Nature Cancer: Triple immunotherapy holds promise for treating pancreatic cancer

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

In this study, the researchers performed comprehensive immunoassays on 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 in the tumor microenvironment significantly improved survival rates in laboratory models, pointing to a potential treatment option
for this notoriously refractory cancer.
The findings of the study were published in the journal Nature Cancer on December 30
, 2022.

Co-corresponding author Professor Ronald DePinho of MD Anderson Cancer Centre said: "This triple therapy has yielded unprecedented efficacy
in our model.
It is widely accepted that immunotherapy is not effective against pancreatic cancer, but this preclinical study suggests that the right combination therapy can attack
it.
In addition, the presence of these targets in human pancreatic cancer specimens raises the exciting possibility that this combination of treatments could one day benefit our patients
.
”

Pancreatic cancer is one of the leading causes of cancer death in the United States, with 80% of patients 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 the tumor microenvironment, but the mechanisms behind this resistance are not fully understood
.

The researchers used high-dimensional immunoassays and single-cell RNA sequencing (scRNA-seq) to study the impact of
various immunotherapies on the tumor microenvironment.
They found that the immune checkpoint proteins 41BB and LAG were highly expressed
in depleted T cells.

When testing antibodies targeting these checkpoints, they observed that tumor progression was slower and survival was significantly improved
in pancreatic cancer models after combination therapy with 41BB agonists and LAG3 antagonists compared to antibodies or other checkpoint inhibitors alone.
Notably, these preclinical studies faithfully reflect human data
on poor efficacy of anti-PD-1 or anti-CTLA-4 treatments.

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

Because this combination of dual treatments didn't completely eliminate the tumor, the researchers also reprogrammed the tumor microenvironment to make the tumor more sensitive
to immunotherapy.
They found that the tumor microenvironment contained a large number of myeloid-derived suppressor cells (MDSCs)
expressing CXCR2.
Inhibition of CXCR2 reduces MDSC migration and blocks tumor growth, but there is no cure
.
This prompted them to start considering a combination
of targeting 41BB, LAG3 and CXCR2.

In 90% of preclinical models, this triple therapy resulted in complete tumor regression and improved overall survival
.
In a more resistant laboratory model, this combination achieved complete tumor regression
in more than 20 percent of cases.

"These results are encouraging, especially given the lack of effective immunotherapy regimens for pancreatic cancer," DePinho said
.
"By targeting multiple synergistic mechanisms that impede the immune response, we give T cells a fighter against these tumors
.
" Of course, we still need to see how this combination translates clinically into safe and effective treatment options, so we invite other researchers to continue their research
on this basis.
We are optimistic that combination immunotherapy will eventually be able to successfully tackle pancreatic cancer, as well as other non-immunogenic cancers
.
”

The authors note that these particular immunotherapy drugs are currently in clinical trials as monotherapies, which means that this triple therapy is expected to be rapidly incorporated into clinical studies
in the future.

Original search

Gulhati, P.
, Schalck, A.
, Jiang, S.
et al.
Targeting T cell checkpoints 41BB and LAG3 and myeloid cell CXCR1/CXCR2 results in antitumor immunity and durable response in pancreatic cancer.
Nat Cancer (2022).
https://doi.
org/10.
1038/s43018-022-00500-z