A new technology has shown promise in treating several types of tumors in mice that do not respond to cancer immunotherapy medications called checkpoint inhibitors.
Results from tests of the so-called Y-trap technology were reported in the article, “Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy,” that was published in the journal Nature Communications.
Y-traps target the same proteins as existing checkpoint inhibitors: cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1)/PD-1 ligand (PD-L1). These proteins are known to help certain white blood cell, called Tregs, suppress anti-tumor immune responses.
In this way, checkpoint inhibitors are expected to free the immune system to attack and kill tumor cells. However, in practice, checkpoint inhibitors work only in some cancer patients.
“The immune system is naturally able to detect and eliminate tumor cells. However, virtually all cancers — including the most common cancers, from lung, breast and colon cancers to melanomas and lymphomas — evolve to counteract and defeat such immune surveillance by co-opting and amplifying natural mechanisms of immune suppression,” Atul Bedi, MD, senior author of the study, said in a press release. Bedi is an associate professor of otolaryngology, head and neck surgery at the Johns Hopkins University School of Medicine.
Y-traps are different from checkpoint inhibitors because they also bind and neutralize transforming growth factor beta (TGFbeta) in addition to CTLA-4 or PD-1/PD-L1. TGFbeta is a protein that induces the activity of Tregs and inhibits anti-tumor immune cells. Y-traps are designed to enhance the body’s own immune response to tumors even more than the existing checkpoint inhibitors by trapping TGFbeta and inhibiting its activity. Y-traps are designed to fight many different kinds of cancer.
One kind of Y-trap tested in mice is made of an antibody to CTLA-4 containing a TGFbeta “trap” in it. After transplanting human cancer cells into mice, the researchers found that their Y-trap eliminated Tregs in tumors and slowed the growth of tumors that had failed to respond to Yervoy (ipilimumab), a checkpoint inhibitor that also targets CTLA-4.
Then they designed a Y-trap that targets PD-L1 and traps TGFbeta. They found that their Y-trap works better than the checkpoint inhibitors Tecentriq (atezolizumab) or Bavencio (avelumab) that also target PD-L1. This Y-trap slowed the growth of tumors that had not responded to these medications.
“These first-in-class Y-traps are just the beginning. We have already invented a whole family of these multifunctional molecules based on the Y-trap technology. Since mechanisms of immune dysfunction are shared across many types of cancer, this approach could have broad impact for improving cancer immunotherapy,” said Bedi. “Y-traps could also provide a therapeutic strategy against tumors that resist current immune checkpoint inhibitors.”
