A combination of chemotherapy with immunotherapy designed to unleash the immune system’s anti-cancer capacity has been shown to be effective against one of the toughest targets in cancer care, pancreatic cancer, in a national randomized clinical trial led by researchers from the Perelman School of Medicine at the University of Pennsylvania and sponsored by the Parker Institute for Cancer Immunotherapy.
The results of the small but promising trial were announced today during a presentation at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, and simultaneously published in natural medicine.
Researchers found that in 34 patients with advanced pancreatic cancer randomized to receive the immunotherapy nivolumab with two chemotherapeutic agents, nab-paclitaxel and gemcitabine, had a one-year survival rate of 57.7%, significantly higher than the historical average of 35% with chemotherapy. only. Findings also included the identification of immune system biomarkers associated with better outcomes. A second treatment of sotigalimab immunotherapy with chemotherapy also appeared more effective in a subgroup of patients, identified with a different set of biomarkers.
This study suggests that there is benefit in combining immunotherapy and chemotherapy in patients with advanced pancreatic cancer and that there may be ways to refine treatment choices based on the patient’s ‘immune health’ . We now hope to evaluate these potential biomarkers in further trials to see if they will allow us to reliably identify patients who will respond best to this and other combination therapies. The most promising biomarkers were measured by an immune system blood test, not by genetic sequencing, which opens the door to a new approach in precision oncology.”
Robert H. Vonderheide, MD, DPhil, Professor at the John H. Glick Abramson Cancer Center and Director of the Abramson Cancer Center, University of Pennsylvania
The most common form of pancreatic cancer, known as pancreatic ductal adenocarcinoma (PDAC), is usually only diagnosed after it has become advanced or metastatic, and is also notoriously aggressive and difficult to treat effectively. . Historically, only about 10% of patients who are diagnosed with PDAC survive for five years, and newly diagnosed patients with metastatic PDAC typically live less than a year, even with optimal chemotherapy.
Standard chemotherapy regimens can stop the growth of PDAC tumors, but only temporarily. New immune-targeting therapies, such as checkpoint blocking antibodies, have been remarkably effective against some other cancers, but almost entirely ineffective; when used alone-; against PDAC.
However, a silver lining has come from preclinical experiments in mouse models of PDAC, and a small initial clinical trial reported by the Vonderheide team last year suggested that adding chemotherapy can significantly disrupt resistance. from pancreatic tumors to immunotherapy-; making the combination more effective than either type of treatment alone. In the new study, they tested this approach on a larger scale.
They randomized a pool of more than 100 patients with metastatic PDAC to receive standard chemotherapy (gemcitabine/nab-paclitaxel) plus one of three immunotherapy regimens: antibody therapy (nivolumab) targeting the “d PD-1 immune ‘switch off’, another antibody treatment (sotigalimab) that activates an immune ‘switch’, CD40, and a combination of anti-PD-1 and pro-CD40 treatments. The main objective of the study was to see if any of these combinations could improve the one-year survival rate for these patients, compared to the historical rate of only 35% for patients who receive chemotherapy alone.
The researchers found that all three groups had one-year survival rates greater than 35%: 57.7% for anti-PD-1 plus chemo, 48.1% for pro-CD40 plus chemo, and 41. 3% for combined immunotherapy plus chemo. Only the first of these results was statistically significant, although in a study with such a small number of patients, only the most striking differences will cross the barrier of statistical significance.
A key part of the clinical approach to difficult cancers such as PDAC is the discovery of factors in the patient that are linked to better outcomes for a given treatment. This allows a better understanding of cancer, and in principle allows doctors to know which treatment to give only to patients who are likely to benefit the most. In this case, the researchers were able to identify factors, including the levels of certain immune cells in the bloodstream pretreatment, that predicted longer survival for the anti-PD-1/chemo and pro-CD40 arms.
Patients who received chemotherapy and both types of immunotherapy did not benefit more than chemotherapy alone. The researchers suspect that the relatively poor results of the two-immunotherapy regimen could be due to excessive T-cell activation that pushed the cells into a state of exhaustion.
Funding and/or immunotherapy doses were provided by the Cancer Research Institute, Parker Institute for Cancer Immunotherapy, Bristol Myers Squibb, and Apexigen. Participating clinical sites included Penn’s Abramson Cancer Center, Dana-Farber Cancer Institute, MD Anderson, Memorial Sloan Kettering, Stanford University, University of California, Los Angles, and University of California, San Francisco .
Padron, L.J. et al. (2022) Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunological analyzes from the randomized phase 2 PRINCE trial. natural medicine. doi.org/10.1038/s41591-022-01829-9.
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