What is TIL therapy and how does it work?
TIL cell therapy (Tumor-Infiltrating Lymphocytes) is a type of adoptive immunotherapy that uses tumour-infiltrating T lymphocytes from the patient to fight cancer.
In essence, a sample of the patient’s tumour is surgically obtained, from which the T lymphocytes already infiltrating the tumour tissue are isolated. These isolated TILs are then cultured and expanded ex vivo (outside the body) until they reach a population of billions of cells in the laboratory. To achieve this massive expansion, the cells are cultured for several weeks in the presence of interleukin-2 (IL-2), a cytokine that stimulates T-cell proliferation. Once the required number of cells has been reached, the activated TILs are infused back into the patient intravenously, where they specifically recognise and attack cancer cells, leaving surrounding healthy cells unharmed.
Before the TIL infusion, patients typically receive a brief lymphodepleting chemotherapy regimen (around one week) in order to temporarily eliminate part of the patient’s leukocytes and “make room” for the transferred lymphocytes. Immediately after the TIL infusion, several additional doses of IL-2 are administered to support TIL survival and activity in the body. Unlike many conventional oncologic treatments that require continuous administration, TIL therapy is usually a single treatment (one cell infusion) per therapeutic course, although it could potentially be repeated in the future if the patient responded well and needed treatment again.
Originally, TIL therapy was developed in the 1980s by Dr Steven Rosenberg and colleagues at the U.S. National Cancer Institute (NCI), showing for the first time that infusion of expanded tumour-infiltrating T lymphocytes could induce tumour regression in metastatic melanoma. Since then, protocols have been refined and TIL therapy has been studied mainly in solid tumours such as melanoma, cervical cancer, head and neck cancer, lung cancer and others. A recent milestone was the FDA’s accelerated approval in 2024 of lifileucel (Amtagvi), the first commercial TIL therapy, for advanced melanoma. In the pivotal clinical trial, lifileucel achieved an objective tumour reduction in 31.5% of patients with metastatic melanoma refractory to prior treatments, with 43.5% of patients maintaining remission for at least one year. This advance demonstrates the potential of TIL therapy to offer effective options even in advanced cancers where other therapies have failed.
What are the key benefits and limitations of TIL therapy?
TIL therapy offers major benefits such as using the patient’s own T cells, broad tumour targeting, and durable responses in some cancers. However, it also has clear limitations, including complex manufacturing, high costs, and treatment-related toxicities.
Key benefits
- Use of autologous cells. It uses the patient’s own T lymphocytes, reducing the risk of immune rejection. Because the cells come from the same patient and do not require genetic modification, TIL therapy tends to be well tolerated, with low intrinsic toxicity.
- Broad specificity (polyclonal response). The TIL product is polyclonal, containing numerous T-cell clones capable of recognising various tumour neoantigens. This enables attack on different subpopulations of cancer cells within a heterogeneous tumour, addressing variability and tumour escape better than therapies directed at a single target.
- Efficient tumour infiltration. After infusion, TILs retain an effector-memory T-cell phenotype with chemokine receptors that facilitate homing back to the tumour and penetration of the tumour microenvironment. This improves their ability to locate and destroy cancer cells in situ.
- Efficacy in refractory tumours. TIL therapy has shown significant response rates in certain advanced cancers that did not respond to standard immunotherapies. For example, in early studies in metastatic melanoma, objective responses were achieved in around half of treated patients, and in the lifileucel study above, 31,5% of heavily pretreated patients experienced tumour reduction, with some durable remissions lasting several years.
- One-time treatment. Unlike chemotherapy or conventional immunotherapies that may require repeated doses, TILs are typically administered in a single procedure, which improves patient convenience. While the peri-infusion protocol is intensive (surgery, cell culture, conditioning chemo, post-infusion IL-2), once completed it usually does not require continuous maintenance. This also means that, once the initial recovery period is over, the risk of new adverse events decreases considerably.
Key limitations
- Complex, personalised process. Manufacturing a TIL treatment is labour-intensive, costly and highly specialised. It requires surgery to obtain the tumour followed by cell processing in a laboratory to isolate and expand T lymphocytes for 4-6 weeks. This process needs trained technical staff, GMP facilities and specialised equipment, which increases cost and limits availability. Patients must also be clinically stable enough to withstand the waiting time and associated procedures (surgery and conditioning chemotherapy).
- Dependence on effective lymphocytes within the tumour. TIL therapy is only feasible if the patient’s tumour contains infiltrating T lymphocytes with antitumour activity. Not all “cold” tumours or those with low immune infiltration are suitable, as there may not be enough useful TILs to isolate. In other words, for the therapy to work there must be, at baseline, at least a repertoire of T cells in the tumour capable of recognising the cancer, something typically seen in melanoma and immunogenic tumours, but less so in cancers with poor immune recognition.
- Immunosuppressive microenvironment. Even after expansion and infusion, TIL effectiveness can be limited by the immunosuppressive tumour microenvironment. Local factors such as immunosuppressive cytokines, regulatory cells and inhibitory ligand expression can lead to dysfunction or “exhaustion” of TILs once inside the tumour, reducing their cytotoxic capacity. This barrier, intrinsic to solid tumours, is one reason why responses to TILs vary between patients and cancer types.
- Limited survival of transferred cells. Infused TILs often have a limited half-life in the patient. Although conditioning chemotherapy and post-infusion IL-2 help their initial expansion, studies have observed that many of these adoptive cells disappear after weeks or months. This may restrict the durability of the antitumour response unless a long-lived memory population is established or TILs are combined with other maintenance therapies.
- Adverse effects from the treatment regimen. While TILs themselves generally do not cause severe adverse reactions, the overall protocol carries risks. Surgery to obtain the tumour has the usual complications of a surgical procedure. Lymphodepleting chemotherapy (usually cyclophosphamide and fludarabine) and high-dose IL-2 post-infusion can cause significant short-term side-effects: fever, anaemia, neutropenia, thrombocytopenia (low red, white cells and platelets), hypotension, breathing difficulty and others. These events occur mainly within the first 1–2 weeks after therapy and, although manageable in an intensive-care setting, limit eligibility, for example, very frail patients or those with cardiac/pulmonary insufficiency may not tolerate the regimen. Unlike CAR-T, TIL therapy usually does not trigger cytokine release syndrome (CRS) or severe neurotoxicity on its own, which is an advantage, but IL-2 and chemotherapy do carry substantial toxicities.
- Limited access and high cost. At present, TIL therapy is delivered only in highly specialised medical centres or within clinical trials. Until lifileucel’s approval in melanoma, it was considered an experimental treatment. Even with a commercial approval, its high cost and complexity mean that few hospitals can initially offer it. This creates inequities in access and logistical delays (for example, having to refer patients to distant centres). Overcoming these hurdles, through process standardisation, automation and cost reductions, will be crucial to expand TIL use in the future.
What is the difference between TIL therapy and CAR-T therapy?
TIL therapy expands tumour-resident T cells without genetic modification, targeting multiple antigens in solid tumours. CAR-T therapy engineers blood T cells with a chimeric receptor against a single antigen, mainly used in blood cancers. The table below summarises key differences between TIL and CAR-T:
In practice, TIL and CAR-T do not compete; they complement each other, each indicated in different areas of oncology. Research continues to improve both: for example, CAR-T for solid tumours and, conversely, genetically enhancing TILs to boost efficacy (combining approaches such as “CAR-TILs” directed at specific antigens). Ultimately, both TIL and CAR-T represent the future of personalised cancer medicine, and understanding their differences helps determine which patients might benefit most from one or the other.
How much does TIL therapy cost? Is it covered by insurance?
TIL therapy is a highly personalised treatment, which translates into a high cost. A clear example is lifileucel, approved for metastatic melanoma, priced at around $515,000 USD per dose. On top of this figure come additional expenses such as hospitalisation, surgery to obtain the tumour sample, conditioning chemotherapy and supportive medications.
In the United States, insurers are expected to cover this therapy for patients who meet medical criteria, similarly to CAR-T therapies. In addition, manufacturers have patient assistance programmes.
In Europe and other countries with public health systems, coverage will depend on cost-effectiveness assessments. If approved, it will likely be limited to specialised centres and selected patients, with public coverage.
¿What role do bioreactors play in producing TIL cells?
Successful manufacturing of a TIL therapy depends on being able to culture billions of T lymphocytes quickly, safely and reproducibly. In this context, bioreactors play a key role as a bioengineering tool to scale up cell production while meeting clinical standards. Initially, TIL expansion was performed in open laboratory systems: T-flasks and gas-permeable culture bags, with technical staff manually feeding and handling the cells. Although these methods enabled the first trials, they had serious limitations: contamination risk due to repeated exposure to the environment, a lot of variability between containers and a process very labour-intensive for specialised staff.
Bioreactors solve many of these challenges. A bioreactor is essentially a closed, controlled culture system that provides cells with an optimal environment (temperature, pH, oxygen, nutrients and growth factors) in an automated manner.
For TIL lymphocytes, protocols have been developed to carry out the rapid expansion phase (REP) in single-use, perfusion bioreactors. This allows production to be scaled to clinical levels while maintaining sterility and process uniformity. Pilot studies have shown it is possible to initiate, expand and harvest TIL populations at therapeutic scale in a closed bioreactor, obtaining cells with a phenotype and function comparable to those grown in traditional bags. Adoption of bioreactors dramatically reduces manual handling and contamination risk, making it easier for more centres to deliver TIL therapy under GMP standards. In fact, bioreactors are considered essential tools for producing cell therapies efficiently and with high quality, as they allow control of cell growth and functions and are scalable to treat more patients.
There are different bioreactor designs used in immunotherapy: from wave-mixed bag systems, to stirred-tank bioreactors adapted for human cell culture, to gas-permeable membrane devices. In TIL expansion, perfusion bioreactors have been successfully used to remove waste products and add nutrients continuously, maintaining an optimal environment for exponential T-cell proliferation. Thanks to these advances, TIL manufacturing is moving from an artisan laboratory process to an automated industrial process, which is essential to bring this therapy to more patients.
Finally, the development of bioreactor infrastructure goes hand in hand with specialised bioprocess suppliers. Companies like TECNIC offer single-use bioreactors and scalable modular systems, specifically designed for the expansion of immune cells such as TILs in controlled settings.
These modern bioreactors come equipped with sensors and controls that monitor critical parameters (pH, dissolved oxygen, cell concentration) to ensure optimal, reproducible cell growth batch after batch. In the context of TIL therapy, and other advanced cell therapies, having reliable, customisable bioreactors is key to turning clinical findings into available treatments. TECNIC, for example, provides comprehensive GMP-ready bioreactor solutions that can be adapted from lab-scale to commercial production, facilitating the transition. In this way, bioreactors and their providers are strategic partners in the mission to bring innovative cell therapies like TIL to the patients who need them, maintaining high standards of quality, safety and efficacy in every cell product.
Frequently Asked Questions (FAQ) on TIL Therapy
TIL therapy (Tumor-Infiltrating Lymphocytes) is a type of immunotherapy that isolates T cells from a tumour, expands them in the lab, and reinfuses them to fight cancer.
Reactive T cells are extracted from the tumour, activated, expanded to billions of cells in bioreactors, and then infused back into the patient after conditioning chemotherapy.
Candidates usually have advanced solid tumours, good organ function, and at least one accessible lesion for TIL extraction, plus fitness to tolerate the treatment regimen.
Side effects mainly come from conditioning chemo and IL-2, such as low blood counts, fever, low blood pressure and infections, typically managed in hospital during the first weeks.
In metastatic melanoma, 30–50% of patients respond, with some achieving complete and durable remission. Clinical trials are testing its efficacy in other solid tumours.
The price of the approved product is about $515,000 USD per treatment, not including hospitalisation or procedures. Total costs can exceed half a million dollars.
TIL therapy expands tumour-resident T cells without genetic modification and targets multiple antigens. CAR-T modifies blood T cells with a chimeric receptor against a single antigen, and is mainly used for blood cancers.
References
- Zhao, Y., Deng, J., Rao, S., et al. (2022). Tumor Infiltrating Lymphocyte (TIL) Therapy for Solid Tumor Treatment: Progressions and Challenges. Cancers (Basel), 14(17), 4160.
- Singh, R. (2024). Beyond the CAR T Cells: TIL Therapy for Solid Tumors. Immune Network, 24(2), e16.
- Phillips, C. (2024, March 5). First Cancer TIL Therapy Gets FDA Approval for Advanced Melanoma. National Cancer Institute – Cancer Currents Blog.
- Gorgas, G. C., Wunderlich, J. R., Smith, F. O., et al. (2009). Single-pass, closed-system rapid expansion of lymphocyte cultures for adoptive cell therapy. Journal of Immunological Methods, 345(1-2), 90–99.
- Garcia-Aponte, O. F., Herwig, C., & Kozma, B. (2021). Lymphocyte expansion in bioreactors: Upgrading adoptive cell therapy. Journal of Biological Engineering, 15, 13.
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This article was reviewed and published by TECNIC Bioprocess Solutions, specialists in bioprocess equipment and innovation for advanced therapies.
