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Divergent effects of 4-1BB antibodies on antitumor immunity and on tumor-reactive T-cell generation.
Cancer Res. 2001 Mar 01; 61(5):2031-7.CR

Abstract

4-1BB is an inducible receptor-like protein expressed rapidly by both CD4 and CD8 T-cells after activation. 4-1BB cross-linking, either by binding to 4-1BBL or by antibody ligation, delivers a costimulatory signal to enhance T-cell activation and proliferation. Previous studies have demonstrated that the administration of 4-1BB monoclonal antibodies (mAbs) induces antitumor immune responses. In the current study using several murine tumors, we examined the systemic effects of 4-1BB mAb on the growth of s.c., intracranial (i.c.), and pulmonary metastases. In addition, the effects of 4-1BB mAb on the generation of antitumor effector T cells were examined. Treatment of 3-day i.c. MCA 205 sarcoma and GL261 glioma with the antibody resulted in prolongation of survival and cure of disease in some mice, whereas only minimal therapeutic effects were observed in established s.c. and pulmonary tumors. No antitumor effects against the poorly immunogenic B16/D5 melanoma were observed. Interestingly, successful treatment of i.c. tumors induced concomitant regression of s.c. tumors. Experiments using severe combined immunodeficient mice and mice depleted of either CD4 or CD8 T cells demonstrated T-cell dependence of the antitumor effects. For generation of effector T cells in the tumor-draining lymph nodes (LNs), administration of 4-1BB mAb had adverse effects, despite the apparent hypertrophy of the LNs. During in vitro activation of tumor-draining LN T cells with anti-CD3 and interleukin 2, the 4-1BB mAb augmented proliferation, resulting in an increase in CD8 T cells. However, they were less therapeutic than not treated LN cells. In adoptive immunotherapy, the coadministration of 4-1BB mAb enhanced the therapeutic efficacy. These results thus demonstrate the limits and potential advantages of 4-1BB antibody interactions with antitumor T cells in vivo and in vitro and suggest that therapeutic interactions of the antibody may be used in a variety of immunotherapeutic approaches.

Authors+Show Affiliations

Department of General Surgery and Center for Surgery Research, Cleveland Clinic Foundation, Ohio 44195, USA. kimj@ccf.orgNo 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, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11280763

Citation

Kim, J A., et al. "Divergent Effects of 4-1BB Antibodies On Antitumor Immunity and On Tumor-reactive T-cell Generation." Cancer Research, vol. 61, no. 5, 2001, pp. 2031-7.
Kim JA, Averbook BJ, Chambers K, et al. Divergent effects of 4-1BB antibodies on antitumor immunity and on tumor-reactive T-cell generation. Cancer Res. 2001;61(5):2031-7.
Kim, J. A., Averbook, B. J., Chambers, K., Rothchild, K., Kjaergaard, J., Papay, R., & Shu, S. (2001). Divergent effects of 4-1BB antibodies on antitumor immunity and on tumor-reactive T-cell generation. Cancer Research, 61(5), 2031-7.
Kim JA, et al. Divergent Effects of 4-1BB Antibodies On Antitumor Immunity and On Tumor-reactive T-cell Generation. Cancer Res. 2001 Mar 1;61(5):2031-7. PubMed PMID: 11280763.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Divergent effects of 4-1BB antibodies on antitumor immunity and on tumor-reactive T-cell generation. AU - Kim,J A, AU - Averbook,B J, AU - Chambers,K, AU - Rothchild,K, AU - Kjaergaard,J, AU - Papay,R, AU - Shu,S, PY - 2001/3/31/pubmed PY - 2001/4/21/medline PY - 2001/3/31/entrez SP - 2031 EP - 7 JF - Cancer research JO - Cancer Res VL - 61 IS - 5 N2 - 4-1BB is an inducible receptor-like protein expressed rapidly by both CD4 and CD8 T-cells after activation. 4-1BB cross-linking, either by binding to 4-1BBL or by antibody ligation, delivers a costimulatory signal to enhance T-cell activation and proliferation. Previous studies have demonstrated that the administration of 4-1BB monoclonal antibodies (mAbs) induces antitumor immune responses. In the current study using several murine tumors, we examined the systemic effects of 4-1BB mAb on the growth of s.c., intracranial (i.c.), and pulmonary metastases. In addition, the effects of 4-1BB mAb on the generation of antitumor effector T cells were examined. Treatment of 3-day i.c. MCA 205 sarcoma and GL261 glioma with the antibody resulted in prolongation of survival and cure of disease in some mice, whereas only minimal therapeutic effects were observed in established s.c. and pulmonary tumors. No antitumor effects against the poorly immunogenic B16/D5 melanoma were observed. Interestingly, successful treatment of i.c. tumors induced concomitant regression of s.c. tumors. Experiments using severe combined immunodeficient mice and mice depleted of either CD4 or CD8 T cells demonstrated T-cell dependence of the antitumor effects. For generation of effector T cells in the tumor-draining lymph nodes (LNs), administration of 4-1BB mAb had adverse effects, despite the apparent hypertrophy of the LNs. During in vitro activation of tumor-draining LN T cells with anti-CD3 and interleukin 2, the 4-1BB mAb augmented proliferation, resulting in an increase in CD8 T cells. However, they were less therapeutic than not treated LN cells. In adoptive immunotherapy, the coadministration of 4-1BB mAb enhanced the therapeutic efficacy. These results thus demonstrate the limits and potential advantages of 4-1BB antibody interactions with antitumor T cells in vivo and in vitro and suggest that therapeutic interactions of the antibody may be used in a variety of immunotherapeutic approaches. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/11280763/Divergent_effects_of_4_1BB_antibodies_on_antitumor_immunity_and_on_tumor_reactive_T_cell_generation_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11280763 DB - PRIME DP - Unbound Medicine ER -