Expert Discusses Promise of CRS-207 Vaccine in Mesothelioma

Thierry M. Jahan, MD

The investigational cancer vaccine CRS-207 may improve response and survival when given with chemotherapy in patients with malignant pleural mesothelioma (MPM) according to results of a phase Ib trial.¹

CRS-207, a live-attenuated, double-deleted Listeria monocytogene engineered to express the tumor-associated antigen mesothelin, was administered with chemotherapy to 38 patients with MPM. Of 34 evaluable patients, 59% (n = 20) had partial response posttreatment and 35% (n = 12) had stable disease, for an overall disease-control rate 94%. Median progression-free survival was 8.5 months and median overall survival had not been reached.

Immunohistochemistry data from 3 patients revealed an increase in tumor-infiltrating lymphocytes (TILs) post—CRS-207. Treatment-associated changes in circulating immune cells and biomarkers were also observed.

The most commonly reported treatment-related adverse events (AEs) include grade 1/2 infusion-related fever, chills/rigors, hypotension, and nausea/vomiting with no treatment-related serious AEs or deaths.

OncLive: Currently, what options do patients with advanced mesothelioma have?

To learn more about this study and the potential of CRS-207 in mesothelioma, OncLive spoke with lead study investigator Thierry M. Jahan, MD, a clinical professor in the Department of Medicine at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center.Jahan: Mesothelioma is a very difficult disease to treat. The standard of care for advanced mesothelioma is chemotherapy with pemetrexed and cisplatin and that yields somewhere between a 20% to 40% response rate and a median survival of about 1 year. The outlook is very bleak. Most of the patients are really not resectable, so there is no surgical outcome for them.

How does treatment with Listeria work?

Therefore, as they are being diagnosed, patients are already “behind the eight ball,” so to speak. The chemotherapy regimen, which was approved 13 years ago—while certainly a step in the right direction—clearly needs more improvement because only a small portion of patients benefit from it.Turns out that mesothelioma, as opposed to normal mesothelial tissue, expresses a protein called mesothelin. Dr Raffit Hassan, one of the lead investigators in this study, has done a lot of work trying to target mesothelin. One of the ways to target it is to use this double-deleted strain of Listeria, in which you delete a couple of genes. One of these genes makes it easier for the bacteria to invade other cells.

By taking that out, it is going to stay put wherever it gets absorbed. The other gene that was removed keeps it from invading liver cells, which greatly reduces its toxicity. Therefore, the product is very safe and, certainly, that has been our experience in administering live bacteria to patients who are relatively fragile. We have not seen any significant toxicity from the use of this treatment.

There is a synergy between the exposure of the Listeria and the immunity that it triggers and the efficacy of the chemotherapy. This is something that had been observed in the lab that we are confirming in patients. The bacterium basically sets up the immune system to target the tumor; in fact, we demonstrated through some biopsies that there is an expansion of the nature killer cells.

What have been the results of this treatment?

All of the TILs that are necessary to distribute the tumor are overexpressed and expanded through the vaccination. That works hand in hand with the chemotherapy, in order to likely improve the response rate.We have seen a big increase in the response to chemotherapy. The way the study is set up, we give people 2 infusions of the bacteria about 2 weeks apart before we start the chemotherapy. Once they’ve had these 2 vaccinations, we start 6 rounds of chemotherapy, and we follow that up with 2 more infusions of the bacteria at the outset of the chemotherapy.

Are there any additional toxicities with the Listeria?

What are the next steps in this research?

What kind of impact could this have on this patient population?

For those patients who have responded and are clinically stable, we move on to a maintenance period where they receive a boost of Listeria every 8 weeks. We have seen some really impressive responses; almost 60% of patients responded. Approximately 94% had some sort of clinical benefit—either stabilization of their disease or an outright response. It is an impressive signal for a small study like this.The toxicity of the chemotherapy was not increased as a result of the Listeria, which was a very nice finding. We have not seen any major toxicities other than fevers and chills, which basically last the day of the infusion. We evaluated patients the day before, the day of, and the day after the infusion, so we have a very really good sense of how they tolerated things. Generally, they are a little bit fatigued by the third day, but they recover from that very quickly.This is a strong enough signal that it will lead to a global randomized trial, which is in the process of being implemented. We believe that the study should be able to get started and enroll its first patient sometime in 2016.It will certainly offer an option to improve the response to the treatment, stabilization, and survival. There are some other possibilities to combine it with other therapeutic approaches as an attempt to improve it further. There are other immune agents being invested in combination. You will hear more on that as we develop things.

Jahan T, Hassan R, Alley. CRS-207 with chemotherapy (chemo) in malignant pleural mesothelioma (MPM): results from a phase Ib trial. Presented at: 2016 European Lung Cancer Conference; April 13-16, 2016; Geneva, Switzerland. Abstract 2080.