New drug combo shows early potential for treating pancreatic cancer
Researchers find three immunotherapy drugs given together can eliminate pancreatic tumors in mice.

Date:
August 6, 2021
Source:
Massachusetts Institute of Technology
Summary:
A team of researchers has developed an immunotherapy strategy
that can eliminate pancreatic tumors in mice. The new therapy, a
combination of three drugs that boost the body's immune defenses
against tumors, is expected to enter clinical trials later this
year.



FULL STORY ========================================================================== Pancreatic cancer, which affects about 60,000 Americans every year,
is one of the deadliest forms of cancer. After diagnosis, fewer than 10
percent of patients survive for five years.


========================================================================== While some chemotherapies are initially effective, pancreatic tumors
often become resistant to them. The disease has also proven difficult
to treat with newer approaches such as immunotherapy. However, a team
of MIT researchers has now developed an immunotherapy strategy and shown
that it can eliminate pancreatic tumors in mice.

The new therapy, which is a combination of three drugs that help boost
the body's own immune defenses against tumors, is expected to enter
clinical trials later this year.

"We don't have a lot of good options for treating pancreatic cancer. It's
a devastating disease clinically," says William Freed-Pastor, a senior
postdoc at MIT's Koch Institute for Integrative Cancer Research. "If
this approach led to durable responses in patients, it would make a
big impact in at least a subset of patients' lives, but we need to see
how it will actually perform in trials." Freed-Pastor, who is also a
medical oncologist at Dana-Farber Cancer Institute, is the lead author
of the new study, which appears today in Cancer Cell. Tyler Jacks, the
David H. Koch Professor of Biology and a member of the Koch Institute,
is the paper's senior author.

Immune attack The body's immune system contains T cells that can recognize
and destroy cells that express cancerous proteins, but most tumors create
a highly immunosuppressive environment that disables these T cells,
helping the tumor to survive.



========================================================================== Immune checkpoint therapy (the most common form of immunotherapy
currently being used clinically) works by removing the brakes on these
T cells, rejuvenating them so they can destroy tumors. One class of immunotherapy drug that has shown success in treating many types of
cancer targets the interactions between PD-L1, a cancer-linked protein
that turns off T cells, and PD-1, the T cell protein that PD-L1 binds
to. Drugs that block PD-L1 or PD-1, also called checkpoint inhibitors,
have been approved to treat cancers such as melanoma and lung cancer,
but they have very little effect on pancreatic tumors.

Some researchers had hypothesized that this failure could be due to
the possibility that pancreatic tumors don't express as many cancerous proteins, known as neoantigens. This would give T cells fewer targets
to attack, so that even when T cells were stimulated by checkpoint
inhibitors, they wouldn't be able to identify and destroy tumor cells.

However, some recent studies had shown, and the new MIT study confirmed,
that many pancreatic tumors do in fact express cancer-specific
neoantigens. This finding led the researchers to suspect that perhaps a different type of brake, other than the PD-1/PD-L1 system, was disabling
T cells in pancreatic cancer patients.

In a study using mouse models of pancreatic cancer, the researchers
found that in fact, PD-L1 is not highly expressed on pancreatic cancer
cells. Instead, most pancreatic cancer cells express a protein called
CD155, which activates a receptor on T cells known as TIGIT.

When TIGIT is activated, the T cells enter a state known as "T cell exhaustion," in which they are unable to mount an attack on pancreatic
tumor cells. In an analysis of tumors removed from pancreatic cancer
patients, the researchers observed TIGIT expression and T cell exhaustion
from about 60 percent of patients, and they also found high levels of
CD155 on tumor cells from patients.



==========================================================================
"The CD155/TIGIT axis functions in a very similar way to the more
established PD-L1/PD-1 axis. TIGIT is expressed on T cells and serves as a brake to those T cells," Freed-Pastor says. "When a TIGIT-positive T cell encounters any cell expressing high levels of CD155, it can essentially
shut that T cell down." Drug combination The researchers then set
out to see if they could use this knowledge to rejuvenate exhausted T
cells and stimulate them to attack pancreatic tumor cells. They tested
a variety of combinations of experimental drugs that inhibit PD-1 and
TIGIT, along with another type of drug called a CD40 agonist antibody.

CD40 agonist antibodies, some of which are currently being clinically
evaluated to treat pancreatic cancer, are drugs that activate T cells
and drive them into tumors. In tests in mice, the MIT team found that
drugs against PD-1 had little effect on their own, as has previously
been shown for pancreatic cancer. They also found that a CD40 agonist
antibody combined with either a PD-1 inhibitor or a TIGIT inhibitor was
able to halt tumor growth in some animals, but did not substantially
shrink tumors.

However, when they combined CD40 agonist antibodies with both a PD-1
inhibitor and a TIGIT inhibitor, they found a dramatic effect. Pancreatic tumors shrank in about half of the animals given this treatment, and in
25 percent of the mice, the tumors disappeared completely. Furthermore,
the tumors did not regrow after the treatment was stopped. "We were
obviously quite excited about that," Freed-Pastor says.

Working with the Lustgarten Foundation for Pancreatic Cancer
Research, which helped to fund this study, the MIT team sought out
two pharmaceutical companies who between them have a PD-1 inhibitor,
TIGIT inhibitor, and CD40 agonist antibody in development. None of these
drugs are FDA-approved yet, but they have each reached phase 2 clinical
trials. A clinical trial on the triple combination is expected to begin
later this year.

"This work uses highly sophisticated, genetically engineered mouse models
to investigate the details of immune suppression in pancreas cancer, and
the results have pointed to potential new therapies for this devastating disease," Jacks says. "We are pushing as quickly as possible to test these therapies in patients and are grateful for the Lustgarten Foundation
and Stand Up to Cancer for their help in supporting the research."
Alongside the clinical trial, the MIT team plans to analyze which types
of pancreatic tumors might respond best to this drug combination. They are
also doing further animal studies to see if they can boost the treatment's effectiveness beyond the 50 percent that they saw in this study.

In addition to the Lustgarten Foundation, the research was funded by Stand
Up To Cancer, the Howard Hughes Medical Institute, Dana-Farber/Harvard
Cancer Center, the Damon Runyon Cancer Research Foundation, and the
National Institutes of Health.

========================================================================== Story Source: Materials provided by
Massachusetts_Institute_of_Technology. Original written by Anne
Trafton. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. William A. Freed-Pastor, Laurens J. Lambert, Zackery A. Ely,
Nimisha B.

Pattada, Arjun Bhutkar, George Eng, Kim L. Mercer, Ana P. Garcia,
Lin Lin, William M. Rideout, William L. Hwang, Jason M. Schenkel,
Alex M.

Jaeger, Roderick T. Bronson, Peter M.K. Westcott, Tyler D. Hether,
Prajan Divakar, Jason W. Reeves, Vikram Deshpande, Toni Delorey,
Devan Phillips, Omer H. Yilmaz, Aviv Regev, Tyler Jacks. The
CD155/TIGIT axis promotes and maintains immune evasion in
neoantigen-expressing pancreatic cancer.

Cancer Cell, 2021; DOI: 10.1016/j.ccell.2021.07.007 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210806104500.htm

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