CD137: An Important Target in T Cell Co-Stimulation

Following on from OX40, our TNF superfamily posts continue with CD137, another important target in T cell co-stimulation.

CD137 Stimulates the Immune System Against Cancer Cells

In contrast to the mode of action of checkpoint inhibitors (which is to block a ligand/receptor interaction) there is another class of immunomodulatory targets in the immuno-oncology world – the co-stimulatory targets.

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For productive activation of a T cell, the cell must recognize its target through engagement of antigen and the cognate T cell receptor. The T cell must also receive co-stimulatory signal(s) in parallel. These signals are generated through the interactions of co-stimulatory ligands and receptors, such as CD137 and its ligand, CD137L.

Therefore, while the goal of checkpoint inhibitors is to block the inhibitory signals that cancer cells use to evade the immune system, agents that target the co-stimulatory machinery are designed to stimulate the immune system against the cancer cells.

CD137 Can Act as a Surrogate Marker for T Cell Activation

CD137 (TNFSFR9) was originally identified as a molecule induced on the surface of activated mouse and human CD4+ and CD8+ T cells, with its expression undetectable on non-activated T cells. It is also found on both NK and dendritic cells. Ligation of the receptor induces T cell proliferation and IL-2 production as well as inhibiting apoptosis.

Strong support for the role of CD137 in antigen specific and reactive effector T cells was the report that T cells could be enriched from blood-based on their CD137 expression, and could subsequently be demonstrated to show antigen specificity, including tumor antigens (1,2). Therefore, CD137 can act as a surrogate marker for T cell activation.

Cells Expressing CD137 are Potent Effector Cells

Further support for the importance of CD137 in antigen reactive effector T cells is reinforced by data suggesting that using CD137 to selectively deplete T cell populations can effectively control alloreactive T cells in the context of GVHD (3).

These observations, taken together, support that cells expressing CD137 are potent effector cells; those desired for immune control of cancer or those unwanted in autoimmune disease. In the case of the former, CD137 is a logical target for I/O applications.

CD137 Agonist Clinical Trials Ongoing Including Combination Studies

The discussion above supports the use of agonistic antibodies targeting CD137 and is reviewed in more detail elsewhere (4-6). There are two antibodies currently in clinical trials:

• utomilumab (PF-05082566; Pfizer)
• urelumab (BMS-663513; Bristol-Myers Squibb)

Of interest is that in a significant number of cases, urelumab was responsible for adverse events, including liver toxicity and fatigue, while utomilumab had no evidence of dose limiting toxicities (5,7). Consistent for urelumab, liver toxicity has been observed in a murine model using anti-CD137 antibodies (8).

Poor Understanding of Different Adverse Event Profile

It remains poorly understood why there is this difference between urelumab and utomilumab, but as is often observed, clinical activity tends to go hand-in-hand with adverse event observations. Whether it is the case that urelumab’s performance on the efficacy side will be superior to that for utomilumab, reflected in the difference in adverse event profile remains to be revealed.

Needless to say, the results from the many clinical studies of the combination of CD137 agonists and checkpoint inhibitors is eagerly anticipated. Stay tuned to the ClinicalTrials.gov links noted above...and refresh your browser often.

Further CD137 Uses Include CAR-T Therapy

Other uses for CD137 as a target have been employed. Interestingly, anti-CD137 is being tested clinically as an ex vivo stimulus for the expansion of TIL destined for re-infusion, and as a strategy to manage so-called T cell exhaustion (9). CAR-T therapy is also exploring the incorporation of CD137 in the second and third generation design of these agents (10).

While we eagerly watch the progress of the clinical trials involving urelumab and utomilumab, both as single agents and in the multitude of combination trials, it will be even more interesting watching where CD137 will be leveraged next.

References

1. Ye at al. CD137 accurately identifies and enriches for naturally occurring tumor-reactive T cells in tumor. Clin Cancer Res 2014;20(1):44-45.
2. Wolfl et al. Activation-induced expression of CD137 permits detection, isolation, and expansion of the full repertoire of CD8+ T cells responding to antigen without requiring knowledge of epitope specificities. Blood 2007;110(1): 201-210.
3. Lee et al. Depletion of alloreactive T-cells by anti-CD137-saporin immunotoxin. Cell Transplant 2015;24(6): 1167-1181.
4. Yonezawa et al. Boosting cancer immunotherapy with anti-CD137 antibody therapy. Clin Cancer Res 2015;21(14): 3113-3120.
5. Chester et al. 4-1BB agonism: adding the accelerator to cancer immunotherapy. Cancer Immunol Immunother 2016;65(10): 1243-1248.
6. Sanchez-Paulete et al. Deciphering CD137 (4-1BB) signaling in T-cell costimulation for translation into successful cancer immunotherapy. Eur J Immunol 2016;46(3): 513-522.
7. Segal et al. Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. Clin Cancer Res 2017;23(8): 1929-1936.
8. Dubrot et al. Treatment with anti-CD137 mAbs causes intense accumulations of liver T cells without selective antitumor immunotherapeutic effects in this organ. Cancer Immunol Immunother 2010;59(8): 1223-1233.
9. Long et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med 2015;21(6): 581-590.
10. Smith et al. Chimeric antigen receptor (CAR) T cell therapy for malignant cancers: Summary and perspective. Journal of Cellular Immunotherapy 2016;2(2): 59-68.