Tumor Necrosis Factor Receptor-related Protein Research Articles

Utility and impact of quantitative pharmacology on dose selection and clinical development of immuno-oncology therapy.

Immuno-oncology (IO) therapies have changed the cancer treatment landscape. Immune checkpoint inhibitors (ICIs) have improved overall survival in 20-40% of patients with malignancies that were previously refractory. Due to the uniqueness in biology, modalities and patient responses, drug development strategies for IO differed from that traditionally used for cytotoxic and target therapies in oncology, and quantitative pharmacology utilizing modeling approach can be applied in all phases of the development process. In this review, we used case studies to showcase how various modeling methodologies were applied from translational science and dose selection through to label change, using examples that included anti-programmed-death-1 (anti-PD-1), anti-programmed-death ligand-1 (anti-PD-L1), anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), and anti-glucocorticoid-induced tumor necrosis factor receptor-related protein (anti-GITR) antibodies. How these approaches were utilized to support phase I-III dose selection, the design of phase III trials, and regulatory decisions on label change are discussed to illustrate development strategies. Model-based quantitative approaches have positively impacted IO drug development, and a better understanding of the biology and exposure-response relationship may benefit the development and optimization of new IO therapies.

Prognostic and predictive significance of GITR in metastatic renal cell carcinoma.

Renal cell carcinoma (RCC) has gradually increased in recent years. There have been significant developments in metastatic RCC in recent years with the introduction of immune control point inhibitors. Glucocorticoid-induced tumor necrosis factor (TNF) receptor-related protein (GITR) is a co-stimulatory molecule and is seen in the highest amounts in activated CD4+ T lymphocytes and CD8+ T lymphocytes, forkhead box protein 3 (FOXP3) positive regulatory T cells (Treg). GITR leads to an increase in interleukin (IL)-2 and CD25 and Interferon Gamma. It shows an anti-tumoural effect by inhibiting the suppressive functions of FOXP3+ regulatory cells (Treg). Therefore, we aimed to evaluate the prognostic and predictive effect of GITR, tumor-infiltrating lymphocytes (CD4+CD8) (TIL), and FOXP3 in patients with metastatic RCC. Patients diagnosed with pathologically confirmed metastatic renal cancer between 2016 and 2021 were included in our study. Clinicopathological features and some laboratory tests were recorded. GITR, CD4, CD8, and FOXP3 were evaluated by immunohistochemistry (IHC) from biopsies or nephrectomy material and recorded. The study included 41 patients. The median progression-free survival (PFS) was 10.5 months, and the median overall survival (OS) was 13.9 months. Median PFS was 7.9 months for the GITR-low group and 18.9 months for the GITR-high group. Median PFS was statistically significant and longer for the GITR-high group than the GITR-low group (p=0.003). When patients who received nivolumab in the 2nd line were evaluated, median PFS was found to be 5.7 months in the GITR-low group and 15.7 months in the GITR-high group. Median PFS was statistically significantly higher in the GITR-high group than in the GITR-low group (p=0.026). In patients with metastatic RCC, higher GITR was associated with better PFS. At the same time, in patients using nivolumab, better PFS was seen in the GITR high group. If supported by prospective studies, GITR can be used as both a prognostic and predictive marker.

Abstract CT123: Trial in progress: First-in-human immunotherapy-trio for advanced head and neck squamous cell carcinoma

Abstract Background: Glucocorticoid-Induced Tumor Necrosis Factor Receptor-related protein (GITR) is a co-stimulatory pathway that when triggered has potent effects on T-cell memory, proliferation and anti-tumor activity. Preclinical models identified significant synergy between anti-GITR agonist therapy and cancer vaccines to generate stronger tumor specific CD8 T cell responses. DPV-001 is an “off-the-shelf” multivalent autophagosome vaccine generated by in vitro manipulation of the autophagy pathway in human cancer cell lines. The vaccine delivers short-lived proteins (SLiPs) and defective ribosomal products (DRiPs) which are likely the dominant epitopes directly presented by MHC class I of tumor cells; but because of proteosomal degradation, are normally unavailable for cross-presentation, hence the delivery via vaccine. We hypothesize that addition of aGITR to DPV-001 vaccine will augment expansion of reactive CD4 and CD8 T cells, attenuate contraction of this response, and improve the therapeutic effect of treatment, and will result in the development of a coordinated T and B cell response to some of the same proteins, detectable using a cutting-edge seromics approach, as a window to TCR target identification for immunodynamic tracking of induced anti-cancer responses at an advanced level. Methods: Patient recruitment began in August 2022, for this first-in-human immunotherapy-trio study of DPV-001, with sequenced checkpoint inhibition (aPD-1 mAb; retifanlimab), with or without aGITR agonist mAb (INCAGN-1949), in recurrent or metastatic HNSCC (NCT04470024). Patient population to include HPV-positive or HPV-negative, ECOG 0-2, with therapy continued until confirmed progression (RECIST 1.1), up to 2 years. Primary objective is safety, DLT ≤ 33%, with secondary efficacy objectives of ORR (PR+CR) and 2 year OS. Initial safety lead-in (n = 3+3 per arm), will be followed by phase Ib expansion of one/both arms if immunologically promising, 28 patients per arm, futility if <4/15 responses. Study Drugs Cyclophosphamide 300mg/m2 IV, priming Day (-2) onlyVaccine (DPV-001)- Day 1 intranodal US bilateral inguinal- Days 8,15 intradermal, then q2wks to week 22- Thereafter q4wks until progression, up to 2 yearsaPD-1 (retifanlimab) 500mg IV q4wks, start Day 15 (Arms 1 & 2)aGITR (INCAGN01876) 300mg IV q2wks, start Day 1 (Arm 2 only) Response (RECIST 1.1) CT weeks 8 and 12, then q3mos Immunologic Monitoring PBL and sera are collected regularly and PBL are evaluated by flow cytometry. Biopsies obtained at baseline, Day 15 and Day 57, analyzed by mIF and 10x scRNA-Seq. Sera analyzed by phage immunoprecipitation (PhIP) sequencing for reactivity against the human proteome. Immune monitoring modifications that allow for improved characterization of immune cell subsets will be presented. Citation Format: Marcus A. Couey, Matthew Taylor, Tarsem Moudgil, Yoshinobu Koguchi, Anne Stadum, Tanisha Christie, William L. Redmond, Christopher Paustian, Ryan Meng, Venkatesh Rajamanickam, Lessli Rushforth, Abigail Peterson, Brady Bernard, Richard B. Bell, Carlo B. Bifulco, Traci L. Hilton, Shawn M. Jensen, Hong-Ming Hu, Brian Piening, Walter J. Urba, Bernard A. Fox, Rom S. Leidner. Trial in progress: First-in-human immunotherapy-trio for advanced head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT123.

Pharmacodynamic activity of BMS-986156, a glucocorticoid-induced TNF receptor-related protein agonist, alone or in combination with nivolumab in patients with advanced solid tumors

The success of immune checkpoint inhibitors has revolutionized cancer treatment options and triggered development of new complementary immunotherapeutic strategies, including T-cell co-stimulatory molecules, such as glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR). BMS-986156 is a fully agonistic human immunoglobulin G subclass 1 monoclonal antibody targeting GITR. We recently presented the clinical data for BMS-986156 with or without nivolumab, which demonstrated no compelling evidence of clinical activity in patients with advanced solid tumors. Here, we further report the pharmacodynamic (PD) biomarker data from this open-label, first-in-human, phase I/IIa study of BMS-986156 ± nivolumab in patients with advanced solid tumors (NCT02598960). We analyzed PD changes of circulating immune cell subsets and cytokines in peripheral blood or serum samples collected from a dataset of 292 patients with solid tumors before and during treatment with BMS-986156 ± nivolumab. PD changes in the tumor immune microenvironment were measured by immunohistochemistry and a targeted gene expression panel. BMS-986156+ nivolumab induced a significant increase in peripheral T-cell and natural killer (NK) cell proliferation and activation, accompanied by production of proinflammatory cytokines. However, no significant changes in expression of CD8A, programmed death-ligand 1, tumor necrosis factor receptor superfamily members, or key genes linked with functional parameters of T and NK cells were observed in tumor tissue upon treatment with BMS-986156. Despite the robust evidence of peripheral PD activity of BMS-986156, with or without nivolumab, limited evidence of T- or NK cell activation in the tumor microenvironment was observed. The data therefore explain, at least in part, the lack of clinical activity of BMS-986156 with or without nivolumab in unselected populations of cancer patients.

GITR Ligation Improves Anti-PD1-Mediated Restoration of Human MMR-Proficient Colorectal Carcinoma Tumor-Derived T Cells.

In contrast to mismatch repair deficient colorectal carcinoma (CRC), MMR proficient (pMMR) CRC does not respond to immune checkpoint blockade. We studied immune checkpoint stimulation via glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) on exvivo functionality of human tumor-infiltrating lymphocytes (TIL) isolated from pMMR primary CRC and liver metastases (CRLM). Using lymphocytes from resected tumor, adjacent tissues, and peripheral blood mononuclear cells (PBMC) of 132 pMMR primary CRC or CRLM patients, we determined GITR expression and the invitro T-cell agonistic activity of recombinant GITR ligation. Here, we show that GITR was overexpressed on TIL when compared with other stimulatory immune checkpoints (4-1BB, OX40). Its expression was enhanced in TIL compared with PBMC and adjacent tissues. Among CD4+ TIL, GITR expression was primarily expressed by CD45RA- FoxP3hi activated regulatory T cells. Within CD8+ TIL, GITR was predominantly expressed on functionally exhausted and putative tumor-reactive CD103+ CD39+ TIL. Strikingly, recombinant GITRL reinvigorated exvivo TIL responses by significantly enhancing CD4+ and CD8+ TIL numbers. Dual treatment with GITRL and nivolumab (anti-PD1) enhanced CD8+ TIL expansion compared with GITRL monotherapy. Moreover, GITRL/anti-PD1 dual therapy further improved anti-PD1-mediated reinvigoration of interferon gamma secretion by exhausted CD8 TIL from primary CRC. GITR is overexpressed on CD4+ and CD8+ TIL from pMMR CRC and CRLM. Agonistic targeting of GITR enhances exvivo human TIL functionality and may therefore be a promising approach for novel monotherapy or combined immunotherapies in primary pMRR CRC and CRLM.

196TiP A phase I study of REGN6569, a GITR monoclonal antibody (mAb), in combination with cemiplimab in patients with advanced solid tumour malignancies

REGN6569 is a fully human immunoglobulin G1 mAb that is highly specific for glucocorticoid-induced tumour necrosis factor receptor–related protein (GITR). GITR is expressed on several immune cell subtypes, notably regulatory T cells (Tregs). REGN6569 has demonstrated in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) with greater cytotoxicity against GITR expressing Tregs than CD8+ T cells. GITR mAbs have shown preclinical antitumour efficacy. Anti-GITR and anti–programmed cell death-1 (PD-1) combination therapy has synergistic biological activity and may optimise immune checkpoint inhibitor (ICI) treatment in patients with advanced solid tumours.

EP16.01-024 Differential Efficacy of Combined GITR Co-stimulation with PD-1 Blockade in Preclinical Non-small Cell Lung Cancer Models

Lung cancer remains as the most lethal cancer disease in Hong Kong. Although blockade of inhibitory immune checkpoints achieved remarkable clinical outcomes, continuous efforts are being made to explore novel therapeutic strategies. We have previously found that anti-programmed cell death protein 1 (anti-PD-1) induced systemic and intra-tumoral upregulation of an immunoregulatory molecule, glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) in a subcutaneous murine lung cancer model.

Combinations of anti-GITR antibody and CD28 superagonist induce permanent allograft acceptance by generating type 1 regulatory T cells.

Type 1 regulatory T (Tr1) cells represent a subset of IL-10–producing CD4+Foxp3− T cells and play key roles in promoting transplant tolerance. However, no effective pharmacological approaches have been able to induce Tr1 cells in vivo. We herein report the combined use of a CD28 superagonist (D665) and anti–glucocorticoid-induced tumor necrosis factor receptor–related protein monoclonal antibody (G3c) to induce Tr1 cells in vivo. Large amounts of IL-10/interferon-γ–co-producing CD4+Foxp3− Tr1 cells were generated by D665-G3c sequential treatment in mice. Mechanistic studies suggested that D665-G3c induced Tr1 cells via transcription factors Prdm1 and Maf. G3c contributed to Tr1 cell generation via the activation of mitogen-activated protein kinase–signal transducer and activator of transcription 3 signaling. Tr1 cells suppressed dendritic cell maturation and T cell responses and mediated permanent allograft acceptance in fully major histocompatibility complex–mismatched mice in an IL-10–dependent manner. In vivo Tr1 cell induction is a promising strategy for achieving transplant tolerance.

Cyclophosphamide enhances the antitumor potency of GITR engagement by increasing oligoclonal cytotoxic T cell fitness

Only a subset of cancer patients responds to checkpoint blockade inhibition in the clinic. Strategies to overcome resistance are promising areas of investigation. Targeting glucocorticoid-induced tumor necrosis factor receptor–related protein (GITR) has shown efficacy in preclinical models, but GITR engagement is ineffective in controlling advanced, poorly immunogenic tumors, such as B16 melanoma, and has not yielded benefit in clinical trials. The alkylating agent cyclophosphamide (CTX) depletes regulatory T cells (Tregs), expands tumor-specific effector T cells (Teffs) via homeostatic proliferation, and induces immunogenic cell death. GITR agonism has an inhibitory effect on Tregs and activates Teffs. We therefore hypothesized that CTX and GITR agonism would promote effective antitumor immunity. Here we show that the combination of CTX and GITR agonism controlled tumor growth in clinically relevant mouse models. Mechanistically, we show that the combination therapy caused tumor cell death, clonal expansion of highly active CD8+ T cells, and depletion of Tregs by activation-induced cell death. Control of tumor growth was associated with the presence of an expanded population of highly activated, tumor-infiltrating, oligoclonal CD8+ T cells that led to a diminished TCR repertoire. Our studies show that the combination of CTX and GITR agonism is a rational chemoimmunotherapeutic approach that warrants further clinical investigation.

First-in-human phase I/Ib open-label dose-escalation study of GWN323 (anti-GITR) as a single agent and in combination with spartalizumab (anti-PD-1) in patients with advanced solid tumors and lymphomas

BackgroundGWN323 is an IgG1 monoclonal antibody (mAb) against the glucocorticoid-induced tumor necrosis factor receptor-related protein. This first-in-human, open-label phase I/Ib study aimed to investigate the safety and tolerability and to...

Research advances in the role of the glucocorticoid-induced tumor necrosis factor receptor-related protein and its ligand in liver diseases

Glucocorticoid-induced tumor necrosis factor receptor (GITR) is a member of the tumor necrosis factor receptor superfamily, and after it specifically binds to GITR ligand (GITRL), the downstream signals mediated by them can not only serve as a costimulatory molecule to promote the proliferation and cytokine secretion of effector T cells, but also affect the proliferation of regulatory T cells and inhibit the function of effector T cells, thereby regulating the inflammatory response and tumor cell-killing effect of effector T cells. GITRL is mainly expressed in antigen- presenting cells and has an intracellular domain, and the binding of GITRL to GITR can affect the function of antigen-presenting cells via receptor/ligand reverse signaling. In liver diseases, GITRL/GITR signal is not only involved in immune rejection after liver transplantation and gene therapy, but also associated with the formation of tumor immune microenvironment and the immune escape of tumor. Further studies are needed to explore the role of GITRL/GITR in the development and progression of other liver diseases.

Structures of mouse and human GITR\u2013GITRL complexes reveal unique TNF superfamily interactions

Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) and GITR ligand (GITRL) are members of the tumor necrosis superfamily that play a role in immune cell signaling, activation, and survival. GITR is a therapeutic target for directly activating effector CD4 and CD8 T cells, or depleting GITR-expressing regulatory T cells (Tregs), thereby promoting anti-tumor immune responses. GITR activation through its native ligand is important for understanding immune signaling, but GITR structure has not been reported. Here we present structures of human and mouse GITR receptors bound to their cognate ligands. Both species share a receptor–ligand interface and receptor–receptor interface; the unique C-terminal receptor–receptor enables higher order structures on the membrane. Human GITR–GITRL has potential to form a hexameric network of membrane complexes, while murine GITR–GITRL complex forms a linear chain due to dimeric interactions. Mutations at the receptor–receptor interface in human GITR reduce cell signaling with in vitro ligand binding assays and minimize higher order membrane structures when bound by fluorescently labeled ligand in cell imaging experiments.

Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy

The two T cell inhibitory receptors PD-1 and TIM-3 are co-expressed during exhausted T cell differentiation, and recent evidence suggests that their crosstalk regulates T cell exhaustion and immunotherapy efficacy; however, the molecular mechanism is unclear. Here we show that PD-1 contributes to the persistence of PD-1+TIM-3+ T cells by binding to the TIM-3 ligand galectin-9 (Gal-9) and attenuates Gal-9/TIM-3-induced cell death. Anti-Gal-9 therapy selectively expands intratumoral TIM-3+ cytotoxic CD8 T cells and immunosuppressive regulatory T cells (Treg cells). The combination of anti-Gal-9 and an agonistic antibody to the co-stimulatory receptor GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein) that depletes Treg cells induces synergistic antitumor activity. Gal-9 expression and secretion are promoted by interferon β and γ, and high Gal-9 expression correlates with poor prognosis in multiple human cancers. Our work uncovers a function for PD-1 in exhausted T cell survival and suggests Gal-9 as a promising target for immunotherapy.

Characterization of the Cell Surface Phenotype and Regulatory Activity of B-Cell IgD Low (BDL) Regulatory B Cells.

B-cell IgD Low (BDL) B cells have been shown to promote immunological tolerance by inducing proliferation of CD4+Foxp3+ T-regulatory cells (Treg) in a glucocorticoid-induced tumor necrosis factor receptor-related protein ligand (GITRL, Tnfsf18)-dependent manner. BDL cells constitute a small subset of splenic B lymphocytes that, in mice, are characterized by the B220+IgMintCD21intCD23+CD93-IgDlow/- cell surface expression profile. In this chapter, we show the flow cytometry gating strategy developed to identify and purify BDL. In addition, we describe an in vitro assay and two in vivo assays to assess BDL regulatory activity by quantitating Treg expansion/proliferation and indicate how they can be used in mouse models of disease. Collectively, these methods are useful to track and quantitate BDL and Treg numbers and assess their regulatory activity in inflammatory disease models.

Sectm1a Facilitates Protection against Inflammation-Induced Organ Damage through Promoting TRM Self-Renewal

Tissue-resident macrophages (TRMs) are sentinel cells for maintaining tissue homeostasis and organ function. In this study, we discovered that lipopolysaccharide (LPS) administration dramatically reduced TRM populations and suppressed their self-renewal capacities in multiple organs. Using loss- and gain-of-function approaches, we define Sectm1a as a novel regulator of TRM self-renewal. Specifically, at the earlier stage of endotoxemia, Sectm1a deficiency exaggerated acute inflammation-induced reduction of TRM numbers in multiple organs by suppressing their proliferation, which was associated with more infiltrations of inflammatory monocytes/neutrophils and more serious organ damage. By contrast, administration of recombinant Sectm1a enhanced TRM populations and improved animal survival upon endotoxin challenge. Mechanistically, we identified that Sectm1a-induced upregulation in the self-renewal capacity of TRM is dependent on GITR-activated T helper cell expansion and cytokine production. Meanwhile, we found that TRMs may play an important role in protecting local vascular integrity during endotoxemia. Our study demonstrates that Sectm1a contributes to stabling TRM populations through maintaining their self-renewal capacities, which benefits the host immune response to acute inflammation. Therefore, Sectm1a may serve as a new therapeutic agent for the treatment of inflammatory diseases.

GITR Agonism Triggers Antitumor Immune Responses through IL21-Expressing Follicular Helper T Cells.

Although treatment with the glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) agonistic antibody (DTA-1) has shown antitumor activity in various tumor models, the underlying mechanism is not fully understood. Here, we demonstrate that interleukin (IL)-21-producing follicular helper T (Tfh) cells play a crucial role in DTA-1-induced tumor inhibition. The administration of DTA-1 increased IL21 expression by Tfh cells in an antigen-specific manner, and this activation led to enhanced antitumor cytotoxic T lymphocyte (CTL) activity. Mice treated with an antibody that neutralizes the IL21 receptor exhibited decreased antitumor activity when treated with DTA-1. Tumor growth inhibition by DTA-1 was abrogated in Bcl6 fl/fl Cd4 Cre mice, which are genetically deficient in Tfh cells. IL4 was required for optimal induction of IL21-expressing Tfh cells by GITR costimulation, and c-Maf mediated this pathway. Thus, our findings identify GITR costimulation as an inducer of IL21-expressing Tfh cells and provide a mechanism for the antitumor activity of GITR agonism.

Biological role of GITR/GITRL in attributes and immune responses of macrophage.

Glucocorticoid-induced tumor necrosis factor receptor family-related protein ligand (GITRL), a member of the tumor necrosis factor superfamily, is expressed in APCs and acts as a costimulatory molecule in the immune system. Although the glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR)/GITRL system has been modulated to promote or decrease T cell-related responses in multiple diseases, studies in macrophages are limited. To address this issue, we compared the expression of GITRL in various types of macrophages and analyzed whether GITRL can affect the fundamental properties and major functions of these cells. Our results demonstrated that M1 polarized macrophages had the highest GITRL levels. Furthermore, GITRL overexpression skewed macrophage polarization toward the M1 phenotype, accelerating proliferation and migration and regulating phagocytosis and killing function. Moreover, GITRL-silenced cells showed a loss of these functions, further confirming its vital role. We also developed an acute peritonitis mouse model, in which macrophages were driven to differentiate into a proinflammatory phenotype with GITRL up-regulation, triggering a positive feedback loop. Our results provide molecular insight into how the GITR/GITRL system modulates innate immune responses, suggesting that manipulation of the GITR/GITRL system to treat diseases depends not only on T cell regulation but also on macrophage participation.

Safety, Tolerability, and Potential Clinical Activity of a Glucocorticoid-Induced TNF Receptor–Related Protein Agonist Alone or in Combination With Nivolumab for Patients With Advanced Solid Tumors

Multiple immunostimulatory agonist antibodies have been clinically tested in solid tumors to evaluate the role of targeting glucocorticoid-induced tumor necrosis factor (TNF) receptor-related protein in anticancer treatments. To evaluate the safety and activity of the fully human glucocorticoid-induced TNF receptor-related protein agonist IgG1 monoclonal antibody BMS-986156 with or without nivolumab in patients with advanced solid tumors. This global, open-label, phase 1/2a study of BMS-986156 with or without nivolumab enrolled 292 patients 18 years or older with advanced solid tumors and an Eastern Cooperative Oncology Group performance status of 1 or less. Prior checkpoint inhibitor therapy was allowed. Monotherapy and combination dose-escalation cohorts ran concurrently to guide expansion doses beginning October 16, 2015; the study is ongoing. The protein agonist BMS-986156 was administered intravenously at a dose of 10, 30, 100, 240, or 800 mg every 2 weeks as monotherapy, and in the combination group 30, 100, 240, or 800 mg plus 240 mg of nivolumab every 2 weeks; same-dose cohorts were pooled for analysis. One cohort also received 480 mg of BMS-986156 plus 480 mg of nivolumab every 4 weeks. The primary end points were safety, tolerability, and dose-limiting toxic effects. Additional end points included antitumor activity per Response Evaluation Criteria in Solid Tumors, version 1.1, and exploratory biomarker analyses. With a follow-up range of 1.4 to 101.7 weeks (follow-up ongoing), 34 patients (16 women and 18 men; median age, 56.6 years [range, 28-75 years]) received monotherapy (4 patients completed initial treatment), and 258 patients (140 women and 118 men; median age, 60 years [range, 21-87 years]) received combination therapy (65 patients completed initial treatment). No grade 3 to 5 treatment-related adverse events occurred with BMS-986156 monotherapy; grade 3 to 4 treatment-related adverse events occurred in 24 patients (9.3%) receiving BMS-986156 plus nivolumab, with no grade 5 treatment-related adverse events. One dose-limiting toxic effect (grade 4 elevated creatine phosphokinase levels) occurred in a patient receiving 800 mg of BMS-986156 plus 240 mg of nivolumab every 2 weeks; BMS-986156 with or without nivolumab exhibited linear pharmacokinetics with dose-related increase after a single dose. Peripheral T-cell and natural killer-cell proliferation increased after administration of BMS-986156 with or without nivolumab. No consistent and significant modulation of intratumoral CD8+ T cells and FoxP3+ regulatory T cells was observed. No responses were seen with BMS-986156 alone; objective response rates ranged from 0% to 11.1% (1 of 9) across combination therapy cohorts, with a few responses observed in patients previously treated with anti-programmed death receptor (ligand) 1 therapy. Based on this cohort, BMS-986156 appears to have had a manageable safety profile, and BMS-986156 plus nivolumab demonstrated safety and efficacy comparable to historical data reported for nivolumab monotherapy. ClinicalTrials.gov identifier: NCT02598960.

GITR agonism triggers antitumor immune responses through IL-21–expressing follicular helper T cells

Abstract Treatment with glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) agonistic antibody (DTA-1) elicits potent antitumor immune responses in various tumor models. In this study, we demonstrate the crucial role of interleukin (IL)-21–producing follicular helper T (Tfh) cells in DTA-1-induced tumor inhibition. Administration of DTA-1 increased IL-21 expression from CD4 T cells, which is mainly made up of Tfh cells, in an antigen specific manner. Furthermore, mice treated with a neutralizing antibody to IL-21 receptor and Bcl6fl/flCD4cre mice exhibited abrogated antitumor activity induced by DTA-1. Mechanistically, IL-4 plays critical roles for the induction of IL-21–expressing Th cells by GITR co-stimulation, which is mediated by Bcl6 and c-Maf. Thus, our findings identify GITR co-stimulation as an inducer of IL-21–expressing Tfh cells and provide a novel mechanism for its antitumor activity.

The distribution of T‐cell subsets and the expression of immune checkpoint receptors and ligands in patients with newly diagnosed and relapsed acute myeloid leukemia

BackgroundPhenotypic characterization of immune cells in the bone marrow (BM) of patients with acute myeloid leukemia (AML) is lacking.MethodsT‐cell infiltration was quantified on BM biopsies from 13 patients with AML, and flow cytometry was performed on BM aspirates (BMAs) from 107 patients with AML who received treatment at The University of Texas MD Anderson Cancer Center. The authors evaluated the expression of inhibitory receptors (programmed cell death protein 1 [PD1], cytotoxic T‐lymphocyte antigen 4 [CTLA4], lymphocyte‐activation gene 3 [LAG3], T‐cell immunoglobulin and mucin‐domain containing‐3 [TIM3]) and stimulatory receptors (glucocorticoid‐induced tumor necrosis factor receptor‐related protein [GITR], OX40, 41BB [a type 2 transmembrane glycoprotein receptor], inducible T‐cell costimulatory [ICOS]) on T‐cell subsets and the expression of their ligands (41BBL, B7‐1, B7‐2, ICOSL, PD‐L1, PD‐L2, and OX40L) on AML blasts. Expression of these markers was correlated with patient age, karyotype, baseline next‐generation sequencing for 28 myeloid‐associated genes (including P53), and DNA methylation proteins (DNA methyltransferase 3α, isocitrate dehydrogenase 1[IDH1], IDH2, Tet methylcytosine dioxygenase 2 [TET2], and Fms‐related tyrosine kinase 3 [FLT3]).ResultsOn histochemistry evaluation, the T‐cell population in BM appeared to be preserved in patients who had AML compared with healthy donors. The proportion of T‐regulatory cells (Tregs) in BMAs was higher in patients with AML than in healthy donors. PD1‐positive/OX40‐positive T cells were more frequent in AML BMAs, and a higher frequency of PD1‐positive/cluster of differentiation 8 (CD8)‐positive T cells coexpressed TIM3 or LAG3. PD1‐positive/CD8‐positive T cells were more frequent in BMAs from patients who had multiply relapsed AML than in BMAs from those who had first relapsed or newly diagnosed AML. Blasts in BMAs from patients who had TP53‐mutated AML were more frequently positive for PD‐L1.ConclusionsThe preserved T‐cell population, the increased frequency of regulatory T cells, and the expression of targetable immune receptors in AML BMAs suggest a role for T‐cell–harnessing therapies in AML.