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Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications.
Cancer Res 2005; 65(24):11712-20CR

Abstract

SGN-40, a humanized immoglobulin G1 (IgG1) anti-CD40 monoclonal antibody, mediates cytotoxicity against human multiple myeloma (MM) cells via suppression of interleukin (IL)-6-induced proliferative and antiapoptotic effects as well as antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we studied the clinical significance of an immunomodulatory drug lenalidomide on SGN-40-induced cytotoxicity against CD138(+)CD40(+) MM lines and patient MM cells. Pretreatment with lenalidomide sensitized MM cells to SGN-40-induced cell death. Combined lenalidomide and SGN-40 significantly induced MM apoptosis, evidenced by enhanced cleavage of caspase-3/8/poly(ADP-ribose)polymerase and increased sub-G(0) cells, compared with either single agent at the same doses. Pretreatment of effector cells with lenalidomide augmented SGN-40-induced MM cell lysis, associated with an increased number of CD56(+)CD3(-) natural killer (NK) cells expressing CD16 and LFA-1. Importantly, pretreatment with lenalidomide or lenalidomide and SGN-40 markedly enhanced NK-cell-mediated lysis of autologous patient MM cells triggered by SGN-40. Lenalidomide also up-regulated CD40L on CD56(+)CD3(-) NK cells, facilitating IL-2-mediated activation of NK cells. In addition, lenalidomide induced the CD56(dim) NK subset, which are more potent mediators of ADCC against target MM cells than the CD56(bright) NK subset. Finally, pretreatment of both effector and target MM cells with lenalidomide markedly enhanced SGN-40-mediated ADCC against CD40-expressing MM cells. These studies, therefore, show that the addition of lenalidomide to SGN-40 enhances cytotoxicity against MM cells, providing the framework for combined lenalidomide and SGN-40 in a new treatment paradigm to both target MM cells directly and induce immune effectors against MM.

Authors+Show Affiliations

Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16357183

Citation

Tai, Yu-Tzu, et al. "Immunomodulatory Drug Lenalidomide (CC-5013, IMiD3) Augments anti-CD40 SGN-40-induced Cytotoxicity in Human Multiple Myeloma: Clinical Implications." Cancer Research, vol. 65, no. 24, 2005, pp. 11712-20.
Tai YT, Li XF, Catley L, et al. Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications. Cancer Res. 2005;65(24):11712-20.
Tai, Y. T., Li, X. F., Catley, L., Coffey, R., Breitkreutz, I., Bae, J., ... Anderson, K. C. (2005). Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications. Cancer Research, 65(24), pp. 11712-20.
Tai YT, et al. Immunomodulatory Drug Lenalidomide (CC-5013, IMiD3) Augments anti-CD40 SGN-40-induced Cytotoxicity in Human Multiple Myeloma: Clinical Implications. Cancer Res. 2005 Dec 15;65(24):11712-20. PubMed PMID: 16357183.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications. AU - Tai,Yu-Tzu, AU - Li,Xian-Feng, AU - Catley,Laurence, AU - Coffey,Rory, AU - Breitkreutz,Iris, AU - Bae,Jooeun, AU - Song,Weihua, AU - Podar,Klaus, AU - Hideshima,Teru, AU - Chauhan,Dharminder, AU - Schlossman,Robert, AU - Richardson,Paul, AU - Treon,Steven P, AU - Grewal,Iqbal S, AU - Munshi,Nikhil C, AU - Anderson,Kenneth C, PY - 2005/12/17/pubmed PY - 2006/2/24/medline PY - 2005/12/17/entrez SP - 11712 EP - 20 JF - Cancer research JO - Cancer Res. VL - 65 IS - 24 N2 - SGN-40, a humanized immoglobulin G1 (IgG1) anti-CD40 monoclonal antibody, mediates cytotoxicity against human multiple myeloma (MM) cells via suppression of interleukin (IL)-6-induced proliferative and antiapoptotic effects as well as antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we studied the clinical significance of an immunomodulatory drug lenalidomide on SGN-40-induced cytotoxicity against CD138(+)CD40(+) MM lines and patient MM cells. Pretreatment with lenalidomide sensitized MM cells to SGN-40-induced cell death. Combined lenalidomide and SGN-40 significantly induced MM apoptosis, evidenced by enhanced cleavage of caspase-3/8/poly(ADP-ribose)polymerase and increased sub-G(0) cells, compared with either single agent at the same doses. Pretreatment of effector cells with lenalidomide augmented SGN-40-induced MM cell lysis, associated with an increased number of CD56(+)CD3(-) natural killer (NK) cells expressing CD16 and LFA-1. Importantly, pretreatment with lenalidomide or lenalidomide and SGN-40 markedly enhanced NK-cell-mediated lysis of autologous patient MM cells triggered by SGN-40. Lenalidomide also up-regulated CD40L on CD56(+)CD3(-) NK cells, facilitating IL-2-mediated activation of NK cells. In addition, lenalidomide induced the CD56(dim) NK subset, which are more potent mediators of ADCC against target MM cells than the CD56(bright) NK subset. Finally, pretreatment of both effector and target MM cells with lenalidomide markedly enhanced SGN-40-mediated ADCC against CD40-expressing MM cells. These studies, therefore, show that the addition of lenalidomide to SGN-40 enhances cytotoxicity against MM cells, providing the framework for combined lenalidomide and SGN-40 in a new treatment paradigm to both target MM cells directly and induce immune effectors against MM. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/16357183/Immunomodulatory_drug_lenalidomide__CC_5013_IMiD3__augments_anti_CD40_SGN_40_induced_cytotoxicity_in_human_multiple_myeloma:_clinical_implications_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=16357183 DB - PRIME DP - Unbound Medicine ER -