CD137 agonist antibody prevents cancer recurrence: contribution of CD137 on both hematopoietic and nonhematopoietic cells

Abstract

Antigen-specific memory T cells (Tms) are essential in the immune surveillance of residual and metastatic tumors. Activation of Tms requires designing vaccines based on tumor rejection antigens, which are often not available to cancer patients. Therefore, it is desirable to have a general applicable approach to activate Tms without extensive knowledge of tumor antigens. Here, we report that activation of antigen-specific Tms could be achieved by the administration of agonistic anti-CD137 monoclonal antibody without additional tumor vaccination, leading to the prevention of recurrence and metastases after surgical resection of primary tumors in mouse models. By reconstitution with CD137-deficient Tms, we demonstrate that expression of CD137 on antigen-specific Tms is only partially required for the effect of anti-CD137 antibody. Other host cells, including those from hematopoietic and nonhematopoietic origins, are also important because ablation of CD137 from these cells partially but significantly eliminates antitumor effect of anti-CD137 antibody. Our findings implicate a potential new approach to prevent recurrence and metastases in cancer patients. (Blood.

Intervention with costimulatory pathways as a therapeutic approach for graft-versus-host disease

“…Agonistic anti-CD137 mAb can expand Treg cells in vivo (our unpublished data). The expansion of Treg cells by agonistic anti-CD137 mAb is dependent upon IL-2 which is secreted by memory T cells (Zhu et al, 2007;Narazaki et al, 2010). Our unpublished results showed that Treg cells primed by anti-CD137 mAb have a higher ability to suppress the proliferation and cytokine production of CD4 + T cells.…”

Emerging Targets in Cancer Immunotherapy: Beyond CTLA-4 and PD-1

“…Its ligand 4-1BBL is expressed on B cells, DCs, macrophages, activated T cells and endothelial cells [94][95][96]. Agonistic CD137 mAb stimulated the proliferation of CD4 and CD8 T cells, mainly CD8 CTL, increased cytokine production, prevent activation induced cell death [94,97] and in absence of cognate signals increases the memory T-cell expansion [98]. Large tumors in mice are eradicated with increased cytotoxic T-cell activity in poorly immunogenic Ag104A sarcoma and highly tumorigenic P815 mastocytoma using agonist CD137 mAb [99].…”

Enhanced antitumor activity mediated by human 4‐1BB‐engineered T cells

“…The amount of in vitrotranscribed mRNA for each chain was 2 lg/10 6 PBMCs. The sequences of the HLA-A2 restricted peptides used in our study are as follows: gp100 209M (IMDQVPFSV) and HBV [18][19][20][21][22][23][24][25][26][27] (FLPSDFFPSV).…”

“…5 To assess the stimulatory potential of DCs on 4-1BB-transduced cells, we produced autologous DCs from those patients and pulsed them with either the specific gp100 209 epitope or an irrelevant peptide (HBV [18][19][20][21][22][23][24][25][26][27] ). After coculture with transduced lymphocytes, we observed an increased IFN-g secretion by 4-1BB-transduced versus GFP-transduced cells (Fig.…”

“…Activation of the 4-1BB/4-1BBL pathway in vivo using, for example, agonistic anti-41BB has led to tumor regression in cancer-bearing mice. [17][18][19] T-cell-mediated immune response against tumor cells has been proven crucial to the elimination of cancer. 20 In this regard, adoptive cell transfer of tumor-infiltrating lymphocytes is an effective approach for the immunotherapy of patients with metastatic melanoma, leading to an objective response rate of 50-70%, with a third of those patients experiencing complete regression of their metastatic tumors.…”