Combined Therapy of PD-1 and CD73

Programmed death 1 (PD-1) is an immune checkpoint protein that negatively regulates T-cell immune function through the interaction with its ligand PD-L1. Blockage of this interaction unleashes the immune system to fight cancer. CD73 is a novel immunoinhibitory protein that plays a key role in tumor growth and metastasis. Owing to its multifaceted capacity for tumor promotion as an emerging immune checkpoint, CD73 is an ideal therapeutic target for cancer treatment, especially in combination with conventional therapy and/or other immune checkpoint inhibitors.

Fig.1 Co-targeting CD73 with other therapies. (Roh, 2020)

Case 1: Targeting CD73 Enhances the Anti-tumor Activity of Anti-PD-1 mAb

Anti-CD73 mAb significantly enhanced the activity of both anti-PD-1 mAb against subcutaneous tumors and established metastatic breast cancer. The combination anti-CD73/anti-PD-1 therapy might effectively abrogate tumor-promoting effects of Tregs. Alternatively, anti-CD73 mAb might block non-enzymatic functions of CD73, which might potentiate immune checkpoint blockade. The mechanism behind anti-CD73/anti-PD-1 mAb combination remains unclear and requires further investigation.

Case 2: Combined Therapy of PD-L1 and CD73 Promotes T Cell Response to EGFR Mutant NSCLC

It has been reported that EGFR mutant tumors (such as NSCLC) express more CD73 compared to EGFR wildtype tumors. In a previous study, scientists compared EGFR mutant cell lines and wildtype cell lines in the in vitro T cell killing assays. Besides, they also investigated the effect of anti-CD73 antibody, either as a monotherapy or in combination with anti-PD-L1 antibody, in promoting tumor growth inhibition using a xenograft mouse model. Mice treated with anti-CD73/anti-PD-L1 combination therapy had significantly smaller tumors compared to mice treated with isotype control, anti-PD-L1 alone or anti-CD73 alone. The combination therapy increased the number of MART1-specific CD8+ T cells in the tumor compared to isotype control, anti-PD-L1 alone and anti-CD73 alone. This combination therapy also increased the frequency of CD62L+ CD45RO+ CCR7+ phenotype in CD8+ T cells in the spleen.

Current CD73 Inhibitor in Clinical Trials

As table 1 shown, early phase trials investigating the merits of a combined anti-CD73/anti-PD1 therapies in patients with solid tumors are underway to ascertain whether or not targeting multiple sites in the pathway can show enhanced anti-tumor effects.

Tab.1 Selection of current CD73 inhibitor clinical trials. (Khair, 2019)

Targeted blockade of CD73 is another promising strategy to enhance the therapeutic activity of PD-1 inhibition. Creative Biolabs provides our customers with the comprehensive and high-quality immune checkpoint research services such as Immune Checkpoint Targeted Small Molecule Drug Development, Custom Immune Checkpoint Protein Development, and Immune Checkpoint Targeted Peptide Development. Welcome to contact us for project quotations and more detailed information.

References

1. Roh, M.; et al. Targeting CD73 to augment cancer immunotherapy. Current Opinion in Pharmacology. 2020, 53: 66-76.
2. Khair, D. O.; et al. Combining immune checkpoint inhibitors: established and emerging targets and strategies to improve outcomes in melanoma. Frontiers in immunology. 2019, 10: 453.

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