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TIL therapies: the impact on cancer research

The biotech industry has been restless the past few weeks anticipating the entry of the first-ever tumor infiltrating lymphocyte (TIL) therapy into the market. Now, the recent approval of Iovance Biotherapeutics’ TIL therapy has made it possible to treat hundreds of thousands of people affected by unresectable or metastatic melanoma in the U.S.

“It’s a big milestone,” said Chantale Bernatchez, head of Process Development at the cell therapy manufacturer CTMC. “For the longest time, people thought this is not something that can be commercialized. Now, it’s proof of principle that TIL therapy can be commercialized.”

The American biotech’s drug lifileucel, known under its brand name Amtagvi, nabbed the U.S. Food and Drug Administration (FDA) win after its success in clinical trials. A global, multicenter study, which tested the drug in patients who had previously been treated with PD-1 inhibitors, found that the drug achieved a 31.5% objective response by Response Evaluation Criteria in Solid Tumors – a criteria to assess tumor burden – out of 73 patients in the primary efficacy analysis cohort. A supporting pooled efficacy set consisted of 153 patients, out of which 31.4% had an objective response. For more than 54% of the patients among them, the responses lasted beyond 12 months.

Iovance’s drug is an autologous therapy, meaning that the cells of a specific patient are removed from tumors, cultured, and reintroduced into the patient’s body. So, each lot of cells is for a particular patient, making it a personalized treatment. 

How do TILs compare with CAR-T therapy?

The FDA decision makes Amtagvi the first non-chimeric antigen receptor (CAR)-T adoptive cell therapy to hit the market. In fact, this class of drugs is the first cell therapy to target a solid tumor. Unlike CAR-T, where cells are retrieved from the blood, TIL therapy takes T cell lymphocytes (white blood cells) from the tumor, where there is an abundance of these cells.

“If T cells recognize tumors, they’re more likely to be found in the tumor. However, if they are not controlling the tumor, that means their functions are somehow lacking, and they are being overcome by the tumor microenvironment. But they are usually found there, in a sort of suppressed state,” said Bernatchez.

Whereas in the blood, Bernatchez pointed out that only a small fraction of antitumor T cells are present. So, taking T cells from the blood and reinfusing them wouldn’t be as effective because these cells lack anti-tumour reactivity. 

In the case of CAR-T therapy, these cells in the blood are withdrawn and engineered – with a CAR – to make them recognize the tumor. This way, they bypass a typical T cell response, and can spot the same antigen on a tumor. And so, these CAR-Ts “become super activated, super highly efficient killers,” Bernatchez explained. However, this comes with a downside.

If the tumor were to lose the (only) target that the CAR recognizes, it could evade the attack and continue to grow. That’s where the perks of TIL therapy come in. TILs can target a slew of antigens, although we aren’t aware which antigen it is targeting. 

“It’s specific to every patient,” said Bernatchez. “The tumors tend to contain mutations that are recognized by the immune system. So a lot of the T cells infiltrating the tumor recognize those mutations, but each patient has a different set of mutations. So, with TIL, we have the ultra personalized T cell therapy because it’s created for you and only recognizes your tumor. With CAR-T, it’s also created for you with your T cells, but we will engineer them to recognize an antigen that is expressed on tumors from most patients.”

And as TILs recognize more antigens, it makes it harder for tumors to develop resistance against them.

Moreover, CAR-T therapy was initially developed to treat blood cancers. While it has been successful in doing so, T cells in the blood rarely migrate to the tumor. So the likelihood of it combating solid tumors is rather low. TILs on the other hand, have greater efficacy when dealing with solid tumors.

While there are a number of ways to culture these cells once they have been sent to the lab to be dissected and fragmented, depending on whether and when the cells are engineered in the culture, how a TIL therapy works remains the same.

The treatment regimen

Prior to being dosed with a TIL, Bernatchez explained that patients are given chemotherapy to wipe out the immune cells from a patient’s blood so that the infused cells have a lot of space to expand into. Then, by exploiting the body’s ability to recognize tumor cells, T cells that have been reinfused into the patient identify and target the tumor. After this, the patient is given high doses of T cell growth factor IL2 for several days to rebuild the immune system. 

During the few weeks after infusion, only the infused cells are circulating in the bloodstream, giving them a head start on the rest of the immune cells.

“Basically, it’s a one-time therapy,” said Bernatchez. “It’s not a drug that you would repeatedly take, it’s just the one time, the patient will stay in the hospital until the white blood cell count in the blood rises back and the platelets come back, because the type of lymphodepletion that the chemotherapy does is transient. So the bone marrow will reconstitute new immune cells that are eventually going to reconstitute the blood fully.” 

Can TIL therapy side effects be managed?

However, TIL therapy does come with side effects. While it’s not the therapy itself, the chemotherapy and the high dose IL2 infusion part of the treatment regimen can trigger neurotoxicities. 

Bernatchez said: “The high dose IL2 can be quite toxic, but it’s mainly through acting on other cells of your body than the T cells; it will nourish the T cells and make them persist but it can also work on endothelial cells and cause vascular leak syndrome which can be fatal.”

High dose IL2 has been approved since the 1980s, and doctors have learned to anticipate these side effects and mitigate them. The other toxicity associated with TIL is on-target off-tumor. For instance, in melanoma, skin pigment-producing cells called melanocytes are overexpressed and become immunogenic. While the TILs’ job is to eliminate cancerous melanocytes, they may also destroy normal skin cells, which may cause vitiligo due to the lack of melanin production, a condition where melanin is lost from the skin leading to pale white patches. If the melanocytes in the eyes or ears are affected, it could result in blurry vision and cause hearing loss.

To combat these side effects, local steroid drops are prescribed to suppress T cells from toxic activities.

As the limelight shines on Iovance’s Amtagvi at present, this regulatory win paves the road for more TIL drugs that are in the making, to enter the market. For example, cell therapy manufacturer CTMC has partnered with biotechs to develop and oversee TIL therapy manufacturing. 

“We are partnering with organizations that have TIL or CAR-T products. So, we offer our expertise to help these organizations that are usually in the early phase think about their process, and how they can improve it,” said Bernatchez. “My group’s role is to adapt processes to be fit for the GMP environment. And part of that looks at what type of bioreactor they’re using, how we can accelerate the time from tumor resection to TIL infusion, while keeping in mind the type of technology they’re bringing.” 

Battling toxicities associated with TIL therapy

One of the companies CTMC works with is Obsidian Therapeutics, which is on a mission to limit toxicities when treating patients with melanoma. Its lead candidate OBX-115 is a TIL cell therapy that is genetically modified to produce a cytokine (IL15) that is membrane-bound. The TIL cells carry their own growth factor, dropping the need for high-dose IL2 infusion post-treatment and, therefore, reducing the risk of toxicities.

For OBX-115, interim results were encouraging, where a 50% (3/6) objective response rate was achieved with two complete responses, according to data published two months ago. 

The other company that CTMC has collaborated with is KSQ Therapeutics, which has blended CRISPR technology with TIL therapy. Having figured out which genes are crucial for T cell function, KSQ Therapeutics has created eTILs, which are gene-edited TILs. Its lead candidate KSQ-001 could offer the possibility of lower dosing and reduced patient conditioning when compared to other cell therapies. It is currently in phase 1 trials. 

“I really think that we’re looking at the next wave of TIL therapy products that are going to be engineered, and hopefully, either more potent or reducing toxicity of the regimen,” said Bernatchez.

TIL candidates move to the clinic

Other biotechs making progress in the field are American clinical-stage companies Turnstone Biologics and Instil Bio. Collaborating with the National Cancer Institute (NCI), Turnstone has developed TIDAL-01, which is currently in the clinic for the treatment of breast cancer, colorectal cancer, and uveal melanoma. Instil Bio’s phase 1 candidate is being evaluated for the treatment of non-small cell lung cancer (NSCLC), ovarian, and renal cell cancer (RCC). 

Although Amtagvi’s FDA clearance opens doors for the field, the price of TIL therapies may be a concern for many. Priced at $515,000 per patient, Amtagvi is slightly more expensive than CAR-T therapies, which cost around  $500,000 for people with blood cancers. Although this is a one-time treatment and insurance will slash some of the costs in the U.S., we are yet to see its entry in other countries, and how much it will cost patients.

“Because they’re the first one to bring this to larger patient access, they will also figure out logistics of training centers, and how to administer those cells; and put all this structure in place to bring this therapy to a large number of centers. They will have to figure out pricing and reimbursement. So it’s difficult to be the first one in a new modality, in a new class of therapeutics. But I think that Iovance is doing this for the field. And, I think it will have a major impact on cell developers. I hope that it stimulates more and more development of new and improved products,” said Bernatchez.

Now that TILs have been approved for melanoma, there is hope that they could be greenlit for other solid tumors in the future. And, as more biotechs make headway, prices could come down and so could dosages.  

Bernatchez said: “I’m excited for the future of cell therapy, I think that the field’s come a long way. It took a long time because of how cumbersome this therapy was at the beginning. Now, a lot of progress is being made in streamlining the manufacturing of TIL, making it easier. So then people really view this as a commercially-viable product. And seeing this being accessible to more patients is really exciting.”