3-drug combo leads to 'unprecedented' response in pancreatic cancer models

Criminal profiling can be the key to catching a killer. The same could be said for immune system profiling, which appears to have helped scientists crack the code on one of oncology’s most notorious villains: pancreatic cancer.

In a study published Dec. 30 in Nature Cancer, scientists at the University of Texas MD Anderson Cancer Center described how they systematically went about profiling the way pancreatic tumors keep a patient’s immune system from fighting their cancer. The researchers’ sleuthing led them to three proteins, which they then targeted in mouse models with a trio of immunotherapies.

Their results showed an overall survival rate of up to 90% through the end of the year-and-a-half-long study—more than half the mice’s life span. The same cancer in people has a five-year survival rate of 11%.  

“As a human immunologist who has been involved in a lot of clinical trials, you’d be surprised that I was surprised that it worked so well, but I really was,” John Connolly, Ph.D., who is not involved in the research but is chief scientific officer at the San Francisco-based Parker Institute for Cancer Immunotherapy, told Fierce Biotech Research.

Suppressing immune suppression

Even among hard-to-treat solid tumors, pancreatic cancer is in a league of its own when it comes to survival mechanisms.

Under normal conditions, the immune system regulates itself with checkpoints, suppression pathways that hold down the “off” switch on T cells that would otherwise attack a person’s own tissue. Pancreatic cancer is especially good at exploiting these pathways by keeping the suppression mechanisms turned on, ultimately “exhausting” the T cells in the area surrounding the tumors, also known as the tumor immune microenvironment. T-cell exhaustion is just what it sounds like: The cells no longer respond to foreign invaders, allowing cancer cells to proliferate undetected.

Pancreatic tumors’ unparalleled ability to suppress T cells makes them highly resistant to immunotherapies. That includes checkpoint-inhibiting drugs like Merck’s PD-1 inhibitor Keytruda and Bristol Myers Squibb's Yervoy, a CTLA-4 inhibitor, on their own or in combination.

“Over the last 20 years, the field has tried many, many different agents to enhance the therapeutic strategies for this disease,” Ronald DePinho, M.D., senior author of the study, said. The statistically significant survival benefits seen in both mice studies and human trials thus far aren’t enough to make a meaningful difference in the clinic, he added.  

But perhaps it was a matter of hunting down and neutralizing the right combination of the right checkpoints, DePinho’s lab reasoned. That would require a clear profile of how pancreatic cancer was impacting the immune system—in other words, its immune “fingerprint,” as Connolly described it.

To find that fingerprint, Pat Gulhati, M.D., Ph.D.—a postdoc in DePinho’s lab—set about cataloguing all the immune checkpoint proteins that were expressed in exhausted T cells found in the tumor immune microenvironment of mice with pancreatic cancer. The researchers also took stock of the ones in both treated and untreated samples from  patients to make sure their findings were clinically relevant, with particular attention to the ones that showed up in highly resistant disease.

In both samples, the researchers found that in addition to PD-1 and CTLA-4, the checkpoint proteins TIM3, 41BB and LAG were also expressed. They then enlisted their mouse models in multiarm studies with antibodies designed to target these proteins along with others they found in their search.

Similar to what had been seen in humans, neither PD-1, TIM3 or CTLA-4 inhibition improved survival. But anti-LAG3 and agonistic 41BB antibodies individually extended the mice’s survival time by about 20% to 30% compared to controls.

“And—as expected because mechanistically they worked quite differently—the combination of the two had additive effects,” DePinho explained. The dual therapy more than doubled their survival time.

Third drug's the charm

But despite living twice as long as untreated models, the two drugs weren’t enough to keep the mice from succumbing to the disease. The researchers wondered whether they could improve the numbers with a third agent.

For that, they turned to CXCR2, a protein that recruits myeloid-derived suppressor cells, or MDSCs, to the tumor immune microenvironment. Summoning MDSCs is another nifty trick up cancer’s sleeve. While normal myeloid cells—which include neutrophils and monocytes—act against foreign invaders, MDSCs have suppressive activity. Cancerous tumors activate them so they turn off T cells. And because they aren’t susceptible to immune checkpoint inhibitors, they’re a common route of treatment resistance.

Like the two-drug combo, treating the mice with a CXCR2 inhibitor called SX-682 once again boosted their survival time by about 30% to 40%. Encouraged, the researchers then tried the three agents together.

After 540 days, all but one of the 10 mice in a group with a highly virulent pancreatic cancer were still alive. Other groups with tumors grown from different cell lines had overall survival rates of around 70%. In models with multifocal, spontaneously arising tumor—a particularly aggressive form—the survival rate was 20%.

None of the animals alive at the study’s end had any signs of cancer.

“These were unprecedented cures seen in a very virulent mouse model of this disease,” DePinho said. Cell sequencing and immune profiling confirmed that drugs had indeed induced a potent immune response, overcoming suppression by the tumors. The study’s models were especially strong because the researchers made an effort to ensure that the immunosuppression patterns they saw in mice were the same as those in samples from human patients, Connolly said.

“They created a nice resistance model that accurately reflected how resistance works in a human,” he explained. “Then they used advanced immunophenotyping and analytical techniques to really dive in and come up with a fingerprint of how resistance is working.”

Speeding to the clinic

All three of the drugs used by the researchers are being studied separately in early-stage clinical trials. Bristol Myers Squibb’s LAG3 inhibitor relatlimab, which is already FDA approved as part of a combination treatment for metastatic melanoma, is one of the drugs being studied in the National Cancer Institute’s MATCH screening trial for solid tumors. Pfizer’s utomilumab, a 41BB agonistic antibody, showed a favorable safety profile in a phase 1 pancreatic cancer trial.

And the CXCR2 inhibitor SX-682, developed by Syntrix, is in a phase 1 trial for pancreatic cancer with Bristol Myers Squibb’s Opdivo.    

Combined with the results of their study, the work already being done with the agents warrants speeding along the process to trying them together in humans, DePinho said.

“I think there’s as much preclinical proof-of-concept one could glean from looking at human specimens, which showed that the targets are there and that they correlate with clinical outcomes,” he said. “And the mouse model, which is a very faithful mouse model of the human disease, shows rather striking and encouraging results.”

Connolly agreed. “There’s a lot of good mouse studies out there, but you really want to translate this to the clinic for it to be meaningful to patients,” Connolly said. “We really want to see that clinical trial get out there.”

Combos galore

Given that only 20 percent of the most aggressive tumors were cured with the triple combination, there’s also potential to try the combo with different agents that work against different suppression mechanisms. DePinho is particularly intrigued by the possibility of testing them with KRAS inhibitors, which have shown signals of efficacy both preclinically and in early stage clinical trials.  

“With the advent of KRAS inhibitors, there is now going to be an opportunity to combine KRAS inhibitors with immune modulatory agents,” he said. “Based on our work, I would put at the top of the list anti-LAG3 and agonist 41BB or the CXCR2 inhibitor.”

Connolly again agreed, noting that the concept makes sense for outsmarting drug resistance. “You want to try to add therapeutics that don’t share a mechanism of resistance,” he said. “The tumor may be able to escape the immune system, but it’s very difficult to escape the immune system and KRAS suppressors.”

In general, the researchers’ approach is ideal for designing multidrug therapies, Connolly said. “Ron’s lab gives you a roadmap on how to make a combination therapy,” Connolly said. “Find the fingerprint of suppression, find the mechanism of resistance and attack that mechanism.”