The researchers tested whether Y-traps would inhibit TGFβ-induced FOXP3 expression in human T cells, in vitro — and they did.3 They next tested Y-traps’ effect on Tregs in mice bearing human tumors. Treatment of tumor-bearing mice with the CTLA4-targeted Y-trap was significantly more effective at reducing tumor-infiltrating FOXP3+ expressing Tregs compared to ipilimumab, they reported, 3 That means that Y-traps counteract FOXP3-expressing Tregs in the TGFβ-enriched tumor microenvironment.3
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The team then sought to test the in vivo antitumor efficacy of Y-traps in human tumor̶bearing mice. The CTLA4-targeted Y-trap was significantly more effective in reducing and counteracting tumor-infiltrating Tregs, activating antitumor immunity, and inhibiting tumor progression than the anti-CTLA-4 antibody ipilimumab, the team concluded.3 Likewise, their PD-L1-targeted Y-trap that disables TGFβ, slowed the growth of tumors that did not respond to PD-L1 antibodies, avelumab, or atezolizumab, which are used in the clinic.3
“Our data demonstrate that Y-traps simultaneously disable immune checkpoints and counteract TGFβ-mediated differentiation of Tregs and immune tolerance, thereby providing a more effective immunotherapeutic strategy against cancers that fail to respond to current immune checkpoint inhibitors,” the team concluded.
Besides their promise for treatment of advanced metastatic cancers, Dr Bedi hopes to see Y-traps applied in a neoadjuvant setting. Treatment with Y-traps could induce an antitumor immune response that reduces the risk of relapse by eliminating residual tumor cells which survive chemotherapy, radiation therapy, or surgery.
The Y-trap paradigm is extremely versatile ― in addition to addressing the immunosuppressive lynchpin of Tregs, Dr Bedi and his team have leveraged the platform to construct a family of Y-traps that address the myriad of other ways in which cancers evade the immune system and induce immune tolerance. “We have developed Y-traps that address the most pressing mechanisms of immune dysfunction in cancer, including T cell exhaustion and tumor-promoting inflammation in the tumor microenvironment,” says Dr Bedi. Y-traps that surmount these hurdles could herald a new generation of cancer immunotherapeutics that leapfrog current immune checkpoint inhibitors.
References
- Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer. 2018;118:9-16. doi:10.1038/bjc.2017.434
- Syed V. TGF-β signaling in cancer. J Cell Biochem. 2016;117(6):1279-1287. doi:10.1002/jcb.25496
- Ravi R, Noonan KA, Pham V, et al. Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy. Nature Comm. 2018;9:741. doi:10.1038/s41467-017-02696-6
