On February 16, 2024, a real milestone was reached in the cell therapy field, as the FDA approved the first cell therapy for solid tumours. The therapy is called Amtagvi (lifileucel), a Tumour-Infiltrating-Lymphocyte (TIL) therapy made by Iovance Biotherapeutics. It is approved for treating patients with unresectable melanoma, providing valuable options to those who have failed to respond to PD-1 and BRAF inhibitors and have exhausted their treatment options.
TILs vs CAR-T cells
Amtagvi is different from CAR-T cell therapies, such as Kymriah®, Yescarta®, Breyanzi® and Abecma®, which have been approved for the treatment of haematological (blood) cancers. Instead of taking T-cells from the blood and modifying them to express a CAR, T cells are extracted directly from the tumour (hence, by nature TIL therapy is only suitable for the treatment of solid tumours). The idea is that by extracting cells in this way, tumour-reactive T cells that are primed to recognise tumour antigens and infiltrate the solid tumour can be enriched. Once the cells have been extracted from the tumour, they are expanded in the lab before being reinfused back into the patient, where their anti-tumour effects are unleashed.
This approach has a number of advantages over CAR-T cell therapy. Firstly, the cells are not subject to genetic modification through potentially mutagenic transduction processes, which has raised some concerns in the field recently. Secondly, the therapy comprises a heterogenous population of T cells which recognise a multitude of tumour antigens, thus reducing the possibility of resistance through antigen loss.
However, TILs can be very hard to work with, which has contributed to the long development time required to reach approval. The therapies in the clinic now are not that different to those in development over 30 years ago, but it has taken a long time to fine-tune the approach in terms of manufacturing and co-treatment regimens. Patients require an intensive conditioning regimen to wipe out their own regulatory T cells, and a post treatment IL-2 regimen to ensure the cells remain active, which is crucial to the success of the therapy but can be very toxic for patients1. This is on top of difficulties in manufacturing the product: in their recent clinical trial, 8/189 patients did not receive their therapy due to manufacturing failure.
Do they work?
The short answer is yes, multiple trials have demonstrated the curative potential of TILs, which has supported the many years of development and investment in these technologies. Iovance published results in 2022 showing that Amtagvi achieved a complete response in 8/153 treated patients, and an objective response in 31.4% of patients2. An earlier academic study launched in 2014 in Europe reported complete responses in 17/80 treated patients, with some patients now approaching 10 years without disease recurrence1.
A number of innovative techniques are being explored to improve the efficacy of TIL therapy. One problem is that in practice, it’s difficult to isolate the tumour reactive T-cells from bystander T-cells, so many of the cells that are reinfused into the patient do not actually provide any anti-tumour effect. Achilles Therapeutics are addressing this by identifying cancer neoepitopes from tumour sequencing data, using their proprietary AI platform. With this information, reactive T-cells can be purified from either the tumour or the blood and expanded in vitro to generate a highly personalised therapy comprising the most effective T-cells. Conversely, Instil Bio have developed a chimeric costimulatory receptor which can be introduced into TILs to effectively supercharge them, enhancing their anti-tumour function in the absence of co-stimulation from the tumour microenvironment.
Future Perspectives
Iovance were first to cross the finish line and saw a warranted spike in their stock price with Amtagvi’s approval, but this has also been great news for others working in the space. With over 75 TIL immunotherapies in different stages of preclinical and clinical development, the field is ripe for competition. Importantly, this will help see improvements in all stages of the process including manufacturing, treatment regimens, and toxicity management, while promoting new innovations such as modified TIL therapies. We are excited to see how this field evolves in light of the successes and challenges experienced by TILs in recent years.
1. Mullard A. Tumour-infiltrating lymphocyte cancer therapy nears FDA finish line. Nat Rev Drug Discov. 2024;23(1):3-7. doi:10.1038/d41573-023-00206-6
2. Chesney J, Lewis KD, Kluger H, et al. Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study. J Immunother Cancer. 2022;10(12):e005755. doi:10.1136/jitc-2022-005755
