MD Anderson Delivers a Triple Punch to Pancreatic Cancer

MD Anderson Cancer_JHVEPhoto

Courtesy of JHVEPhoto/GettyImages

A recent study by researchers at the University of Texas MD Anderson Cancer Center found that targeting checkpoints in both T cells and myeloid suppressor cells led to a curative response in pancreatic cancer models. 

While pancreatic ductal adenocarcinoma (PDAC) is typically considered non-immunogenic, the team, led by Ronald DePinho, M.D., professor of cancer biology and past president of MD Anderson, may have discovered an immunotherapeutic path forward in a cancer with a dire prognosis.

In the paper, published December 30th in Nature Cancer, the researchers describe how targeting T cell checkpoints 41BB and lymphocyte activation gene-3 (LAG-3) and myeloid cell CXCR1/CXCR2 led to complete tumor regression in 90% of preclinical models and 20% of autochthonous tumor models representing higher resistance cases.

A Translational Head-Start

Two factors exist here that could mean a translational head-start for the discovery. One, 41BB and LAG-3 are also found in human pancreatic cancer samples, and two, each agent is currently being investigated as a monotherapy.

Ronald DePinho_MD Anderson
Ronald DePinho, M.D.

In an interview with BioSpace, DePinho said the increase in survival was “more significant than almost anything we have seen in the last 20 years.”

DePinho said the iKPC mouse models for PDAC, developed in his lab at MD Anderson, are built on the signature of mutations that occur in the human disease and faithfully recapitulate the human (cancer).”

Over the past 20 years, myriad immunotherapy agents have been tried – and all failed to budge the intractable cancer.

“There have been dozens, if not more than 100 agents tested in this model and in clinical trials that failed to move the needle on the disease, including PD1 and anti-CTLA4, which alone or in combination have had no effect,” DePinho said.  

Pancreatic cancer has consistently shown its obstinacy against PD1 and CTLA4 checkpoint inhibitor therapies. Researchers have attributed this resistance to an immunosuppressive tumor immune microenvironment (TIME).

Reprogramming the TIME

Thus, drug developers have turned to other approaches, including novel molecules, mRNA-based combinations and new delivery vehicles for checkpoint inhibitors. Still others, such as DePinho’s team, seek to reprogram the TIME with novel combinations.

The scientists hypothesized that other immunosuppressive mechanisms could be at play in pancreatic cancer. Undertaking an unbiased analysis of the immune regulatory molecules found on exhaustive T cells, they discovered that LAG3 and 4IBB were “robustly expressed in the mouse model, as well as in human tumor specimens.”

Then, they uncovered the second key to the combination - a preponderance of myeloid suppressor cells and a significant representation of suppressive tumor-associated macrophages.

“That got us thinking that perhaps targeting some of these other molecules might get us inroads to getting some responses in the disease,” DePinho said.

Inroads are urgently needed in a cancer with one of the lowest survival rates. Between 2012 and 2018, the 5-year survival rate for pancreatic cancer was 11.5%, according to the National Cancer Institute. Nearly 50,000 Americans succumbed to the disease in 2022, accounting for 8.2% of all cancer deaths.

LAG-3 was validated as a legitimate checkpoint inhibitor in April 2022 when Bristol Myers Squibb won approval for Opdualag, a LAG-3-blocking antibody combination, for metastatic melanoma.

DePinho explained that along with being expressed on t cells, LAG-3 is also expressed on myeloid and other immune cells.

“It could be that one of the reasons LAG-3 is effective in eliciting responses is because of this plurality of activities that it has,” he said. “It’s not just taking the brakes off the T cells, but it is also enhancing the anti-tumor activity of other arms of the immune system.”

Meanwhile, CXCR2 is being assessed in early trials for several cancers.

In previous papers, DePinho’s lab showed that when you knock down CXCR2, colon and prostate cancers, for example, become sensitized to anti-PD1 therapy, which usually does not impact these tumors.

The next steps for the MD Anderson team include further testing the combination in models of multifocal disease where only 20% of the mice were cured.

“The question is, why is it not 90% or 100%?” DePinho said. “We're very interested in understanding what the residual mechanisms are that allow these cancer cells to evade the immune system.” 

DePinho emphasized the importance of acting on myeloid cells in immuno-oncology. While a significant advancement, only 15 to 25% of patients respond durably to Merck’s anti-PD1 drug Keytruda. A substantial fraction of the non-responders, he said, have myeloid-related mechanisms.  

“I think an important frontier for biopharma in this decade will be to not only work on these alternative checkpoints but to turn their attention to the myeloid compartment,” DePinho said.

KRAS Combinations? 

DePinho is most excited about the other area of progress is KRAS, which he said is the signature mutation of pancreatic cancer. KRAS is a tumor maintenance gene that promotes the anabolic growth of the tumor. In a 2014 paper published in Cell, DePinho showed that cancer disappeared when KRAS is turned off. 

He suggested that coupling a KRAS approach with an immune mechanism like LAG-3 or 41BB would be another possible frontier.

In December, Mirati Therapeutics’ Krazati (adagrasib) became just the second KRAS therapeutic on the market, joining Amgen’s Lumakras (sotorasib) in KRAS G12C-mutated non-small cell lung cancer.

Adagrasib is also being studied in Phase II trials for pretreated PDAC. In data presented last year, treatment with adagrasib led to median progression-free survival of 6.6 months.

Back to news