Foundings
A pilot study led by UCLA Health Jonsson Comprehensive Cancer Center researchers suggests that for people with borderline resectable pancreatic cancer, giving an immunotherapy drug in combination with chemotherapy before surgery is safe and may improve long-term outcomes.
The findings showed that treating patients with the combination therapy before surgery resulted in a higher rate of successful tumor removal, increased the time before the cancer progressed and prolonged overall survival compared to historical controls. The researchers also found that the addition of the immunotherapy component did not increase significant adverse side effects and did not lead to significant postoperative complications.
This is one of the first trials reported with a PD1 inhibitor in neoadjuvant pancreatic cancer, and we found that this new approach was associated with positive outcomes, including enhancing the function of cytolytic T cells, a key component of the immune system responsible for the attack on cancer cells. In addition, the observed increase in the immunosuppressant adenosine indicates a potential resistance mechanism that we can target in a follow-up study to enhance the body’s ability to fight cancer even better.”
Dr. Zev Wainberg, co-director of the UCLA Health GI Oncology Program and first author of the study abstract
“This trial uniquely integrated UCLA research groups with expertise in pancreatic adenocarcinoma, allowing access to the patient’s tumor tissue beyond what is normally accessible,” said Jason Link, associate professor of surgery and study author. “With these available resources, we were able to identify granular changes in antitumor immunity that may have contributed to positive results in this new trial.”
Record
Pancreatic cancer is one of the most difficult cancers to treat. Only 12% of people diagnosed with this particularly aggressive disease live longer than five years and most treatments -? including conventional chemotherapies, targeted therapies and immunotherapies – are unsuccessful in treating it. Previous studies combining chemotherapy and PD1 inhibitors, a type of immunotherapy drug that helps the immune system recognize and destroy cancer cells more effectively, have not shown improvements in the treatment of people with pancreatic cancer. However, prior to this study, the use of the combination of chemotherapy and immunotherapy has not been tested in the neoadjuvant setting.
Method
The study included 28 patients (16 men, 12 women) with marginally resectable pancreatic cancer. Twenty-six (93%) of the participants completed at least three cycles of combination therapy and 24 (86%) underwent surgery. Genetic sequencing was performed on 21 resected post-treatment tumors, six patient-matched pre-treatment diagnostic biopsies, and nine resected tumors from non-trial patients treated with chemotherapy alone.
Results
At a median follow-up of 24 months, median progression-free survival was 34.8 months and median overall survival was 35.1 months. For patients who underwent pancreatectomy, the 18-month overall survival rate was 90%. There were two pathological complete responses and two near complete responses. Compared with pretreatment biopsies, RNA sequencing of resected specimens revealed higher expression of CD8 and Granzyme A. In patients with pathologic node-negative disease, increased Granzyme A expression was associated with significantly improved progression-free survival. Adenosine-related gene expression increased in 50% of samples after treatment and correlated with adenosine-producing CD73 expression.
Effect
This research opens new avenues for investigating the role of immunotherapy in early stages of pancreatic cancer, potentially offering more effective treatment options for patients with borderline resectable pancreatic cancer. This Phase 2 trial is ongoing.
“This was a real team effort. By treating patients before surgery, not only were we able to see if the drug combination worked, but by collecting surgical resection tissue, we went back to the lab to study why this combination doesn’t always work.” said Dr. Timothy Donahue, chief of surgical oncology and professor of surgery at the David Geffen School of Medicine at UCLA and senior author of the study. “We have identified some drivers that will form the basis for subsequent studies, again in the preoperative setting by our multidisciplinary team. Through these efforts, we are working to redefine the standard of care for pancreatic cancer.”
Authors
Other authors, all from UCLA, include Drs. David Dawson, Dr. Lee Rosen, Dr. Stephen Kim, Dr. Mark Girgis, Dr. Jon King, Dr. Joe Hines, Dr. Saeed Sadeghi, Dr. Olga Olevsky, Dr. Deborah Wong, Harsimran Multani, Jenna Davis, Lisa Yonemoto, Ann Marie Siney, Christine Kivork, Chi-Hong Tseng.
Conferences
Wainberg will present the findings at the annual meeting of the American Association for Cancer Research (AACR) on Monday, April 8 in the Clinical Trials Minisymposium session titled, “Advances in Immunotherapy,” from 2:30 to 4: 30 pm
