New class of immunotherapy targets found in pancreatic and other cancers

For patients with pancreatic cancer, the benefits from immunotherapy treatments with immune checkpoint inhibitors or cell therapies have been limited so far. This is partly because pancreatic cancers create an environment that blocks an effective immune response. Also, these tumors have few neoantigens, or mutant proteins, which normally allow the immune system to recognize them as unhealthy cells.

But MD Anderson researchers have discovered a new target, called Vestigial-like 1 (VGLL1), in pancreatic cancers as well as bladder, breast, stomach, lung and ovarian cancers, which could enable innovative immunotherapy approaches in these cancers. The study was published in Nature Communications.

VGLL1 represents the first of a new class of tumor target, called cancer-placenta antigens. These are found at high levels in tumors, but in healthy tissues they’re normally found only in the placenta. This makes them attractive immunotherapy targets, explains Gregory Lizée, Ph.D., corresponding author on the study.

“That’s a key when developing tumor-specific therapies. You want to have the target present in large amounts in the tumor but not in normal cells, so you don’t create autoimmune toxicities,” he says.

Based on this study, the researchers are planning a clinical trial to evaluate a form of immunotherapy called endogenous T cell therapy, in order to target VGLL1 in certain patients with these cancers.

Identifying immunotherapy targets by analyzing patient tumors

Lizée and his laboratory team have long been interested in identifying new cancer-specific targets like VGLL1. Through a collaboration with the Pancreatic Cancer Moon Shot®, part of MD Anderson’s Moon Shots Program®, the group analyzed patients’ tumors to develop vaccines that could be used to treat cancer.

For these vaccines, they looked for cancer-specific protein fragments, or peptides, using a technique called mass spectrometry. These same cancer peptides could then be used in a vaccine to train the immune system to recognize and attack the tumor.

As part of this work, the researchers identified peptides from the VGLL1 protein in multiple patients.

“As we looked into it, we thought VGLL1 looked like a very interesting target in cancer, particularly pancreatic cancer where we don’t have many useful targets,” says Lizée.

In addition to being preferentially found in cancers compared with most normal tissues, increased levels of VGLL1 were associated with worse patient outcomes. This suggested that the protein plays some role that enables the cancers to be more aggressive.

Developing cancer therapies targeting VGLL1

Endogenous T cell therapy is a treatment approach pioneered by Cassian Yee, M.D., also a corresponding author on the study.

The process begins by collecting T cells from the blood of a patient. Then, in the laboratory, researchers isolate those T cells that recognize specific targets on the tumor. After that, they perform very complex procedures to expand those cells to a large number before giving the tumor-specific T cells back to the patient in an infusion.

In this study, Yee and his team were able to isolate T cells that recognized VGLL1 from the blood of patients. In the laboratory, those cells were effective at killing cultured cancer cells from a variety of cancer types.

“These results suggest that targeting VGLL1 is a compelling strategy for developing treatment approaches across multiple cancer types,” says Yee. “We are particularly excited to evaluate endogenous T cell therapies as an innovative option for patients without current immunotherapy options.”

Researchers led by Yee are now designing a clinical trial to evaluate this treatment strategy in patients whose tumors express VGLL1.

Searching for new cancer-placenta antigens

While the current study only reports on the discovery of VGLL1, defining this new class of tumor antigens offers the opportunity to find other therapeutic targets. The researchers are now actively searching for new cancer-placenta antigens that could be leveraged in new therapies.

They’re also trying to better understand how VGLL1 contributes to cancer development. Understanding this may help to clarify why these targets found normally only in the placenta are turned on in cancer cells -- and why VGLL1 contributes to a worse prognosis. These discoveries could open up even more avenues for drug development.

“This is really defining a new category of tumor targets,” says Lizée. “We’re excited about pursuing therapies for this class of antigens, both in pancreatic and other cancers, here at MD Anderson.”

More information about the paper, including collaborators, funding support and disclosures can be found here.

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