Pancreatic cancer is one of the most deadly and aggressive cancers afflicting patients and confounding medical researchers. The drug development industry is replete with earnest failed attempts, including testing new immunotherapies at finding an effective therapy for this unmet medical need. As a recent Fierce Biotech story headline read: “Another effort on pancreatic cancer flops…”

It is a very grim disease for those afflicted. The survival rate for those diagnosed with this disease is less than 25% for one year and only 10% for five years. Though it is a relatively rare cancer it is the third leading cause of cancer death. Because early warning signs are few and the disease is usually not discovered until the cancer has developed in a later stage.

Oncolytics Biotech Inc. based in Calgary, Alberta, Canada is trying a new approach. The company is developing pelareorep, a safe and well-tolerated intravenously delivered immuno-oncolytic virus (IOV) that kills cancer through a unique mechanism of action with two components, selective tumor lysis and activation of the innate and adaptive immune systems, creating an inflamed phenotype to treat a variety of solid tumors and hematological malignancies.

“Pelareorep selectively replicates in permissive cancer cells and turns or wakes up the immune system to see and fight the cancer. It does this by activating both the innate and adaptive immune systems; converting immune unresponsive ‘cold tumors’ into immune responsive ‘hot tumors’ says Oncolytics Chief Medical Officer and surgical oncologist Rita Laeufle, MD, PhD.

Leading the clinical development of pelareorep Dr. Laeufle brings more than 15 years of experience in drug development in oncology. Prior to Oncolytics she served as Vice President of Clinical Development & Medical Affairs at SFJ Pharmaceuticals where she developed a clinical program for a new drug substance class in colon cancer. Previously, Dr. Laeufle was Senior Vice President, Clinical Development of Oncology at Coherus Biosciences where she developed a biosimilar strategy for Avastin, prior to which she was Senior Medical Director, Global Medical Affairs at Clovis Oncology, where she led the Medical Affairs strategy for their PARP inhibitor, Rucaparib. Dr. Laeufle completed medical school at Medical School Albert Ludwig University Freiburg i.Br. Germany, where she received her Ph.D. in exploring Her2 oncogenes in brain cancer.

WuXi AppTec communications, as part of new series on innovation asked Dr. Laeufle why pancreatic cancer was so difficult to treat and how she believes Oncolytics’ new approach might be the answer.

WuXi: What is your opinion about the challenges in pancreatic cancer, early screening and diagnosis? Are there any specific biomarkers?

Rita Laeufle: Unfortunately, pancreatic cancer has no screening method and is usually diagnosed at a very late stage. There is no biomarker that can identify early pancreatic cancer, and most of the early detected pancreatic cancer is chance findings. These include for example, during Gall bladder surgery perioperative inspections or back pain diagnostics via MRI. For patients who are known to carry the BRCA1/2 mutation, early screening for development of pancreatic cancer may be considered, but this is a very low mutation affecting only approximately five percent of all pancreatic cancer patients.

WuXi: What are the hot targets in the field of drug development for pancreatic cancer?

Rita Laeufle: Aggressive chemotherapy is still the mainstay for pancreatic cancer and no targeted agents have been approved in this indication. Immunotherapy studies, including mainly single agent checkpoint inhibitor regimens, are ongoing but none of them have led to a success yet. The future for pancreatic cancer treatment will most likely be combination immunotherapy regimens, with immune stimulating agents, such as our oncolytic virus pelareorep and an anti-PD-1/PD-L1, possibly with chemotherapy as well.

WuXi: In recent years, what breakthroughs have been made in drug development for pancreatic cancer?

Rita Laeufle: Breakthroughs in pancreatic cancer therapy are yet to come. FOLFIRINOX, a triplet of chemotherapy, Gemcitabine and Abraxane, were approved several years ago, but they come with significant toxicity. The breakthrough will likely and ideally be immunotherapy combinations that will reduce the use of chemotherapy in this indication.

WuXi: How is your drug different from existing pancreatic cancer treatments? Is it a new approach? What have been results of your research so far?

Rita Laeufle: It is a new approach that involves a combination treatment regimen with our oncolytic virus, pelareorep, a checkpoint inhibitor, and may involve standard of care chemotherapy.

What we know is that immunotherapy with a checkpoint inhibitor alone can work very well, but only in a very limited number of cancer patients. Overall, these drugs have not led to a successful treatment option in pancreatic cancer, as it is a very heterogeneous disease and only a few patients may benefit from these new agents.

One of the main reasons checkpoint inhibitors do not work well for pancreatic cancer is that it is not a very immunogenetic disease. This means, that immune cells are not present, or have a very low presence in the tumor, but they are needed for checkpoint inhibitors to work. Our approach with our virus “ignites” the immune system within the tumor, creating a tumor microenvironment that is better suited for checkpoint blockade.

Our first data from pancreatic cancer led to an Orphan Drug Designation from the FDA. In these studies, we saw that treatment with pelareorep in combination with chemotherapy increased certain immune cells in the tumor, and the subsequent treatment with checkpoint inhibitor has resulted in durable long-term responses that have not been observed in heavily pre-treated patients within this indication.

WuXi: What is the specific mechanism of action?

Rita Laeufle: Pelareorep selectively replicates in permissive cancer cells and turns or wakes up the immune system to see and fight the cancer. It does this by activating both the innate and adaptive immune systems, converting immune unresponsive ‘cold tumors’ into immune responsive ‘hot tumors’.

Cancer cells infected with pelareorep release inflammatory cytokines. This inflammatory milieu activates natural killer cells and promotes the migration of natural killer cells, dendritic cells, and T cells to the tumor microenvironment. The release of the tumor and viral associated antigens are taken up by antigen presenting cells, which then process and present antigens to T cells. This trains the adaptive immune system to recognize and kill cancer cells. An adaptive immune response allows for existing cancer cells to be eliminated, constant cancer cell surveillance, relapse prevention, and increased overall survival, as we’ve observed in both pancreatic and metastatic breast cancer studies.

WuXi: How did you choose to focus on pancreatic cancer? It has been a very difficult disease to treat.

Rita Laeufle: Pancreatic cancer is not our key focus, but there is an unmet medical need and early data on pancreatic cancer indicates that pelareorep could stimulate the immune response in these patients. Oncolytics is collaborating with Dr. Devalingam Mahalingam from Northwestern University who is currently conducting a clinical study with pelareorep in combination with Keytruda in advanced pancreatic cancer patients.

WuXi: Are you planning to develop the drug through regulatory approval and market it?

Rita Laeufle: We have always planned to partner before going into phase 3 in metastatic breast cancer but would like to maintain some rights to North America and participate in marketing but suspect our partner would drive most of those efforts. Beyond breast cancer and other cancers, we are currently evaluating for development, pancreatic cancer is extremely valuable to Oncolytics, as there is a clear unmet need for these patients.

WuXi: Have patients been involved in the development of your drug other than participating in clinical trials, of course?

Rita Laeufle: Absolutely. We currently work with patient advocates – often cancer survivors – that help with the conduct of our clinical studies.

WuXi: What major challenges have you faced in trying to bring a new drug for pancreatic cancer to patients?

Rita Laeufle: Pancreatic cancer is a heterogeneous disease and the treatment options are limited to chemotherapy. There is at present no biomarker that has been identified that could help to target the disease with other agents – and many studies in pancreatic cancer have failed to demonstrate a treatment benefit. Oncolytics has identified a biomarker that we are now working to confirm and validate. It should identify patients with pancreatic cancer – and other indications – that can successfully respond to treatment with pelareorep. The major challenge is to move quickly to confirm the biomarker in a larger patient population.

WuXi: What lessons have you learned during the development process?

Rita Laeufle: It is important to understand which patients are responding to treatment as early in the treatment course as possible. In the case of pelareorep we learned that we must look at early emerging biomarker data, such as new T cells and T cell expansions, as those are most likely the patients who respond to this novel treatment approach and benefit.

WuXi: Have you benefitted from FDA initiatives, such as breakthrough therapy and fast track designations? If so how?

Rita Laeufle: Yes. We have been granted an Orphan Drug Designation from the FDA for pancreatic cancer. The FDA is also supporting and encouraging biomarker driven treatment decisions. Most of the approvals that receive fast track designations are based on and biomarker approach. With further emerging data on biomarker we will reach out for guidance on how to optimize a potential fast registration

WuXi: What other drug candidates do you have in the pipeline?

Rita Laeufle: Currently we focus on the development of Pelareorep.

WuXi: What do you think of the concept of focal therapy whereby the FDA would look favorably on clinical trials of new treatments that would ultimately reduce or delay the need for organ removal like the pancreas?

Rita Laeufle: Pancreas resections are generally done at an early stage of the disease, but unfortunately it is often not diagnosed early enough for this to be possible. The stage at which clinical studies are conducted in pancreatic cancer with immunotherapy – including our Oncolytic virus Pelareorep – is in the advanced setting. In this case, the only way to reach all tumor tissue is through systemic delivery, intravenously. This can broadly reach the tumor and may prevent tumor growth – create stable disease – and even lead to tumor reduction that we call response. Both of which we have seen in our study. It’s important to note the obvious here, but you can’t live without your pancreas and advanced pancreatic cancer is not an indication for transplant.

WuXi: Looking at the entire drug development process, from discovery all the way to drug approval, what would be the 4 or 5 key areas or processes you would change or improve in order for companies to bring more and better drugs to patients each year?

Rita Laeufle: With a good understanding of how the drug ‘works’, how it combines with other agents, whether it is safe as single agent or to combine, a drug can move into larger clinical studies. However, instead of running large studies and exposing patients that may not benefit from the drug, I would like to see more biomarker focused efforts to identify patients that benefit from the treatment and focus on these patients. That may require more time in the early stage but can streamline the registration studies and focus on patients that benefit and most likely the studies can be done faster as less patients are required to confirm the clinical benefit.

WuXi: What will be the one or two most significant technological advances in drug development over the next year or two?

Rita Laeufle: Simplifying diagnostic tests to identify biomarkers that inform clinical success.