3.6 CD27 (TNF Receptor Superfamily Member 7)
CD27, also known as TNF receptor superfamily member 7 (TNFRSF7), is a
co-stimulatory receptor expressed on various immune cells, normally
expressed on CD4+ and CD8+ T cells, natural killer (NK) cells and
thymocytes, and on memory B cells (primed B cells) [337]. CD27 is
expressed on naive CD4+ and CD8+ T cells, while most other
co-stimulatory TNFRs are produced only after T cell activation
[338]. Its ligand, CD70 (CD27-L, TNFSF7), is primarily expressed on
activated NK cells, APCs such as dendritic cells, and on some subsets of
activated T (conventional- and regulatory T cells) and B cells. The
interaction between CD27 and CD70 plays a critical role in regulating
immune responses, particularly in promoting T cell activation and memory
formation [339, 340].
When CD27 on T cells engages with CD70, it initiates signaling pathways
that enhance T cell activation, survival, and effector function. This
includes promoting T cell proliferation and cytokine production, such as
interleukin-2 (IL-2), interferon-gamma (IFN-γ), and tumor necrosis
factor-alpha (TNF-α) [337, 341, 342]. These cytokines are crucial
for orchestrating effective immune responses against infections and
tumors. In addition to its role in T cell activation, CD27 signaling
also contributes to the generation and maintenance of memory T cells.
Memory T cells are essential for providing long-lasting immune
protection against previously encountered pathogens and tumors [337,
341, 342].
Preclinical research has shown that CD27 agonists can enhance
tumor-specific T cell responses, promote tumor regression, and improve
survival in animal models. Agonistic anti-CD27 antibodies in a murine
model of melanoma, led to reduction in growth of lung metastases and
subcutaneous tumors, due to enhanced effector function and persistence,
and reduced PD-1 expression of tumor infiltrating CD8(+) T cells
[343]. In a study by Sakanishi et al. on mice with syngeneic T-cell
lymphoma, a non-depleting agonistic mAb against CD27 demonstrated
promise for cancer therapy by co-stimulating the induction of
tumor-specific cytotoxic T lymphocytes (CTLs) [344]. A study by
French et al. discovered that administering agonistic anti-CD27 mAbs
without a DC maturation signal completely protected tumor-bearing mice,
offering a highly potent method for enhancing antitumor T-cell immunity
[345]. Yang et al. conducted a study showing that TanCAR-T cells,
which target CD70 and B7-H3, displayed improved antitumor activity and
addressed the issues of antigenic heterogeneity and variability across
multiple tumor tissue samples [346].
The monoclonal antibody (mAb) targeting CD27, known as varlilumab (also
referred to as CDX-1127 or 1F5), has progressed into clinical trials
following promising results in preclinical studies [347, 348]. In
transgenic mice expressing hCD27, the fully human IgG1 monoclonal
antibody 1F5, which has agonist activity, effectively induced
proliferation and cytokine production from hCD27-Tg-derived T cells when
combined with TCR stimulation [348]. Early phase clinical trials
have been done or are underway, for evaluating CD27 agonists either as
monotherapy [NCT0146013440] [NCT0101591121] [NCT0221689044]
[NCT0149782145] [NCT01813539+NCT0275925046] or in combination
with other treatment modalities, including checkpoint inhibitors
[NCT04081688] [NCT03038672], anti-CD20 monoclonal antibody,
Rituximab [NCT03307746], and chemotherapy [NCT04023526/
NCT04150887]. Fourth-generation CAR-T cell targeting CD70 is also
undergoing clinical trials [NCT03125577]. The combination of CD27
agonists with checkpoint inhibitors, for example, aims to enhance the
efficacy of immune checkpoint blockade by augmenting T cell activation
and overcoming immunosuppressive mechanisms within tumors. Preliminary
data from these trials show promising results (well tolerated with
promising biological and early clinical activity) [349, 350].