Evaluating the Cellular Targets of Anti-4-1BB Agonist Antibody during Immunotherapy of a Pre-Established Tumor in Mice

Abstract

BackgroundManipulation of the immune system represents a promising avenue for cancer therapy. Rational advances in immunotherapy of cancer will require an understanding of the precise correlates of protection. Agonistic antibodies against the tumor necrosis factor receptor family member 4-1BB are emerging as a promising tool in cancer therapy, with evidence that these antibodies expand both T cells as well as innate immune cells. Depletion studies have suggested that several cell types can play a role in these immunotherapeutic regimens, but do not reveal which cells must directly receive the 4-1BB signals for effective therapy.Methodology/Principal FindingsWe show that re-activated memory T cells are superior to resting memory T cells in control of an 8-day pre-established E.G7 tumor in mice. We find that ex vivo activation of the memory T cells allows the activated effectors to continue to divide and enter the tumor, regardless of antigen-specificity; however, only antigen-specific reactivated memory T cells show any efficacy in tumor control. When agonistic anti-4-1BB antibody is combined with this optimized adoptive T cell therapy, 80% of mice survive and are fully protected from tumor rechallenge. Using 4-1BB-deficient mice and mixed bone marrow chimeras, we find that it is sufficient to have 4-1BB only on the endogenous host αβ T cells or only on the transferred T cells for the effects of anti-4-1BB to be realized. Conversely, although multiple immune cell types express 4-1BB and both T cells and APC expand during anti-4-1BB therapy, 4-1BB on cells other than αβ T cells is neither necessary nor sufficient for the effect of anti-4-1BB in this adoptive immunotherapy model.Conclusions/SignificanceThis study establishes αβ T cells rather than innate immune cells as the critical target in anti-4-1BB therapy of a pre-established tumor. The study also demonstrates that ex vivo activation of memory T cells prior to infusion allows antigen-specific tumor control without the need for reactivation of the memory T cells in the tumor.

Decreased levels of alternative co-stimulatory receptors OX40 and 4-1BB characterise T cells from head and neck cancer patients

“…shown to be the ␣␤ T cells (Lin et al 2010). Of note, a fully human IgG4 anti-CD137 (4-1BB) antibody is under development and has shown promising signs of clinical efficacy.…”

Immunomodulating antibodies in the treatment of metastatic melanoma: The experience with anti-CTLA-4, anti-CD137, and anti-PD1

“…Its binding by the natural ligand (CD137L) or an agonist antibody provides co-stimulation in a CD28 independent way for CD4 + and CD8 + T-lymphocytes (Wilcox et al, 2002). Surface expression of CD137 is detectable on activated effector CD8 + and CD4 + cells, and also to activated NK cells, NKT cells, T reg lymphocytes, dendritic cells (DC), macrophages, neutrophils, and eosinophils (Lin et al, 2010). Recent evidence indicates that it is also functionally expressed in tumor capillary endothelial cells (Ascierto et al, 2010a).…”

The New Era of Cancer Immunotherapy

“…CTLA-4 blockade combined with 4-1BB stimulation in the context of a B16 melanoma vaccine resulted in increased tumor rejection compared to either treatment alone in mice bearing B16 tumors (Curran et al, 2011). In addition, the combination of an anti-4-1BB mAb with adoptive T-cell therapy resulted in increased survival and resistance to rechallenge in the murine thymoma model E.G7 (Lin et al, 2010). Urelumab (BMS-663513), a human agonist mAb targeting 4-1BB, was investigated in patients with ovarian cancer, renal cell carcinoma, and melanoma (Sznol et al, 2008).…”