 51Cr-releasing assay, and RT-PCR analysis, respectively. We observed that a low concentration of 0.01 microg/ml basiliximab effectively targeted CD4+CD25(bri) Treg cells while preserving CD4+CD25(dim) activated T cells in vitro. This concentration of basiliximab significantly augmented interferon (IFN)-gamma production of ELs when interleukin (IL)-2 was added on day 0 or on day 1 after basiliximab. In the clinical study, intracavitary administration of basiliximab on day 0 followed by OK-432 on day 7 was as safe, well-tolerated, and effective as using OK-432 alone, and a low-dose of 0.002-0.005 mg/kg basiliximab could target CD4+CD25(bri) cells for at least 3 days while relatively preserving CD4+CD25(dim) cells. Foxp3 expression of ELs was not changed definitely by the intracavitary basiliximab. These results suggest that low-dose basiliximab can target Treg cells in vitro and in vivo, and subsequently augment the activation of ELs. Locoregional immunotherapy of malignant effusion using the Treg cell-conditioning regimen with low-dose basiliximab followed by OK-432 administration on day 0 or on day 1 should be evaluated for clinical efficacy in the next phase II trial.
Okawaki
Makoto
M
Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi 1-2-3, Minami-hu, Hiroshima 734-8551, Japan.
Yamaguchi
Yoshiyuki
Y
Okita
Riki
R
Ohara
Masahiro
M
Okada
Morihito
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D001201:Ascites / Q000628:therapy; D000077552:Basiliximab; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D010844:Picibanil / Q000008:administration & dosage*; D016066:Pleural Effusion, Malignant / Q000276:immunology / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D011993:Recombinant Fusion Proteins; D010844:Picibanil; D007371:Interferon-gamma; D000077552:Basiliximab