CD27-Mediated Regulatory T Cell Depletion and Effector T Cell Costimulation Both Contribute to Antitumor Efficacy

CD27, a member of the TNFR superfamily, is constitutively expressed in most T cells and plays crucial roles in T cell effector functions. The costimulation and antitumor activity of CD27 agonistic Abs have been well documented in mouse models. Clinical testing of a human IgG1 anti-CD27 Ab, varliluma...

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Published in:The Journal of immunology (1950) 2017-12, Vol.199 (12), p.4110-4123
Main Authors: Wasiuk, Anna, Testa, James, Weidlick, Jeff, Sisson, Crystal, Vitale, Laura, Widger, Jenifer, Crocker, Andrea, Thomas, Lawrence J, Goldstein, Joel, Marsh, Henry C, Keler, Tibor, He, Li-Zhen
Format: Article
Language:English
Subjects:
Animal models
Antitumor activity
Apoptosis
Cancer
CD27 antigen
Depletion
Effector cells
Exhaustion
Immune response
Immunoglobulin G
Immunomodulation
Immunoregulation
Immunotherapy
Immunotherapy and Vaccines
Isotypes
Lymphocytes
Lymphocytes B
Lymphocytes T
Lymphoma
Transgenic mice
Tumor necrosis factor receptors
Tumors
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Summary:CD27, a member of the TNFR superfamily, is constitutively expressed in most T cells and plays crucial roles in T cell effector functions. The costimulation and antitumor activity of CD27 agonistic Abs have been well documented in mouse models. Clinical testing of a human IgG1 anti-CD27 Ab, varlilumab (clone 1F5), is ongoing in cancer patients. In this study, we set out to further understand CD27 as an immunomodulatory target and to address the mechanism of antitumor efficacy using different IgG isotypes of 1F5 in human -transgenic mice. 1F5mIgG1, the only isotype engaging inhibitory FcγRIIB expressed in B cells, elicited the most potent and broad immune response, but terminal differentiation, exhaustion, and apoptosis in the activated effector T cells were inevitable. Accordingly, this isotype was the most effective in eradicating BCL1 lymphoma but had limited efficacy in s.c. tumors. Conversely, 1F5mIgG2a, which interacts with cells expressing activating FcγRs, led to moderate immune activation, as well as to prominent reduction in the number and suppressive activity of regulatory T cells. These combined mechanisms imparted potent antitumor activity to 1F5mIgG2a, particularly against the s.c. tumors. 1F5hIgG1, varlilumab, showed balanced agonistic activity that was prominent at lower doses and depleting activity that was greater at higher doses. 1F5hIgG1 had good antitumor activity in all tumor models tested. Thus, both agonist and depleting properties contribute to the antitumor efficacy of CD27-targeted immunotherapy, and modulation of these activities in patients may be achieved by varying the dose and regimen.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1700606