Targeting GITR in cancer immunotherapy - there is no perfect knowledge

Area of Science:

• Immunology
• Cancer Immunotherapy
• Molecular Biology

Background:

• Glucocorticoid-induced TNFR-related protein (GITR) is a member of the TNFR superfamily, crucial for modulating both acquired and innate immunity.
• GITR is expressed on immune cells like regulatory T cells (Tregs) and natural killer (NK) cells, influencing immune responses.
• Its role in promoting T effector function and inhibiting Treg-mediated suppression makes GITR a significant target for cancer immunotherapy.

Purpose of the Study:

• To explore the potential of GITR agonists as a cancer immunotherapy strategy.
• To analyze the discrepancy between promising preclinical data and disappointing clinical outcomes of GITR agonists.
• To investigate the impact of antibody structure, valency, and Fc functionality on anti-tumor efficacy.

Main Methods:

• Review of preclinical studies on GITR agonists in cancer models.
• Analysis of clinical trial data for GITR agonists.
• Mechanistic investigation into antibody-dependent cellular cytotoxicity (ADCC) and other effector functions.
• Exploration of structure-activity relationships for GITR agonists.

Main Results:

• Preclinical studies demonstrated potent anti-tumor efficacy of GITR agonists, both as monotherapy and in combination with agents like PD-1 blockade.
• Clinical trials with multiple GITR agonists have yielded disappointing results, contrasting with preclinical findings.
• Emerging mechanistic insights suggest that antibody characteristics (structure, valency, Fc functionality) play a critical role in mediating anti-tumor effects.

Conclusions:

• GITR remains an attractive target for cancer immunotherapy due to its immune-stimulating properties.
• The inconsistency between preclinical and clinical efficacy of GITR agonists may be explained by antibody-specific mechanisms.
• Further research into antibody design and Fc engineering is crucial for optimizing GITR-targeted cancer therapies.