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Rational design of anti-GITR-based combination immunotherapy
Roberta Zappasodi1,2, Cynthia Sirard3, Yanyun Li1,2
1Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nature Medicine
|May 1, 2019
Summary
Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) agonism alone did not yield significant clinical responses in advanced cancer patients. Combining GITR agonism with PD-1 blockade shows promise for overcoming tumor resistance by reinvigorating T cells.
Area of Science:
- Immunology
- Oncology
- Translational Medicine
Background:
- Immune checkpoint blockade enhances anti-tumor T cell responses but has limitations.
- Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) is a promising immunotherapy target for promoting effector T cells and reducing regulatory T cell suppression.
Purpose of the Study:
- To evaluate the safety and immune effects of the anti-GITR antibody TRX518 in patients with advanced cancer.
- To provide preclinical evidence for combining GITR agonism with checkpoint blockade.
Main Methods:
- Phase 1 clinical trial of TRX518 monotherapy in patients with advanced cancer.
- Preclinical studies in mice with advanced tumors to investigate mechanisms of resistance and combination strategies.
Main Results:
- TRX518 monotherapy reduced regulatory T cells (Tregs) in circulation and tumors, serving as a biomarker.
- Despite Treg reduction and increased effector T cell (Teff):Treg ratios, substantial clinical responses were not observed.
- In preclinical models, GITR agonism alone was insufficient to overcome tumor resistance due to T cell exhaustion; however, PD-1 blockade reinvigorated T cells and overcame resistance.
Conclusions:
- While TRX518 demonstrates immune modulation, monotherapy is insufficient for significant clinical benefit in advanced cancers.
- Combining GITR agonism with PD-1 blockade is a rational strategy to enhance anti-tumor immunity and overcome resistance in refractory tumors.
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