What GITR agonists are in clinical trials currently?

Introduction to GITR and its Role in Immunotherapy

Definition and Biological Function of GITR
Glucocorticoid-induced tumor necrosis factor receptor (GITR) is a member of the tumor necrosis factor receptor (TNFR) superfamily that is predominantly expressed on activated T cells and regulatory T cells (Tregs) as well as on other immune cells such as natural killer (NK) cells and neutrophils. Its canonical role is to modulate T-cell activation through co-stimulation. When engaged by its ligand (GITRL), which is typically expressed on antigen-presenting cells and endothelial cells, GITR transduces signals that not only amplify effector T-cell activity but also attenuate the suppressive function of Tregs. This dual mechanism makes GITR a promising immunomodulatory target because the receptor can shift the balance in the tumor microenvironment toward an active antitumor immune response.

Importance of GITR in Cancer Immunotherapy
GITR represents an attractive target in oncology primarily because of its capacity to enhance effector T-cell functions and simultaneously inhibit Treg-mediated suppression, which is a common hallmark of many immunosuppressive tumors. Preclinical models have demonstrated that agonist antibodies designed to stimulate GITR can lead to tumor regression by increasing cytotoxic CD8+ T-cell proliferation and by depleting tumor-infiltrating Tregs. This rationale has spurred the rapid development of multiple GITR agonists in clinical research. In the context of cancer immunotherapy, GITR-targeting agents are being tested both as standalone therapies and in combinations with established checkpoint inhibitors, such as anti-PD-1 and anti-CTLA-4 antibodies, in an effort to overcome resistance observed with monotherapies and to further enhance antitumor responses.

Overview of GITR Agonists

Mechanism of Action
GITR agonists are designed to mimic the natural ligand (GITRL) and trigger receptor-mediated intracellular signaling events that bolster effector T-cell activation. These molecules generally work through receptor cross-linking. They achieve this by binding bivalently to the GITR receptor on T cells and, in many cases, also by engaging Fc receptors on immune effector cells to induce clustering of GITR molecules. This cross-linking leads to potent stimulation of the nuclear factor κB (NF-κB) pathway and mitogen-activated protein kinase (MAPK) cascades. The outcome is an increased proliferation of CD8+ and CD4+ T-effector cells, enhanced cytokine release, and an overall shift in the immune balance in favor of antitumor activity. Importantly, some agents also exhibit the capability to interfere with the suppressive function of Tregs either by directly affecting their survival or by modulating Foxp3 expression, a hallmark transcription factor for Treg identity.

Potential Therapeutic Applications
The therapeutic potential of GITR agonists lies in their applicability across a range of cancer types, especially those characterized by a highly immunosuppressive tumor microenvironment. Beyond solid tumors, preclinical studies indicate potential applications in hematologic malignancies through the modulation of lymphoma-specific T cells. Moreover, because GITR agonism can operate in tandem with other immunotherapies, several clinical trials evaluate these agents in combination regimens. For instance, combining GITR agonists with PD-1 inhibitors or conventional chemotherapeutic agents has shown promising antitumor efficacy in early-phase studies. This strategic combination aims to enhance the breadth and depth of the antitumor immune response, effectively overcoming resistance mechanisms that tumors may develop when subjected to single-modality therapy.

Current Clinical Trials of GITR Agonists

List of GITR Agonists in Clinical Trials
A number of GITR agonists are currently under clinical investigation. These include:

• INCAGN1876 – A GITR agonist explored in combination with a PD-1 inhibitor and stereotactic radiosurgery in recurrent glioblastoma patients.

• GWN323 – An anti-GITR monoclonal antibody being studied both as a single agent and in combination with PDR001 (an anti-PD-1) in patients with advanced solid tumors and lymphomas.

• ASP1951 – A GITR agonistic antibody evaluated as monotherapy and in combination with pembrolizumab in subjects with advanced solid tumors.

• REGN6569 – An anti-GITR monoclonal antibody assessed in combination with cemiplimab for the treatment of adult patients with advanced solid tumor malignancies.

• BMS-986156 – A fully human GITR agonist antibody that has been investigated both as a single agent and in combination with ipilimumab or nivolumab in patients with advanced or metastatic lung/chest or liver cancers.

• TRX518 – A well-studied GITR agonist that has been tested in phase I settings both as a monotherapy and in combination with agents such as gemcitabine, pembrolizumab, or nivolumab in advanced solid tumors.

• INCAGN01876 – A GITR agonistic antibody currently undergoing evaluation in several phase I/II studies either as a monotherapy or in combination with immune therapies in subjects with advanced or metastatic malignancies, including head and neck squamous cell carcinoma.

• OMP-336B11 – A GITR targeting agent under a phase 1a open-label, dose escalation study in subjects with locally advanced or metastatic solid tumors.

Additionally, some ongoing trials (such as in head and neck squamous cell carcinoma) investigate the benefit of incorporating a GITR agonist into combination immunotherapy regimens, although the exact identity of the GITR targeting agent in these studies is less explicitly defined in the public domain.

Status and Phases of Clinical Trials
The clinical development of GITR agonists spans various phases of investigation with the following general trends:

• INCAGN1876 is currently being evaluated in a phase II study in patients with recurrent glioblastoma in combination with PD-1 inhibition and stereotactic radiosurgery. Its initiation has been timed to leverage the known benefits of local high-dose exposure in brain tumors, where a robust immune response is desired.

• GWN323 is under phase I/Ib investigation in patients with advanced solid tumors and lymphomas. Its dual agent design, used both as a monotherapy and in combination with an anti-PD-1 antibody, aims to optimize tolerability and identify synergistic antitumor effects as part of early clinical exploration.

• ASP1951 is in phase 1b testing, primarily focusing on its safety profile and initial signs of efficacy in patients with advanced solid tumors. Preliminary dosing and tolerability data are being collected to inform potential combination strategies with immune checkpoint inhibitors such as pembrolizumab.

• REGN6569 has been advanced into a phase 1 study of combination therapy with cemiplimab in adult patients with advanced or metastatic solid tumors. Early reports suggest that its use in combination may lead to favorable immune modulation while maintaining an acceptable safety profile.

• BMS-986156 has been evaluated both as a monotherapy and in combination regimens. Phase I/II trials have documented its safety and pharmacodynamic profiles, with combination cohorts tested alongside ipilimumab and nivolumab. These studies report acceptable tolerability, with the combination strategy providing promising preliminary efficacy signals in selected advanced cancer cohorts.

• TRX518 has undergone early-phase clinical investigation in patients with advanced solid tumors in both a monotherapy context and combined with chemotherapy or checkpoint inhibitors. In these early-phase settings, the agent has demonstrated modulation of T-cell subsets (including reductions in Tregs) and some degree of clinical activity, though monotherapy responses appear modest.

• INCAGN01876 is being explored in a range of phase 1/2 studies spanning various advanced malignancies, including studies specifically focusing on head and neck cancers. The multiple clinical trials (with similar identifiers but different expansion cohorts) indicate a broad interest in evaluating its antitumor effects when combined with other immunomodulatory agents.

• OMP-336B11 is in a first-in-human phase 1a open-label, dose escalation study. This early-phase trial is designed primarily to assess the safety, tolerability, and pharmacokinetics of the agent in subjects with locally advanced or metastatic solid tumors.

The clinical trials for these agents have been initiated predominantly within the last decade, with many studies initiated after the promising results observed in preclinical models, and public postings of clinical trial data on platforms such as ClinicalTrials.gov supporting their credibility and ongoing evaluation.

Preliminary Results and Findings
Early-phase clinical data for several of these agents have provided useful insights that are guiding further development:

• For INCAGN1876, preliminary results in the context of recurrent glioblastoma suggest that when combined with PD-1 inhibitors and localized radiation, the immune response within the tumor microenvironment is enhanced, though full clinical efficacy data are pending as the study progresses into later phases.

• GWN323’s phase I/Ib study has largely focused on safety and tolerability, with evidence of GITR engagement and immune activation (such as increases in activated T cells) being observed. While objective responses have been modest overall, the combination with anti-PD-1 agents may improve efficacy in subsets of patients.

• ASP1951 has shown a tolerable safety profile in its phase 1b study. The observed pharmacodynamic effects include increased T-cell activation and immune modulation, which are consistent with its intended mechanism of impairing Treg-mediated immunosuppression. However, robust clinical responses have not yet been uniformly reported.

• REGN6569, when combined with cemiplimab, has demonstrated an acceptable safety profile in phase I studies with early pharmacodynamic markers indicating robust immune engagement. The combined regimen aims to leverage dual immune activation mechanisms, although definitive efficacy outcomes are still under investigation.

• BMS-986156 has been extensively evaluated in combination with other agents. In initial studies, it has exhibited a favorable safety profile and achieved receptor saturation at certain dose levels. While monotherapy results were limited, the combination cohorts have shown a trend toward enhanced clinical responses relative to historical data for PD-1 inhibitors alone.

• TRX518, despite demonstrating T-cell modulation—including reductions in circulating and intratumoral Tregs—in early-phase studies, has not yet translated into significant monotherapy success, suggesting its optimal use may be in combination with chemotherapy or checkpoint inhibitors.

• INCAGN01876 has been part of several early-phase combination trials, and preliminary data from these trials have indicated that the agent is well tolerated and capable of modulating the immune microenvironment to favor an antitumor response. Increased proliferation of effector T cells and decreases in suppressive Treg subsets have been observed, although clinical response rates remain to be fully clarified as these studies mature.

• OMP-336B11 is still in the dose-escalation phase, and while no detailed efficacy data have been published yet, early pharmacokinetic findings are anticipated to inform future clinical application decisions once safety is established.

Collectively, these data highlight that the majority of GITR agonists in clinical development exhibit acceptable safety profiles and induce measurable immunologic changes. Yet, the challenge remains to translate these immunologic effects into durable and significant clinical responses as part of combination treatment regimens with other immunotherapies or modulatory agents.

Challenges and Future Prospects

Challenges in Developing GITR Agonists
Despite a compelling biological rationale, the clinical development of GITR agonists is not without challenges. One major hurdle is achieving robust clinical efficacy when these agents are used as monotherapies. Early-phase trials, particularly those evaluating agents such as TRX518, have demonstrated that while immune modulation (including Treg depletion and effector T-cell activation) can be achieved in the peripheral blood and within the tumor microenvironment, translating these effects into objective tumor responses remains challenging.

Another challenge relates to the optimization of dose and scheduling. GITR agonists exhibit bell-shaped dose response curves due to the requirement for precise receptor cross-linking. Excessive dosing may lead to receptor monovalency rather than the desired bivalency, thereby reducing agonist activity. This unique pharmacodynamic behavior necessitates careful dose titration and real-time pharmacodynamic monitoring to ensure that receptor saturation is achieved without loss of efficacy.

Furthermore, the heterogeneity of patient tumors—in terms of both immune landscape and intrinsic tumor biology—complicates the development of a universal GITR agonist treatment strategy. Differences in GITR expression, basal levels of immune suppression by Tregs, and the presence of multiple compensatory immunosuppressive pathways mean that patient selection and biomarkers for response will be critical. In this regard, combination strategies are being actively explored, but these too bring in challenges such as potential overlapping toxicity and complex pharmacokinetic interactions.

Finally, translational challenges are evident when comparing preclinical models with human clinical results. Animal models often show robust responses to GITR agonism that are not always mirrored in human trials, partly due to species-specific differences in GITR signaling and differences in the tumor microenvironment complexity.

Future Research Directions and Potential Developments
Looking forward, future research on GITR agonists is likely to focus on several key areas to overcome current challenges and realize their full therapeutic potential.

One major direction is the optimization of combination therapies. Given that monotherapy with GITR agonists has shown limited clinical efficacy, combining these agents with other immunomodulatory treatments—such as PD-1 blockade, CTLA-4 inhibitors, or even cancer vaccines—remains the focus of several ongoing trials. Future studies are expected to refine these combination regimens, assess optimal dosing strategies, and identify biomarkers of response that can guide patient selection.

Another promising avenue is the development of next-generation GITR agonists that can better mimic the natural ligand’s multimeric state. For instance, agents like REGN6569 and INCAGN01876 are being engineered to optimize receptor oligomerization and downstream signaling. Such structural improvements may translate into more profound and sustainable antitumor immune responses.

In addition, innovative trial designs and dynamic aggregation of clinical endpoints, as highlighted by recent studies on clinical trial endpoints and biomarker-based analyses, may improve the assessment of these therapies’ true clinical benefits. Combining robust translational endpoints with clinical efficacy endpoints will help better define the “active” dose and correlate immunologic changes with clinical outcomes.

There is also a need for developing improved assays for monitoring GITR receptor engagement and immune activation in patients. Advanced imaging technologies and flow cytometry–based methods could allow for real-time adjustments of therapy and more personalized approaches to dosing. Understanding the pharmacodynamics at the cellular level will ultimately enhance the clinical translation of preclinical findings.

Finally, the continued exploration of patient-reported outcomes and their integration with molecular biomarkers presents an opportunity to refine the clinical evaluation of GITR agonists. Such multidimensional endpoints may facilitate the identification of patient subsets who are most likely to benefit, thereby reducing the heterogeneity that currently hampers efficacy assessments in larger patient populations.

In summary, the landscape of GITR agonists in clinical trials currently includes several promising agents such as INCAGN1876, GWN323, ASP1951, REGN6569, BMS-986156, TRX518, INCAGN01876, and OMP-336B11. These agents are being tested in various phase I, Ib, and II trials across multiple types of advanced malignancies, often in combination with other immunotherapies. The underlying mechanism of action—enhancing effector T-cell responses and reducing Treg suppression—remains consistent among these agents, although their clinical efficacies vary according to dose, schedule, and combination strategies. The preliminary findings from early-phase studies have demonstrated acceptable safety profiles and promising immunologic activity, even though significant objective responses have not been uniformly observed. Major challenges include achieving optimal dosing for receptor cross-linking, managing inter-patient heterogeneity, and translating preclinical successes into robust clinical outcomes. Future research is focused on refining combination regimens, optimizing next-generation designs that better mimic natural GITRL structure, improving biomarker-driven patient selection, and employing innovative clinical trial designs that integrate multidimensional endpoints.

In conclusion, current clinical investigations confirm that several GITR agonists are actively being evaluated in various clinical settings, with the ultimate goal of harnessing their unique immunomodulatory properties to overcome tumor-induced immunosuppression. While early-phase results are encouraging in terms of safety and immune activation, further studies—especially those incorporating well-designed combination strategies and robust biomarker analyses—are essential to fully realize the therapeutic potential of these agents in cancer treatment. The future of GITR agonist development holds promise provided that ongoing research addresses the inherent challenges of dose optimization, patient heterogeneity, and translational discrepancies between preclinical models and human disease. Continued advancements in this field are expected to contribute significantly to the broader landscape of cancer immunotherapy by providing new avenues for overcoming immune resistance and improving patient outcomes.