Researchers identify immunologic basis of ‘exceptional survival’ in pancreatic cancer
Patients with pancreatic cancer who had tumors with a combination of the highest neoantigen number and the most abundant CD8-positive T-cell infiltrates survived significantly longer than those without those tumor characteristics, according to study results.
“These results are exciting — particularly in the field of pancreatic cancer, which can be a very difficult diagnosis and treatment for a patient to contend with,” Vinod P. Balachandran, MD, surgical oncologist and member of the David M. Rubenstein Center for Pancreatic Cancer Research at Memorial Sloan Kettering Cancer Center, said in a press release. “For years, research on T cells in pancreatic cancer has been limited, as reports suggest that very few of these cells recognized the disease.”
T-cell immunity has been associated with prolonged survival among certain long-term pancreatic cancer survivors. However, the relevant antigens associated with these outcomes has not been established.
Balachandran and colleagues analyzed the immune profile of 150 individuals with pancreatic cancer in hopes of identifying differences in tumor characteristics between patients who survived the longest and those who had poorer outcomes. The analysis included 82 long-term survivors (median survival, 6 years) and 68 controls matched for stage and treatment (median survival, < 1 year).
Researchers performed various immunologic, genomic and computational analyses to identify immune landscapes and neoantigens.
Results showed patients whose tumors had the highest number of neoantigens and the most abundant CD8-positive T-cell infiltrates achieved the longest survival.
“Before our work, the largest in-depth study looking at long-term survivors of pancreatic cancer had only eight patients — we had 82,” Balachandran said in the release. “This is a step forward in possibly being able to rationally predict which neoantigens will be the most effective at stimulating an immune response.”
HemOnc Today spoke with Balachandran about the study and the potential clinical implications of the results.
Question: What prompted this research?
Answer: We wanted to identify mechanisms of long-term survival in pancreatic cancer. Five-year survival rates for pancreatic cancer remain low, at about 7%. There are rare patients who survive much longer. Although there has been evidence in the literature that this may be partially T-cell mediated, the relevant antigens have remained unknown.
Q: What did you find?
A: Tumors of the long-term survivors had 12-fold greater densities of activated CD8-positive T cells than tumors of short-term survivors. When we assessed whether CD8-positive T-cells might be recognizing neoantigens in long-term survivors, we found tumors with both the highest neoantigen number and the most abundant CD8-positive T-cell infiltrates — but neither alone — identified the longest survivors. We went on to identify unique qualities of these neoantigens that we think render them more immunogenic to CD8-positive T cells, and we found that patients whose tumors had higher neoantigen qualities had greater survival than patients with tumors of lower qualities. We also found evidence that T cells recognizing the highest quality neoantigens persisted in the blood of patients up to 12 years after surgery. We found this interesting because it suggested these higher-quality neoantigens might be effective at stimulating long-lived T-cell responses.
Q: Did the findings surprise you?
A: Yes, we were surprised. Our findings bring new considerations to the commonly held views of pancreatic cancer that this tumor type has no neoantigens for the immune system to attack and that immune cells — including T-cells — cannot be found in the tumor or fight it off.
Q: What are the clinical implications of the findings?
A: There are two major implications. First, we think neoantigen quality might be a biomarker for immunogenic tumors. Second, our model can allow us to rationally predict which neoantigens might be the most immunogenic and, therefore, suitable for use in vaccine therapies.
Q: Is there potential in the near future for a vaccine?
A: In collaboration with Stand Up to Cancer, the Lustgarden Foundation, Genentech and BioNTech, we are using these new results to design an innovative clinical trial of personalized cancer vaccines in pancreatic cancer patients. We are aiming to introduce a new paradigm of personalized immunotherapy treatments for both pancreatic and other cancers, as well as identify new strategies for cancer vaccination in humans.
Q: What else needs to be confirmed in subsequent research?
A: The question of whether neoantigen quality can be a biomarker of response to immunotherapy in pancreatic cancer is an outstanding question. In a companion paper that came out along with our paper, identical neoantigen quality parameters identified patients who responded better to checkpoint blockade immunotherapy in melanoma and lung cancer. Given these findings, we will test whether neoantigen quality can identify patients with pancreatic cancer who achieve better response to immunotherapy in Precision Promise, a national clinical trial by the Pancreatic Cancer Action Network.
Q: Is there anything else that you would like to mention?
A: Globally, these findings may point to possible, common, quantifiable principles of immune recognition of cancer mutations. It also underscores the need for a deeper understanding of how the immune system interacts with mutations in pancreatic cancer, as immunotherapies may be promising future treatments for these patients. – by Jennifer Southall
Balachandran VP, et al. Nature. 2017;doi:10.1038/nature24462.
For more information:
Vinod P. Balachandran, MD, can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065.
Disclosure: Balachandran reports no relevant financial disclosures.