A Rare Story of Hope in Pancreatic Cancer Treatment
A clinical trial based on discoveries made by Columbia researchers is showing promising results and expanding to include more patients
Jeff W. was a healthy and vibrant 58-year-old movie producer, husband, and father of two when he began experiencing stomach pains while in Eastern Europe for work. He visited a local clinic, where nothing was found on an ultrasound. Upon arriving back in the United States, he got a CT scan that revealed a mass on his pancreas.
Jeff scheduled surgery at Columbia with John Chabot, MD, an expert in a complex gastrointestinal surgery known as the Whipple (pioneered by Columbia surgeon A.O. Whipple in the 1930s) that is commonly used to treat pancreatic cancer.
Unfortunately, in cases where the surgeon opens the patient up and discovers the cancer has spread to other organs, finishing the surgery is not recommended due to the extensive recovery and the need for the patient to start systemic treatment right away.
“I could tell looking at my stomach in the recovery room that it was bad news as my surgery was not complete,” Jeff recalls. “The one thing that was amazing in that exact moment is that Dr. Chabot was holding my hand when he told me it was stage 4 and that he had removed lesions in my liver. This man who I didn't know is holding my hand telling me the bad news, but I felt like he cared. He right away told us about a clinical trial Columbia had going on led by Dr. Gulam Manji, and my family and I spent the next few weeks doing everything we could so I could get into this trial.”
Committed to finding a cure
The trial that Jeff entered is based on preclinical research first conducted by Columbia oncologist Gulam Manji, MD, PhD, in a laboratory led by Kenneth Olive, PhD, before Manji opened his own laboratory and continued the work.
For the better part of 40 to 50 years, the only treatment for pancreatic cancer has been surgery and old-school chemo. “Unfortunately, this disease has been recalcitrant when responding to new therapies. There hasn’t been much progress for generations,” says Olive.
“With pancreas cancer, the current treatment options are inadequate for most patients, regardless of the stage,” Manji adds. “Many have tumors that will return, and treatments are often palliative in nature."
“The exciting thing is that we believe this is changing now as we bridge directly from the lab to the clinic,” Olive says.
Based on his lab findings, Gulam Manji (right, with Columbia collaborator Kenneth Olive) opened a clinical trial for pancreatic cancer patients to put the findings to the test. Manji says: “We need to make certain that the successes in the lab are translated to patients in hopes of identifying new therapies that will change the outcome of this devastating and aggressive disease. This is my passion.”
In Olive’s lab, mice are genetically engineered to develop pancreatic cancer with tumors similar to those found in humans so researchers can understand the biology of what’s happening.
“We have stories here that begin in our labs and feed the best of the preclinical studies into clinical studies,” Olive says. “Our dream is to have something emerge from one of our labs and move into patients and make a difference.”
Moving quickly from bench to bedside
It’s one of those discoveries that is now being tested with Jeff and other patients.
Manji’s lab studies immunosuppressive pathways important in pancreatic cancer. Since their introduction, immunotherapies that stimulate the immune system to attack cancer have had great success against some cancers, but not pancreatic.
One reason appears to be a defense created by pancreatic tumors. In mice, previous research at Cold Spring Harbor Laboratory has shown that certain cells within pancreatic tumors release cytokines, substances that prevent immune cells from entering the tumor microenvironment. The researchers also showed that treatment with a cytokine inhibitor and a PDL1 inhibitor (a type of immunotherapy) opened the gateway for immune cells and caused the tumors to shrink after only six days.
The research, published in 2013, inspired Manji, then a fellow at Columbia, to find out what would happen if mice were treated for longer periods of time and with different combinations of drugs, including gemcitabine, a chemotherapy drug that is suspected of having immune-modulating effects.
Only one regimen helped mice live longer: a triple-combination therapy of a cytokine (CXCR4) inhibitor (AMD3100), an immunotherapy drug (mDX400, a mouse version of a PDL1 inhibitor), and gemcitabine.
In particular, the treatment that was most effective began with the CXCR4 inhibitor, which "unmasked" the tumor cells, before giving immunotherapy followed by chemotherapy.
“We found that only this triple therapy showed an increase in the ratio of cancer-killing T cells to the regulatory T cells that keep cancer cells hidden from the immune system,” Manji says.
Testing triple-combination therapy in patients
Successes in the lab are fantastic, Manji says, but “we need to make certain that the successes in the lab are translated to patients in hopes of identifying new therapies that will change the outcome of this devastating and aggressive disease. This is my passion.”
Manji launched a clinical trial to test the triple therapy, enrolling 11 patients with newly diagnosed pancreatic cancer. (The results were presented at the American Association for Cancer Research Special Conference in Cancer Research: Pancreatic Cancer on Sept. 28, 2023.)
Jeff’s tumor started shrinking within eight weeks of starting the therapy. A year later, the tumor had shrunk by 53%, with no new growths elsewhere.
“Every time I get a scan and I see the tumor shrinking, it’s incredible,” Jeff says.
Importantly, he feels great and is grateful to Columbia. “I come once a week and get treated. It’s been an incredible experience going from no hope to feeling like I’m on the path to being cured. From the most compassionate nurses who I met on day one, I have felt what’s happened to me at Columbia has been amazing,” he says.
“I’m living proof that immunotherapy treatment can work for pancreatic cancer, and I was really lucky to be at Columbia at the right time in the right place to find these amazing doctors who care about curing pancreatic cancer.”
Other trial patients also have had promising results: The study found that tumors in seven of the patients shrank by at least 30%, and three patients had stable disease (meaning their tumors neither shrank nor progressed).
The results were so promising that Manji launched a randomized trial of 108 patients with the University of California San Francisco, Medical College of Wisconsin, Brown University, and Northwell Hospital joining Columbia as participating sites.
Expanding the trial to more patients is an opportunity to see if the results can be replicated in a larger sample size and will determine if the treatment has real promise, Manji says.
Hope for the future
Chabot has been at Columbia for 40 years, having progressed from intern, resident, and fellow to professor, mentor, and now executive director of the Pancreas Center. This puts him in the unique position of being able to reflect on how far Columbia—and medicine in general—has come toward measurable results.
“One reason I am optimistic is we have built the entire infrastructure so that when we have the idea, it can be explored without having to look for collaborators,” he says. “The number of patients with pancreatic cancer we treat gives us more opportunities to help people through clinical trials."
There's a sense of urgency about pancreatic cancer at Columbia's Pancreas Center, says the center's executive director John Chabot (right, with oncologist Gulam Manji). “The number of patients we treat gives us more opportunities to help people through clinical trials," Chabot says.
Manji echoes this sentiment. “Having one foot in the lab, creating my own studies, and seeing a large number of patients allows me to help get more patients into trials,” he says. “It also helps having an office right down the hall from Dr. Chabot, who can tell me when he has a patient that may be right for one of our trials.”
Science has become more collaborative across the board, according to Chabot, and the field of pancreatic cancer especially so.
“We must have a sense of urgency about this disease," he says. "Even though we’ve made significant progress, we have a long way to go, but there surely is real hope for the future.”
References
More information
Gulam Manji, MD, PhD, is associate professor of medicine at Columbia University Vagelos College of Physicians and Surgeons and director of pancreas medical oncology.
Kenneth Olive, PhD, is associate professor of medicine at Columbia University Vagelos College of Physicians and Surgeons and directs the oncology precision therapeutics imaging core within the Herbert Irving Comprehensive Cancer Center at Columbia University.
John Chabot, MD, is the David V. Habif Professor of Surgery at Columbia University Vagelos College of Physicians and Surgeons, chief of the GI/endocrine surgery division, and executive director of the Pancreas Center.