Are TILs the next big thing in cancer treatment?

DDW’s Megan Thomas speaks with Dr Chantale Bernatchez, Director of Cell Therapy Process Development at CTMC, about tumour infiltrating lymphocyte (TIL) therapy and what's on the horizon for this new class of cell therapy. TIL therapy is a form of cancer immunotherapy. It's an autologous cell therapy, meaning cells are extracted from one patient and returned to the same patient. Bernatchez believes TILs hold promise for two key reasons: they address the heterogeneity of solid tumours and can be lab-engineered to restore their function. Heterogeneity of solid tumours According to Bernatchez, addressing the heterogeneity of solid tumours is crucial.Chimeric antigen receptor T-cells (CAR-T) is another T-cell therapy effective for blood cancers, using T-cells from the blood. These T-cells don't normally recognise tumours and are lab-engineered to uniformly recognise one tumour determinant, which may allow some tumour cells to escape. Comparitively, TILs occur naturally. Bernatchez says: “We isolate T-cells from the tumour tissue. T-cells accumulate at this location because they recognise something from the tumour. But they recognise it through their natural mechanisms by using their T-cell receptor. If you harvest those T-cells, then you harness a T cell population that has a breadth of tumour antigen targeting which is very different from the single antigen targeting that good CAR T-cell therapies can offer. The issue with the TIL, though, is that because they have been in a tumour trying to fight it, but failing at it, they have impaired function.” Regulatory approval: Amtagvi Iovance are using TIL successfully in melanoma, treating patients with large numbers of T-cells to overcome their natural functional impairments. This year, after four decades of scientific experimentation, the FDA approved Iovance’s lifileucel (Amtagvi), the first treatment for cancer using TILs. Bernatchez says the next generation of TIL products are exploring ways to engineer T-cells to be more potent. She says: “Hopefully, we will eventually need fewer of these engineered T-cells to be able to bring about cures. We want to find a cure and ensure patients experience long-term durable responses." Bernatchez comments on antibody-based therapies. She says: “They target T-cells in the body, so you don't have to grow cells outside the body for these therapies. By reactivating all the T-cells in your body, anti-tumour or not, these therapies have caused side effects that are autoimmune in nature because some T-cells elsewhere in your body will target determinants on your normal cells.” The changing landscape When Bernatchez started working with cell therapies at MD Anderson Cancer Center in 2007, the therapies available for metastatic melanoma patients were few. First came the targeted therapies with the B RAF inhibitor and MEK inhibitors, which cause rapid response, but of which most patients become resistant. Bernatchez explains that the duration of response is not very long, and patients become difficult to treat after they recur. Checkpoint blockades were also in clinical trials at the same time as the B RAF and MEK inhibitor and were approved shortly after. Bernatchez says: “From the moment they were FDA approved, it was a small revolution in the melanoma field because they have high response rates and can produce durable responses." We now know that responses to TIL after patients progress on these new therapies are a bit lower: it used to be a solid 50%, now it's more 25-30%. “We still see durable responses”, says Bernatchez. With Iovance’s approval, it is attempting to move TIL therapy into earlier stages of the disease. Key breakthroughs Key breakthroughs, according to Bernatchez, include the first proof-of-concept that proved immunotherapy could treat cancer with high dose IL2, approved in the 1980s. Then, between the 1980s and around 2010, checkpoint blockade came in and people tried vaccination, though not very successfully. Bernatchez adds: “They’re coming back with cancer vaccines, but complemented with checkpoint blockade. That works better, leading to significant improvements in patient survival as opposed to checkpoint blockade alone.” The use of tumour-infiltrating lymphocytes (TILs) for the treatment of cancer. Future outlook “Immunotherapy is here to stay,” says Bernatchez. “It has given us the most powerful anti-tumour responses both for blood cancers and solid tumours." However, Bernatchez thinks immunotherapy is currently too costly and that as the field evolves and technology develops, the cost of goods comes down, making these therapies more affordable. For personalised cellular therapies such as TIL and CAR-T, Bernatchez says the good thing is that this is a one-time therapy. While the upfront cost is higher, the overall cost may not be more than other cancer drugs that must be given repeatedly, such as checkpoint blockade. Overall, she says we need the cost to decrease for accessibility - even outside of the US. Bernatchez thinks this will come with industrialisation of cell therapies, incorporating more automation, and with the development of new bioreactors. But it remains difficult for TIL therapy specifically to standardise the process of producing the TIL and consistently manufacture a product of similar potency, since the starting material for the therapy, the patient’s very own tumour tissue, is different for every patient. Thus, everybody gets a different product; you only get treated with your own T-cells. Bernatchez continues: “We need to find what makes it consistently potent. I don't think the field is there yet. I think when we identify exactly what the potent part of the product is within the larger number of cells, then we'll be able to reduce the number of cells and the cost will make more sense." She gives an example from the CAR-T field where there was a realisation that beyond the genetic engineering of the T cells with the CAR molecule, the fitness of the T cells in which the CAR molecule is expressed is an important determinant of the product potency. It has been demonstrated that expression of the CAR molecule in less differentiated, naïve-like, T cells, produces a more potent CAR-T product requiring the infusion of fewer CAR-T cells in the patient to control the tumour. Bernatchez adds: “We need to better define the critical quality attributes of our product to then be able to reduce the dose and increase the potency.” The role of technology In the cell therapy field, Bernatchez says the process tends to be associated with the potency of the product, because the way you grow the T-cells may change their functional status. She adds: “We are trying to get to these critical quality attributes and seeing which type of bioreactors will help us grow the right type of cells. I think that we are now able to evaluate different types of bioreactors and offer different levels of automation. “It's exciting for me to see what the next few years show about the potency of these products that we're working on. I think TILs are the best solution that we have right now to fight solid tumours.” Early companies can either develop their products in-house, or they can outsource it. She thinks a lot of companies are coming up with great ideas on how to engineer TIL, like what gene to put in them or remove from them to make them work better. But it is crucial to develop these ideas into a viable clinical product in a timely manner to enable clinical proof of concept. “A lot of time can be wasted in reinventing the wheel on how to manufacture TIL,” she says. “I feel that newcomers to the field may optimise their process based on the tumours they can procure from commercial sources, which may not be representative of the patient population they plan to treat in terms of types of pretreatments they received. It's difficult to get tumour material from representative patients when you're developing your product before you begin clinical testing. This increases the odds of manufacturing failures early in the trial and sometimes leads to a lot of successive iterations in the manufacturing process during early phases of development that a company navigates through. So, I think the place you choose to manufacture and the relationship you develop with them will really either facilitate or be a hurdle in your development.” From DDW Volume 25 – Issue 4, Fall 2024 Read the digital issue Biography: Dr Chantale Bernatchez is Head of Process Development at CTMC. With more than 25 years of experience in the fields of immunology and T-cell therapy, Dr Bernatchez has been instrumental in advancing academic and biotechnology work in TIL and CAR-T biology, process development, and manufacturing. She holds four patents on TIL/adoptive cell therapy.