Nature Cancer: Triple immunotherapy has the potential to treat pancreatic cancer

Researchers at the University of Texas MD Anderson Cancer Center have discovered a novel immunotherapy combination that targets checkpoints in T cells and myelosuppressor cells, successfully reprogrammed the tumor immune microenvironment (TIME), and significantly improved anti-tumor responses
in preclinical models of pancreatic cancer.

In the study, published today in the journal Nature Cancer, researchers conducted comprehensive immunoassays of pancreatic cancer in mice and humans, systematically identified the mechanisms of immunotherapy resistance, and investigated potential therapeutic targets
.
They found that neutralizing several different immunosuppressive mechanisms of TIME greatly improved survival in laboratory models, pointing to a potential treatment option
for this notoriously deadly and unresponsive cancer.

"In our model, this triple therapy resulted in an unprecedented efficacy response," said
corresponding author Dr.
Ronald DePinho, professor of cancer biology.
"The prevailing view is that pancreatic cancer is not affected by immunotherapy, but this preclinical study suggests that it may be susceptible to the right combination therapy
.
In addition, the presence of these targets in human pancreatic cancer specimens raises the exciting possibility that this combination of treatments could one day help our patients
.
”

Pancreatic cancer is one of the leading causes of cancer death in the United States, in part because 80 percent of cases are diagnosed at an advanced stage
.
Pancreatic cancer is also considered "non-immunogenic," meaning it does not respond to
commonly used anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitors.
This is partly due to immunosuppressive conditions in TIME, but the mechanism behind this resistance is not fully understood
.

The researchers used high-dimensional immunoprofiling and single-cell RNA sequencing to study the impact of
various immunotherapies on TIME.
They found specific immune checkpoint proteins 41BB and LAG, which are highly expressed
in depleted T cells.

When testing antibodies against these checkpoints, the researchers observed that models treated with a combination of 41BB agonists and LAG3 antagonists had slower tumor progression, higher levels of anti-tumor immune markers, and significantly improved survival compared to antibodies alone or other checkpoint inhibitors
.
Notably, these preclinical studies faithfully reflect human data
on the lack of efficacy of anti-PD-1 and anti-CTLA-4 treatments.

The researchers also confirmed that the two therapeutic targets were present in human pancreatic cancer samples, with 81% and 93% of patients, respectively, carrying 41BB and LAG3-expressing T cells
.

Since this dual treatment combination did not completely eliminate established tumors, the researchers also examined efforts
to reprogram TIME to further sensitize tumors to immunotherapy.
At baseline, TIME contained a large number of myeloid-derived suppressor cells (MDSCs) expressing CXCR2, a protein
associated with the recruitment of immunosuppressive cells.
Inhibition of CXCR2 alone reduces MDSC migration and stops tumor growth, but is not curable
.
This prompted the researchers to consider targeting a combination
of 41BB, LAG3 and CXCR2.

In 90% of preclinical models, it was these three combinations that led to complete tumor regression and improved
overall survival.
In a more rigorous laboratory model, the combination achieved complete tumor regression
in more than 20 percent of cases.

DePinho said: "These results are encouraging, especially given the lack of effective immunotherapy regimens
for pancreatic cancer.
By targeting multiple synergistic mechanisms that impede the immune response, we can give T cells a chance to attack these tumors
.
Of course, we still need to see how this combination translates into safe and effective treatment options in the clinic, and we invite other researchers to build
on these results.
We are optimistic that pancreatic cancer, along with other non-immunogenic cancers, can eventually become vulnerable
through combination immunotherapy.
”

The authors note that these specific immunotherapies are currently undergoing clinical trials as monotherapies, suggesting that it is possible to rapidly translate this triple therapy into clinical studies
.