Phase IB Study of GITR Agonist Antibody TRX518 Singly and in Combination with Gemcitabine, Pembrolizumab, or Nivolumab in Patients with Advanced Solid Tumors

Davar, Diwakar; Zappasodi, Roberta; Wang, Hong; Naik, Girish S.; Sato, Takami; Bauer, Todd M.; Bajor, David L.; Rixe, Olivier; Newman, Walter; Qi, Jingjing; Holland, Aliya; Wong, Phillip; Sifferlen, Lianna; Piper, Diane; Sirard, Cynthia A.; Merghoub, Taha; Wolchok, Jedd D.; Luke, Jason J.

doi:10.1158/1078-0432.ccr-22-0339

Cited by 22 publications

(13 citation statements)

References 62 publications

(94 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The data demonstrated that T cell reinvigoration with PD-1 blockade can overcome resistance of advanced tumours to anti-GITR monotherapy [ 528 ]. Another phase Ib study using the GITR agonist (TRX518) alone and in combination with gemcitabine, pembrolizumab or nivolumab showed that TRX518 monotherapy + anti-PD1 combination was associated with intratumoral T regs reductions and CD8 + increases and activation in patients with advanced solid tumours [ 529 ]. The safety, tolerability and potential clinical activity of a GITR agonist (BMS-986156) alone or in combination with nivolumab in patients with advanced solid tumours was also a focus of a phase I/IIa dose-escalation and cohort-extension clinical trial (NCT02598960).…”

Section: Resultsmentioning

confidence: 99%

The Role of Different Immunocompetent Cell Populations in the Pathogenesis of Head and Neck Cancer—Regulatory Mechanisms of Pro- and Anti-Cancer Activity and Their Impact on Immunotherapy

Starska

2023

Cancers

View full text Add to dashboard Cite

Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive and heterogeneous groups of human neoplasms. HNSCC is characterized by high morbidity, accounting for 3% of all cancers, and high mortality with ~1.5% of all cancer deaths. It was the most common cancer worldwide in 2020, according to the latest GLOBOCAN data, representing the seventh most prevalent human malignancy. Despite great advances in surgical techniques and the application of modern combinations and cytotoxic therapies, HNSCC remains a leading cause of death worldwide with a low overall survival rate not exceeding 40–60% of the patient population. The most common causes of death in patients are its frequent nodal metastases and local neoplastic recurrences, as well as the relatively low response to treatment and severe drug resistance. Much evidence suggests that the tumour microenvironment (TME), tumour infiltrating lymphocytes (TILs) and circulating various subpopulations of immunocompetent cells, such regulatory T cells (CD4+CD25+Foxp3+Tregs), cytotoxic CD3+CD8+ T cells (CTLs) and CD3+CD4+ T helper type 1/2/9/17 (Th1/Th2/Th9/Th17) lymphocytes, T follicular helper cells (Tfh) and CD56dim/CD16bright activated natural killer cells (NK), carcinoma-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), tumour-associated neutrophils (N1/N2 TANs), as well as tumour-associated macrophages (M1/M2 phenotype TAMs) can affect initiation, progression and spread of HNSCC and determine the response to immunotherapy. Rapid advances in the field of immuno-oncology and the constantly growing knowledge of the immunosuppressive mechanisms and effects of tumour cancer have allowed for the use of effective and personalized immunotherapy as a first-line therapeutic procedure or an essential component of a combination therapy for primary, relapsed and metastatic HNSCC. This review presents the latest reports and molecular studies regarding the anti-tumour role of selected subpopulations of immunocompetent cells in the pathogenesis of HNSCC, including HPV+ve (HPV+) and HPV−ve (HPV−) tumours. The article focuses on the crucial regulatory mechanisms of pro- and anti-tumour activity, key genetic or epigenetic changes that favour tumour immune escape, and the strategies that the tumour employs to avoid recognition by immunocompetent cells, as well as resistance mechanisms to T and NK cell-based immunotherapy in HNSCC. The present review also provides an overview of the pre- and clinical early trials (I/II phase) and phase-III clinical trials published in this arena, which highlight the unprecedented effectiveness and limitations of immunotherapy in HNSCC, and the emerging issues facing the field of HNSCC immuno-oncology.

show abstract

Section: Resultsmentioning

confidence: 99%

The Role of Different Immunocompetent Cell Populations in the Pathogenesis of Head and Neck Cancer—Regulatory Mechanisms of Pro- and Anti-Cancer Activity and Their Impact on Immunotherapy

Starska

2023

Cancers

View full text Add to dashboard Cite

show abstract

“…For this reason, GITR represents an ideal targetable immunomodulatory receptor that could provide a powerful tool to diminish the suppressive potential of intratumoral Treg and enhance anti-tumor immunity. Of note, different clinical trials are testing GITR agonist antibodies in combination with immune checkpoint inhibitors in advanced tumors (92)(93)(94)(95). On this basis, considering the increased frequencies of NK and T cells expressing GITR, the use of agonistic GITR combined with blocking PD-1 and/or TIGIT antibodies could be beneficial in patients with HNSCC.…”

Section: Discussionmentioning

confidence: 99%

Impaired intratumoral natural killer cell function in head and neck carcinoma

Mele

Pessino²,

Trisolini³

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

Natural killer (NK) cells are emerging as unique players in the immune response against cancer; however, only limited data are available on tumor infiltrating NK cells in head and neck squamous cell carcinoma (HNSCC), one of the most common cancer. Occurrence of HNSCC is closely related to the immune microenvironment, and immunotherapy is increasingly being applied to this setting. However, the limited success of this type of treatment in this tumor calls for further investigation in the field.Surgical HNSSC specimens of 32 consecutive patients were mechanically and enzymatically dissociated. Tumor cells were separated from infiltrating cells by short centrifugation and infiltrating NK cells were phenotypically and functionally characterized by multiple antibody staining and flow cytometry. Tumor infiltrating NK cells in HNSCC showed a peculiar phenotype predominantly characterized by increased NKG2A and reduced Siglec-7, NKG2D, NKp30 and CD16 expression. This phenotype was associated with a decreased ability to perform antibody-dependent cellular cytotoxicity (ADCC). However, NK, CD4 and CD8 shared an increment of glucocorticoid-induced tumor necrosis factor-related (GITR) costimulatory receptor which could be exploited for immunotherapy with agonistic anti-GITR antibodies combined with checkpoint inhibitors.

show abstract

“…TRX‐518 (also known as Tab6C8 in the manuscript), its murine surrogate mAb was shown effective in the B16 melanoma model with monotherapy (6C8, Leap Therapeutics, Cambridge, MA, USA; US20170137527 A1). TRX518 monotherapy and in combination showed limited clinical responses associated with immune activation in clinical studies [ 39 ]. Mouse GITR has been shown to signal effectively as a dimer while, in contrast, human GITR requires trimerization [ 40 , 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

Development of a fully human anti‐GITR antibody with potent antitumor activity using H2L2 mice

Tong

Liu²,

Qi³

et al. 2022

FEBS Open Bio

View full text Add to dashboard Cite

Glucocorticoid‐induced TNF receptor‐related (GITR) can act as a co‐stimulatory receptor, representing a potential target for safely enhancing immunotherapy efficacy. GITR is triggered by a GITR ligand or an agonist antibody and activates CD8 + and CD4 + effector T cells, reducing tumor‐infiltrating Treg numbers and resulting in activation of immune responses and tumor cell destruction by effector T cells. GITR is an attractive target for immunotherapy, especially in combination therapy with immune checkpoint inhibitors, as is being explored in clinical trials. Using H2L2 transgenic mice encoding the human immunoglobulin variable region and hybridoma technology, we generated a panel of fully human antibodies that showed excellent specific affinity and strong activation of human T cells. After conversion to fully human antibodies and engineering modification, we obtained an anti‐GITR antibody hab019e2 with enhanced antitumor activity in a B‐hGITR MC38 mouse model compared to Tab9H6V3, an anti‐GITR antibody that activates T cells and inhibits Treg suppression from XenoMouse. As a fully human antibody with its posttranslational modification hot spot removed, the hab019e2 antibody exerted more potent therapeutic effects, and may have potential as a novel and developable antibody targeting GITR for follow‐up drug studies.

show abstract

Phase IB Study of GITR Agonist Antibody TRX518 Singly and in Combination with Gemcitabine, Pembrolizumab, or Nivolumab in Patients with Advanced Solid Tumors

Cited by 22 publications

References 62 publications

The Role of Different Immunocompetent Cell Populations in the Pathogenesis of Head and Neck Cancer—Regulatory Mechanisms of Pro- and Anti-Cancer Activity and Their Impact on Immunotherapy

The Role of Different Immunocompetent Cell Populations in the Pathogenesis of Head and Neck Cancer—Regulatory Mechanisms of Pro- and Anti-Cancer Activity and Their Impact on Immunotherapy

Impaired intratumoral natural killer cell function in head and neck carcinoma

Development of a fully human anti‐GITR antibody with potent antitumor activity using H2L2 mice

Contact Info

Product

Resources

About