Patients with malignant pleural mesothelioma (MPM) experienced greater than 90% disease control and 59% response rate after immunotherapy with live bacterium combined with chemotherapy, findings from a phase 1b trial presented at the European Lung Cancer Conference have shown.1
“Malignant pleural mesothelioma is a cancer of the lining of the lung and is rare but difficult to treat,” said Thierry Jahan, MD, professor of medicine at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, California. “Standard of care treatment with pemetrexed and platinum compound chemotherapy gets a 30% response rate but a modest impact on survival. So there is a clear unmet need in targeting this specific population.”
The mesothelin antigen is strongly expressed in the tumors of patients with MPM. This study used CRS-207, a strain of Listeria monocytogenes bacterium that expressed mesothelin and has reduced pathogenicity.
“In our early studies, CRS-207 induced an antimesothelin response and cellular tumor-specific immunity in patients with mesothelin-expressing tumors,” said Jahan. “We also have data suggesting that this immunotherapy works synergistically with chemotherapy, so testing the effect of this immune-targeting agent with chemotherapy was a natural step.”
The current study examined the affect of CRS-207 combined with standard chemotherapy in patients with advanced unresectable mesothelioma who were candidates for chemotherapy. It included 38 patients who received 2 infusions of CRS-207 2 weeks apart, up to 6 cycles of pemetrexed plus cisplatin 3 weeks apart, followed by 2 additional CRS-207 infusions 3 weeks apart. Eligible patients received maintenance CRS-207 every 8 weeks. Patients were followed every 8 weeks until disease progression.
After a median follow up of 9.4 months (range: 0.2-28.1 months), 59% of the patients achieved a partial response and 35% had stable disease, for an overall disease control rate of 94%. Median progression free survival was 8.5 months.
“Patients receiving the combination of CRS-207 and chemotherapy had a deep response, with more than 90% disease control,” said Jahan.
Temperature spike and rigors were the main side effects associated with CRS-207. These were related to the infusion and resolved within 24 hours.
“The safety of the agent was remarkable,” said Jahan. “It really does appear to be safe, and was well-tolerated in combination with pemetrexed and platinum chemotherapy. There didn’t seem to be any cumulative toxicity.”
Tumor-infiltrating lymphocytes had marked recruitment and expansion after the therapy was administered in the 3 patients analyzed by immunohistochemistry. Infiltrating CD8+ cells, macrophages, and natural killer cells were also enhanced.
“We saw good immune activation which confirmed the preclinical hypotheses for utilizing this agent,” said Jahan. “It appears to activate both innate and adaptive immunity and then develops a synergistic efficacy with the chemotherapy.”
Jahan concluded: “CRS-207 is an exciting agent for patients with mesothelioma. Our preliminary results are encouraging, suggesting superior clinical activity when added to standard chemotherapy. This supports assessing the impact of CRS-207 in a randomized trial, which is currently in the planning stages and should be underway within this calendar year.”
1. Jahan T. 208O_PR: CRS-207 with chemotherapy (chemo) in malignant pleural mesothelioma (MPM): Results from a phase 1b trial. Presentation at: 2016 European Lung Cancer Conference; April 13-16, 2016; Geneva, Switzerland.