TILs Taking on Solid Tumors

In February 2024, the FDA approved the first T-cell therapy for a solid tumor: Amtagvi (lifileucel), developed by Iovance Biotherapeutics. The therapy is indicated for adults with advanced melanoma – after patients have tried other options, such as immune checkpoint inhibitors and targeted therapy. 

The therapy makes use of tumor-infiltrating lymphocytes (TIL) – naturally occurring immune cells that are highly patient specific. TILs recognize distinct tumor markers on the surface of cancer that are unique to each patient. TIL cells are collected from a patient’s tumor and then “reinvigorated” and expanded in Iovance’s manufacturing process. When the cells are infused back into the patient, they should gain the ability to better fight the cancer.

Here, we speak with Friedrich Graf Finckenstein – an oncologist who has seen every corner of drug development from small molecules to biologics, and now T-cell therapy. Today, he is the Chief Medical Officer at Iovance. He described his decision to join the company in 2019 as akin to “jumping on a speeding train.”

What is your background and history in big pharma?
 

I’m a pediatric hematologist oncologist. I trained and I practiced at an academic institution in Hamburg, Germany. As well as working with kids with cancer, I also did work in the adult oncology ward, including bone marrow transplantation, high-dose chemo, and stem cell rescue work with adults. Today, some of those diseases can now be treated with targeted medicines. Years ago, high-dose chemo and bone marrow transplantation were the only options, but they didn’t work very well and were highly toxic. It’s been great to see the evolution!

In the early part of my career, I also did a lot of lab research involving molecular biology and transcription factors in rare solid tumors in kids. I stepped into drug development with industry in the 2000s. I joined Bristol Myers Squibb (BMS) because of my prior experience with sarcoma biology, holding various roles of increasing responsibility, mostly in the small molecule area targeting different molecular features of tumors that were of interest at the time, including epidermal growth factor receptors. BMS was one of the first companies to bring an immuno-oncology project forward with ipilimumab (Yervoy), and then the company started working on anti-PD-1 therapy, later leading to nivolumab (Opdivo). I transitioned into this space as part of a move into later-phase clinical research. 

I ran one of the registrational trials for nivolumab in non-small cell lung cancer, which was a big deal because it was the first tumor outside of the “usual suspects” that are sensitive to immunotherapy. Back then, it was really only melanoma and renal cell cancer that were considered as sensitive to any sort of changes of the human immune system. It was a big step for the immuno-oncology field and I’m glad I had the opportunity to be part of it.

After that, I stepped back into earlier clinical research and took on a leadership position at Roche in Basel, Switzerland, where I was responsible for the entire early development portfolio and oncology. This was a very interesting time because, in a large organization like that, you have a lot of infrastructure and resources behind you to do some really good projects. I then joined Iovance in mid-2019 as chief medical officer.

Why move into cell therapy?
 

I started with the small molecules and molecularly targeted medicines – and I saw how these worked for defined populations that have certain molecular drivers. Next, I stepped into immuno-oncology, where it seemed that the anti-PD-1 therapies seemed to work for broad populations. It was a powerful approach – a paradigm shift. When you see a success like that you want to experience it again. For me, cell therapy had the promise of doing that because it overcomes some of the limitations of a systemically administered drug that is generally turning on the dials and switches of the immune system to make it go after the cancer cells. Cell therapy can be used for specific indications and the work that was going into it was exciting. I wanted to be part of it.

My jump to a smaller company was also a very conscious effort. I had spent a lot of time in big pharma. I enjoyed the powerhouse and the resources, but the environment also came with all the infrastructure and the frameworks needed to make the right decisions in the context of a large organization. I wanted to experience a more agile, flexible setting where decisions could be made faster and where the focus is tighter; after all, many biotechs only have one asset in development.

What made you choose Iovance?
 

When looking at the biotech field, I asked myself, “Where can I really contribute?” I looked at both engineered and non-engineered cell therapies, and I started talking with Iovance. After looking at the data they had already generated, I saw the potential and the high chance for their TIL therapy succeeding into what could potentially be the first single-administration T cell therapy for solid tumors. This was a big deal! 

People had demonstrated that cell therapy works for hematologic diseases, but now there was a keen focus to translate this to solid tumors. One of the biggest barriers in getting engineered cell therapy to work for solid tumors, however, is the immune escape mechanisms that solid tumors employ, the tumor microenvironment, and heterogeneity both within the patient and also between patients. Despite the challenges, the data showed that the Iovance cell therapy was working well. The company had published a very exciting dataset in melanoma and presented data at ASCO. Importantly, the therapy was working in patients who had run out of other options. I decided that this was the company I wanted to join. I felt like I was jumping on a speeding train!

How does the therapy work?
 

The field had known for some time that TILs were promising. A pioneer in the TIL field, Dr. Steven Rosenberg (today chief of the surgery branch at the National Cancer Institute), had been working on TILs since the late 1980s. The first clinical trials with TIL were done in the 1990s and generated really exciting data – specifically in melanoma – decades prior to immune checkpoint inhibitors becoming the standard of care. Iovance has taken the approach from academia and developed it into a drug with a scalable, controlled manufacturing process. My job was to come on board and get the drug into a place where it could be submitted for regulatory approval.

To create the therapy, we remove a piece of tumor tissue from the patient and then multiply the TIL cells. There are two reasons for why this is a good thing. First, we can give many more TIL cells back to the patient that can help fight the tumor. Second, by removing the TIL cells from an environment that has been holding them back, we can reinvigorate the TIL cells to give them a better chance at doing their jobs and helping to clear the cancer.

Most of us probably have a few cells inside of our bodies that are trying to do something crazy. Mutations over time may mean certain cells don’t follow their genetic instructions anymore – and they may start to multiply. The immune system often removes these cells, but if it doesn’t succeed then a patient can develop cancer. Tumors can evolve to evade the immune system by slowing the T cells down, switching them off, or not letting them into the tumor cells. If we remove a T cell from this environment, it can recover.

Before Iovance developed their process, patients had to go to the hospitals and institutions that were able to do this in their own research labs. These patients would have to wait for the cells to be made (which could take up to 6 weeks). This isn’t something you can submit for approval to a health authority for review – because all centers will do it in their own way, there is not a standardized product. Iovance brought control to the approach and developed a centralized manufacturing process that can be reviewed and approved – and scaled to treat greater numbers of patients. We call our manufacturing process “Gen 2” – because a lot of work went into reducing the duration of the manufacturing process down to 22 days. We are also working on a Gen 3 process, which could reduce manufacturing to 16 days.

Could TILs take on other types of solid tumor?
 

Amtagvi works by taking advantage of the patient’s own immune system. In principle, this isn’t limited to a specific type of solid tumor. Indeed, academic institutions have already run some clinical trials showing that TIL has promising activity in tumor types outside of melanoma. We will be looking to develop the therapy for other tumor indications beyond melanoma.

Another key focus is bringing the therapy to earlier treatment lines. Right now, the approval of Amtagvi is for patients who have progressed on or have had at least one prior line of therapy for advanced disease, including checkpoint inhibitors, which are the frontline standard of care. It is used for patients who have progressed in their disease and are out of other options. But what if we could bring the therapy to earlier treatment settings prior to progression? Historical data show that TIL therapy might lead to higher response rates, longer response, duration, and even cure rates if used before checkpoint inhibitors. In an ongoing phase III trial, we are combining Amtagvi with the checkpoint inhibitor pembrolizumab (Keytruda), which is the standard of care, to see if we can improve outcomes in frontline advanced melanoma.

What could be possible in the future?
 

We have a strong focus and a lot of activity ongoing with clinical trials for patients with non-small cell lung cancer, which means I’ve come full circle (non-small cell lung cancer is where I started in drug development with nivolumab)! There are so many patients with lung cancer and there is a huge unmet need. Yes, there are checkpoint inhibitors, which are usually combined early on with chemotherapy, but many patients are not cured. We are currently conducting a phase II study where we are exploring our TIL cell therapy in patients with advanced non-small cell lung cancer that have received chemo and immune checkpoint inhibitors, and we intend to use the data to submit to a health authority for review. This is a very large patient population and the data, so far, are very exciting. We think a cell therapy for lung cancer could be possible. 

We are also looking at some additional tumor types, and we are working on what we call next-generation TIL therapy products.” We are looking to use genetic modifications to make them more potent and more active. Other engineered cell therapies dial in specificities for certain antigens, which limit their potential to just the tumor cells that have that antigen. We are taking advantage of TIL therapies being polyclonal and with lots of specificities that are tailor made for the patient because they were made by the patient’s own immune system. We are knocking out checkpoint chains, with PD-1 being an obvious target. Indeed, we have another clinical trial exploring a TIL product with a PD-1 knockout, but there are other breaks that T cells have that we could consider knocking out as well. We could also engineer an additional gas pedal for the TIL cells that would strengthen them by allowing them to express their own growth factors; we call this approach tethered cytokines.

For the near future, I think the focus will be on optimizing what we have now. TILs are very individualized therapies. 

But let’s not end by talking about the future – let’s talk about now! We really believe that Amtagvi is a breakthrough therapy and we’re excited to bring it to patients who, right now, have no other options. We have to focus on expanding access and bringing the therapy to more geographic areas too. Our manufacturing teams are working “full blast” to get this therapy to as many patients as possible!