Immunotherapy is one of the biggest things in oncology at the moment and San Carlos-based Lion Biotechnologies Inc., is pushing ahead using tumor-infiltrating lymphocytes (TILs) to destroy solid tumors.
With Maria Fardis, Ph.D., taking the reins as CEO in June of 2016, the company has made progress in laying the foundation for goals and milestones it hopes to achieve in 2017.
In June, Lion announced it raised $100 million in capital through a private-placement equity offering.
Fardis spoke with Bioscience Technology about the promise of TIL technology, clinical trials underway and key partnerships that are helping to shape the company’s path forward.
Originally a scientist herself, Fardis received a Ph.D. in organic chemistry from the University of California Berkley. Fardis worked at Gilead for about a decade, while simultaneously pursing her MBA, which allowed her to move into the business front and see the full scope of drug development.
She was very interested in oncology at the time and made the move to a company called Pharmacyclics, where she oversaw the development of the blockbuster cancer drug ibrutinib (IMBRUVICA®). AbbVie later acquired the company for $21 billion, according the The Street.
“It was a wonderful experience to see a product from very early development all the way to commercialization and post-marketing,” Fardis said.
Fardis then became Chief Operating Officer of Acerta Pharma, where she was in charge of development of acalabrutinib, possibly a best in class BTK inhibitor, building a full team with more than 20 ongoing clinical trials. The company was acquired by Astra Zeneca for $4 billion upfront payment and up to $7 billion including milestones, in February of 2016, and soon after Fardis took her position at Lion.
Fardis believes that in order to achieve a deep response in oncology that cell therapy is the way to go, and that is what struck her interest in the company, which was developing immunotherapies based on TIL technology.
Like other immunotherapies, TIL therapy leverages the body’s natural defense system against cancer using a patient’s own T cells.
TILs are a specific type of T cell that attack cancer by migrating and targeting cancer cells by the recognition of neoantigens, which are unique proteins present on tumor cells.
Professor Steven A. Rosenberg, Chief of Surgery Branch and Senior Investigator of Head, Tumor Immunology section of the National Cancer Institute, pioneered TIL technology and has been working on it for over a decade. In 2011, Lion identified it as a scientific asset, which has since become the core of the company, and entered into a licensing agreement with NCI to begin development toward commercialization.
The company didn’t have enough funding to create a full development team, so it took a few years to bring the two necessary pieces together – which Fardis said are, of course funding needed to execute plans, and a team of people that “are thinking and breathing TILs, day in and day out.”
Using the immune system to attack cancer
So while TILs are part of the body’s natural defense system against tumors, what happens is that the tumor is intelligent and creates a negative hostile environment, where TILS are essentially “frozen” and unable to do their job, Fardis said.
What Lion does is remove the TILs from the suppressive microenvironment and then in the lab multiply them into multiple billions of cells using the T-cell growth factor, interleukin 2 (IL-2). Seven days before the TILs are reinfused into the body, the patient undergoes lymphodepletion, via chemotherapy, in order to remove the negative microenvironment from the tumor and maximize the effectiveness of the TILs.
Once the patients receive the expanded TILs, it’s followed up with up to six doses of IL-2 to allow the cells to continue growing and ensure the cells feel at home and comfortable so they can do their job of attacking the tumors, Fardis explained.
Melanoma and beyond
Lion’s primary focus and the bulk of Rosenberg’s data has been in melanoma. A randomized Phase 2 trial in 101 metastatic melanoma patients had encouraging results thus far, with high, durable objective response rates.
The overall response rate in the patients was 56 percent, with complete responses observed in 24 percent of patients. Some patients from other trials have remained free of the disease for more than 10 years.
Twenty-three of the 24 participants who saw a complete response, were still in complete response at a median follow up of 30 to 47 months.
There was also a complete response rate of 29 percent reported in 34 patients that had failed other options such as Anti-CLTA4 or Anti-PD1.
Adverse effects of treatment were mainly known side effects of chemotherapy and administration of high dose IL-2.
The findings were published in July of 2016 in the Journal of Clinical Oncology.
Rosenberg also has some preliminary data on cervical cancer, so the company is also pursuing that avenue, in addition to head and neck cancer.
Fardis explained the rationale behind head and neck cancers: “In cases of cervical cancers there was a hypothesis that the presence of HPV (human papillomavirus) allows for recognition of that antigen by the TILs, so other diseases where they might have the HPV antigen could be very good targets for TILs.”
Head and neck cancer has a very large prevalence of HPV presence, so it makes logical sense, scientifically to look at them as potential targets, Fardis said.
Lion is currently enrolling a Phase 2 clinical trial for the treatment of refractory metastatic melanoma using autologous TIL (LN-144) followed by IL-2 at multiple sites across the U.S.
Key partnerships and collaborations
Lion has a number of key partnerships that are helping them undertake clinical trials. A close and important partner is NCI, which completed the melanoma study and is currently enrolling a second Phase 2 study in ocular melanoma.
The company is also exploring TILs as a combination therapy, which is often how oncology is tackled, Fardis said, with physicians wanting to treat the patient the first time around without recurrence. NCI is also currently enrolling participants for a Phase 2 study that will investigate TILs in combination with Merck’s checkpoint inhibitor Keytruda, in patients with melanoma.
Another institution Lion works closely with is the Moffitt Cancer Center in Florida. Lion has a research group out of Tampa, Fla., right across the street from Moffitt and both are collaborating on two clinical trials in melanoma patients. One Phase 2 trial has already been completed, but final results have not been released, while the other is a Phase 1 trial currently enrolling, to investigate TIL in combination with Bristol-Myers Squibb’s Opdivo.
Karolinska Institute is collaborating with Lion to explore a novel TIL cocktail for treatment of glioblastoma, as well as pancreatic cancers. The Phase 1 studies are anticipated to begin in mid-2017.
MedImmune, a subsidiary of AstraZeneca, is another partner, though no clinical trials have begun yet, as the companies are still considering what indication they would like to explore, Fardis said.
Upcoming goals for 2017
Fardis said 2016 was an important year, where the company built a lot of capacity, but she is more excited for the upcoming year.
She touched on three functions that Lion plans to focus on during 2017: clinical development, manufacturing, and regulatory functions.
From the manufacturing perspective the focus has been on two directions. One, is shortening the duration of the process of manufacturing. Although Rosenberg was able to shorten it into an approximately five to six-week process at NCI, Fardis would prefer to have this shorter. She has said publicly that the preliminary work is focused on making the processes about 30 percent shorter, or around four weeks. She’s optimistic that the manufacturing time can be reduced even further.
Secondly, Fardis wants additional lines of manufacturing, so more contract manufacturing organizations (CMO’s) working closely with the company. Lion recently announced a three-year manufacturing services agreement with manufacturing organization WuXi AppTec, Inc., and they also have a relationship with Lonza. Fardis said there are two other organizations the company is working with closely, but have not made public announcements as of yet. So the main manufacturing milestones the company hopes to achieve is building about four U.S. based capacity lines, as well as pursing EU capacity.
“On the clinical front we are running the Phase 2 melanoma study and we expect to complete enrollment as well as provide some clinical and pre-clinical data at an upcoming scientific forum,” Fardis said, though she declined to say which one. The company is also looking forward to starting the cervical cancer and head and neck cancer studies mentioned earlier, as well as collaborating with Karolinska on the pancreatic and glioblastoma indications.
“So we hope by the end of 2017 to be looking at five indications with TILS to see where our best set of data is,” Fardis said.
Finally, from a regulatory perspective, Lion plans to engage the Food and Drug Administration to ensure there is a clearly defined regulatory path for the company’s key product, which is called LN-144, in melanoma.
“We are starting to talk to EU authorities in 2017, in anticipation of clinical trial conduct and otherwise.”
One thing Fardis wanted to emphasize was the importance of a good team. When she started in June there were about 20 team members, but the company has since grown to around 60 people.
“At the end of the day it’s the people that make a drug successful – you do need a good asset of course, no question about it, but it is the people who ultimately make it happen,” Fardis said, adding that she thinks they now have a wonderful team in place in order to accomplish their goals.
“It [2016] has been a great year, but 2017 is a much bigger year for us, and we now have the team members, as well as the technology and the infrastructure for us to execute it.”
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