Tumour-infiltrating lymphocyte (TIL) therapy has been investigated as a treatment modality for melanoma for almost 20 years. As an autologous cell therapy, manufacturing the infusion product is a highly specialised process involving tumour harvest and the extraction and large-scale ex vivo expansion of TILs.

Before TIL infusion, the patient undergoes lymphodepletion, which reduces the proportion of myeloid immune suppressive cells and creates space for the incoming lymphocytes. Once infused, TILs are further stimulated by IL-2 treatment. Successful TIL therapy depends on the infusion product containing tumour-reactive T cells that, on infusion, generate an anti-tumour immune response that causes disease regression. The high level of neoantigens in melanoma makes this the ideal setting for TIL therapy, with tumours often containing multiple clones of tumour-reactive immune cells.

Numerous academic and pharma-led studies have investigated the efficacy of TILs in the melanoma setting, with response rates ranging from very low to 50%. However, none of these studies has included a standard of care (SOC) control arm.

Results from the first randomised, multi-centre, Phase III trial investigating TIL therapy in unresectable Stage III-IV melanoma were announced at this year’s ESMO Congress. The majority of patients entering the trial (86%) were refractory to anti-PD-1 therapy, having received either Merck & Co’s Keytruda (pembrolizumab) or Bristol-Myers Squibb’s (BMS) Opdivo (nivolumab) in the first line. Patients were randomised 1:1 to receive either TIL therapy or BMS’ Yervoy (ipilimumab) 3mg/kg every three weeks for up to four cycles.

TIL therapy more than halved the risk of progression compared with Yervoy, with a median progression-free survival (PFS) of 7.2 months versus 3.1 months. The overall response rate (ORR) for TILs was 48.8% versus 21.4% for Yervoy, with complete response (CR) rates of 20.2% and 7.1% respectively. Median overall survival (OS) was higher in the TIL-treated arm (25.8 months) than in the Yervoy arm (18.9 months), but this did not reach statistical significance.

This is a landmark study, demonstrating that TIL therapy can outperform checkpoint inhibition and is a very promising therapeutic option following the failure of immune checkpoint inhibition. While these findings demonstrate the huge potential of TIL therapy, outcomes can certainly be improved further and investigations expanded to other oncology indications.

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A limited number of TIL studies outside of the melanoma setting have been reported and include cervical cancer and non-small cell lung cancer (NSCLC). A proportion of NSCLCs are highly mutated, particularly amongst smokers, and human papillomavirus (HPV) infection is the primary cause of more than 99% of cervical cancers, both of which are predicted to result in large numbers of tumour-reactive lymphocytes. To date, no randomised data have been reported for either of these indications. Advances in TIL therapy technology and optimisation of the therapy protocol are required to further improve the outcome in melanoma patients and expand this therapeutic strategy into additional oncology indications.

Current barriers in TIL therapy include the toxicity of lymphodepletion (cyclophosphamide/fludarabine), the toxicity of IL-2 stimulation, and the activity of IL-2 on other immune cells, such as T-regs, which attenuate any anti-tumour immune response. The use of engineered immune cytokines that selectively induce the expansion of TILs is being investigated as an alternative to IL-2 stimulation. This strategy would enable reduced intensity lymphodepletion, avoid IL-2 toxicity and eliminate the IL-2 simulation of suppressive immune cells. This approach would not significantly alter the TIL manufacturing process or increase the time from tumour resection to TIL infusion.

Improvement to the TIL product itself is an area of intense research. There is very marked variation in the number of neoantigen-specific T cells within the infused TIL product, with this ranging from less than 0.1% to more than 10%. Response to TIL therapy correlates with the number of neoantigen-reactive T cells, stressing the need for a new approach for patients with low numbers of tumour-reactive T cells. Furthermore, truncal neoantigens, which are present in all malignant subclones, must be a T cell target, in addition to any neoantigen targets present in only sub-populations of T cells.

A novel approach presented at the ESMO Congress was the generation of an autologous T cell receptor (TCR) therapy from TILs to create a highly neoantigen reactive T cell product. This would involve isolation of both TILs and cancer cells from the resected tumour, with subsequent sequencing of tumour neoantigens in the cancer cells, and TCR sequencing in the TILs. Synthetic gene libraries would then be used to generate reporter cells expressing neoantigens, and reporter T cells expressing potential neoantigen reactive TCRs. Following this, screening would be performed to identify the most tumour-reactive TCRs, which would then be used to manufacture a multi-specificity TCR T cell product. While this approach is in the early stages of development, it is an exciting avenue of research.

Enormous progress has already been made in the TIL therapy area, and TIL therapy may soon be the SOC in patients with immune checkpoint inhibitor refractory advanced melanoma in markets that have the available infrastructure. It is hoped that further advancements in TIL therapies will improve response rates further and enable TIL therapy to become a treatment option across a wider range of oncology indications.