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Immunotherapies designed to exploit the host immune system to specifically target cancer cells exploded onto the oncology scene in the mid-1980s, when the first such agents started to show success in melanoma and renal cell carcinoma.
Immunotherapies designed to exploit the host immune system to specifically target cancer cells exploded onto the oncology scene in the mid-1980s, when the first such agents started to show success in melanoma and renal cell carcinoma.1 In particular, immune checkpoint inhibitors (ICIs), which block signals that dampen T-cell activity, are a major breakthrough, yielding the possibility of long-term clinical benefit across a growing number of tumor types.2
Although ICIs have been tested in many patients, they are not universally effective, and finding ways to increase the number of patients who respond to immunotherapeutic approaches has become a central focus of ongoing research.3,4
One strategy is to target other signals that regulate T-cell activity, such as the glucocorticoid-induced tumor necrosis factor receptor—related protein (GITR) pathway, which provides a stimulatory signal to T cells.5
Using an analogy that compares the immune system to an automobile, investigators describe the mechanism of ICIs that target inhibitory checkpoints such as PD-1/ PD-L1 and CTLA-4 as “releasing the brakes” on the immune system” whereas agonists of stimulatory receptors such as GITR function by “stepping on the gas.”6
Developing GITR agonists has proved challenging, with initial trial results demonstrating favorable safety profiles but limited therapeutic activity.7-9 Persistence may yet pay off, however, as recent study findings highlight the significant potential for synergy between GITR agonists and the ICIs that inspired their development.8
In ongoing studies, several GITR agonists have demonstrated objective responses and antitumor activity in patients with advanced solid tumors when administered in combination with PD-1 inhibitors, including pembrolizumab (Keytruda) and nivolumab (Opdivo).10-12
Unleashing T Cells
The efforts to exploit GITR activity for anticancer therapy start with an understanding of T-cell biology. T cells are central to the antitumor immune response; their potent cytotoxic activity can be elicited by tumor-specific antigens, resulting in tumor destruction. Because of its potency, T-cell activation is tightly regulated via a complex, multistep process coordinated by a range of cell-surface receptors.13-15
The initial activation signal comes from T-cell receptors upon recognition of foreign antigens displayed on major histocompatibility complex 1 molecules on the surface of antigen-presenting cells (APCs).13-15
For a T cell to become fully activated, secondary antigen-independent costimulatory signals are required, generated by interactions between costimulatory receptors on the T-cell surface and their ligands on APCs. The major costimulatory receptor is CD28, a member of the immunoglobulin superfamily, but there are many others, including several members of the tumor necrosis factor (TNF) superfamily of receptors.14-16
In addition to activating receptors, T cells also express inhibitory receptors, which block proliferation and induce a state of unresponsiveness. This helps to limit the amplitude and duration of the T cell—mediated immune response and prevent damage to healthy cells.
The T cell—mediated immune response is also kept in check by regulatory T cells (Tregs), which have an immunosuppressive function, downregulating the activation and proliferation of effector T cells (Teffs).13-15
Below the Radar
Evidence of an antitumor immune response can be seen in the presence of tumor-infiltrating immune cells, and results from numerous studies have correlated a high number of these cells with improved prognosis in various cancers, including colorectal, esophageal, breast, and ovarian cancers.17 Despite this, one of the hallmarks of cancer cells that dictates their malignant capabilities is their ability to evade the antitumor immune response.18
One method of immune evasion is exploiting the inhibitory receptors on Teffs, switching them off when they enter the tumor microenvironment. High expression of PD-L1, which binds to the most widely studied inhibitory receptor, PD-1, has been observed on both tumor cells and other cells in the tumor microenvironment.19 This dysregulates the antitumor immune response and fosters tumor growth.
Tregs also have been found at elevated levels in the tumor microenvironment in numerous studies, but these have a more complicated prognostic role. High Treg density can be predictive of poor prognosis in some tumors but improved outcome in others, suggesting that the effect may be context dependent.13
Growing appreciation of the mechanisms of immune evasion has inspired the development of immunotherapy-based drugs to overcome evasion and reinstate an effective antitumor immune response.20
In particular, monoclonal antibodies blocking inhibitory molecules on T cells, the so-called ICIs, have proved highly successful. The list of FDA-approved drugs in this class and their approved indications continues to grow.2,21
Stepping on the Gas
Despite their impressive pedigree, ICIs are not universally beneficial, and resistance after an initial response is common. Equally important in driving effective antitumor immunity are the costimulatory receptors. Development of agonists targeting these receptors has been a central focus of ongoing research.3,5
One such receptor is GITR, a member of the TNF superfamily of receptor proteins that share homology in a cysteine-rich signature within their extracellular domain. GITR is part of a small subset of proteins within this superfamily, none of which possess the characteristic death domains, although there is some evidence that they may still initiate apoptosis by interacting with SIVA proteins that contain one and which share a costimulatory role.16,22-24
GITR itself lacks any enzymatic activity; thus, following activation by its ligand (GITRL), it binds to several members of the TNF receptor—associated factor (TRAF) family, which serve to either potentiate (TRAF4 and 5) or negatively regulate (TRAF2) downstream signaling. GITR signaling ultimately culminates in activation of the nuclear factor κ B transcription factor.16,22-24
Naïve T cells express no to low levels of GITR, but GITR is upregulated on activated Teffs and Tregs and remains at high levels for several days. GITR has also been found on other hematological cells, including B cells and natural killer (NK) cells and on some nonhematologic cells, reflecting diverse cellular roles. The highest levels of GITR expression are seen on Tregs, where it is constitutively expressed. GITRL is predominantly expressed by activated APCs, but high levels of expression have also been observed on endothelial cells.21-24
The precise function of GITR signaling is still being worked out, but it is dependent on the type of cell and the context in which it is activated (Figure25). On Teffs, GITR activation boosts activity in a number of ways, including lowering the threshold for CD28 signaling.16,22-24,26
The physiological consequences of GITR activation on Tregs are quite distinct from those on Teffs; it blocks their immunosuppressive functions, most likely both via direct inhibition and by promoting Teff resistance to Treg-mediated suppression.16,22-24
Initial preclinical studies performed with a murine antibody, DTA-1, showed great promise for GITR agonists, with increased numbers of Teffs that produced more cytokines and fewer Tregs.16
Several GITR agonists have entered clinical development; however, despite showing excellent safety profiles, none have shown significant antitumor activity to date as single agents.
Leap Therapeutics’ TRX518 was the first in the class. In a phase I study, patients with advanced solid tumors received a single dose of TRX518, ranging from 0.0001 to 8 mg/ kg. In the 40 patients enrolled, of whom 10 had melanoma, 9 had non—small cell lung cancer, 7 had colorectal cancer, and 14 had other cancer types, there were no dose-limiting toxicities (DLTs). The most common treatment-related adverse events (AEs) were cough, fatigue, nausea, vomiting, abdominal pain, dyspnea, and anorexia. Among evaluable patients, there were no objective clinical responses, and the best response was stable disease (SD) in 4 of 28 patients.7
Although there was no notable impact on Teffs or NK cells in the blood, TRX518 monotherapy did effectively deplete Tregs from blood and tumor specimens; specifically, GITR-positive Tregs were depleted in a dose-dependent manner.8
Clinical development of TRX518 has continued, but other GITR agonists have been shelved. Amgen was developing AMG 228, and results from a first-in-human study were published in 2018. The drug was administered every 3 weeks at escalating doses, from 3 to 1200 mg, in 30 patients with advanced solid tumors.
Despite being well tolerated up to the maximum dose, with no DLTs, and treatment-related AEs including fatigue, infusion-related reaction, pyrexia, decreased appetite, and hypophosphatemia, there was no evidence of T-cell activation or antitumor activity.27 No clinical trials of AMG 228 are ongoing, and it is no longer listed in the Amgen pipeline.
Development of AstraZeneca’s MEDI1873, a GITRL fusion protein, also appears to have been discontinued for strategic reasons, according to a 2018 investor’s report.28 In a phase I trial, MEDI1873 produced changes in immune cell composition, an acceptable AE profile, and SD in a substantial number of patients with advanced solid tumors.9
An open question in the development of GITR agonists relates to the importance of their ability to engage Fc γ receptors (FcγRs) on the T-cell surface and to induce antibody-dependent cellular cytotoxicity (ADCC). In preclinical studies with DTA-1, FcγR engagement was shown to be a potentially important mechanism of GITR-positive Treg depletion.5,16
All of the GITR agonists currently in development are immunoglobulin G1 (IgG1)based and should be able to induce ADCC.29 However, TRX518 is aglycosylated, a design that was intended to reduce effector functions, such as ADCC, to stop the antibody from potentially depleting Teffs.30,31
Merck has developed 2 GITR agonists. One of these, MK-1248, is IgG4-based. As such, it has significantly reduced FcγR-mediated ADCC activity, which could affect its efficacy. In a phase I trial, the results of which were presented at the 2018 American Society of Clinical Oncology Annual Meeting, MK-1248 was tested as monotherapy and in combination with the PD-1 inhibitor pembrolizumab in 37 patients with advanced solid tumors.
The most common AEs were vomiting, anemia, decreased appetite, abdominal pain, cough, diarrhea, nausea, fatigue, headache, and pyrexia. There were no DLTs in either arm, and the arms showed similar rates of serious AEs (30% with monotherapy and 29% in the combination arm). The combination of MK-1248 and pembrolizumab yielded 1 complete response (CR) and 2 partial responses (PRs).10
Combination is the Key
The status of MK-1248 is unclear, with no ongoing clinical trials listed in the Clinicaltrials.gov database, but the results of the above study highlight the potential of combination therapy with ICIs, which has now become the central focus of ongoing clinical development of GITR agonists (Table).
In a recent study, researchers delineated the rationale behind the efficacy of this combination strategy. Clinical trials suggest that GITR agonists are highly effective at depleting intratumoral Tregs without affecting Teffs numbers, leading to an increase in the Teff:Treg ratio. Yet, this does not correspond to antitumor efficacy.
The same phenomenon is observed in mice with established tumors, but mice with earlystage tumors are more responsive to GITR agonism. The mice with established tumors were found to have PD-1—positive T cells in their tumor specimens. Researchers hypothesized, therefore, that in established tumors, Tregs accumulate and exert their immunosuppressive effects prior to treatment and that these effects, including making the Teffs unresponsive, cannot be overcome by Treg depletion alone, rendering the tumor resistant to GITR agonism.8
Merck’s second GITR agonist, MK-4166, is being evaluated in a phase I trial as monotherapy (n = 48) or in combination with pembrolizumab (n = 65). MK-4166 was administered at escalating doses of 0.0015 to 900 mg every 3 weeks and pembrolizumab at a fixed dosage of 200 mg every 3 weeks in patients with metastatic solid tumors.
It was well tolerated up to the maximum dose, with only 1 DLT that was possibly related to MK-4166 in the monotherapy arm. The most common AEs were fatigue, infusion-related reaction, nausea, abdominal pain, and pruritus. In the combination arm, the objective response rate (ORR) was 9%.
In patients with ICI-naïve melanoma treated in a dose-expansion cohort, the ORR was 69%, including 4 CRs and 5 PRs. No responses were observed in patients who had previously been treated with ICIs.11
Another GITR agonist, BMS-986156, has shown promise in combination with nivolumab in patients with advanced solid tumors.12 Meanwhile, TRX518 is being evaluated in a repeat dosing dose-escalation study as monotherapy and in combination with gemcitabine, pembrolizumab, or nivolumab.30
Jane de Lartigue, PhD, is a freelance medical writer and editor based in Gainesville, Florida.