Author: Dr Andrew Furness The Royal Marsden NHS Foundation Trust, London, UK
In a phase I/II trial presented at ESMO Virtual Congress 2020, treatment with ex vivo expanded tumour-infiltrating lymphocytes (TIL) combined with immune checkpoint inhibitors before and after cell infusion was associated with benefit (partial response or stable disease >4.5 months) in nine of 25 patients with 12 different cancer diagnoses (Abstract 1022MO).
The treatment schedule involved administration of a single dose of ipilimumab prior to tumour tissue procurement. A first dose of nivolumab was administered during hospitalisation, following commencement of lymphodepleting conditioning chemotherapy 2 days before TIL transfer. Patients thereafter received 14 days of low-dose interleukin-2 (IL-2) therapy before discharge and nivolumab continued every 2 weeks from the first infusion for a total of four doses.
Although TIL therapy is not an entirely novel approach, the feasibility of TIL isolation and expansion from tumours of low immunogenic potential and the safety/efficacy of combining TIL therapy with immune checkpoint inhibition peri-procurement/post-cell transfer is still a matter of investigation.
It is not possible to draw any definite conclusions regarding efficacy from this early phase study, given the small number of patients treated within each tumour type. However, it is encouraging to see that around one-third of patients appeared to derive benefit.
Treatment appeared to be generally well tolerated, with a side-effect profile comparable to that observed using TIL-based adoptive cell therapy in advanced melanoma trials, with the addition of checkpoint inhibitor-associated immune-related adverse events. Given the novelty of this combined approach, it will be crucial to gain more detail on the pattern of toxicities, including the types of side-effects, the timing of their development and whether checkpoint inhibitors potentiated any TIL- or IL-2-related toxicity. Translational readouts will help to determine any impact on TIL isolation and/or expansion.
One of the most interesting features of the study findings from my perspective is that they support the clinical feasibility of this combined approach. Firstly, ex vivo expansion of TIL was generally achievable; 30 of the 31 patients recruited into the study had successful TIL expansion. Not only was ex vivo expansion feasible, the product was also generated relatively rapidly, with a median expansion time of 24 days. Taken together with the efficacy data, these findings suggest that the technique is clinically practicable and warrants further investigation in tumour subtypes of perceived lower immunogenicity.
The schedule of checkpoint inhibitor administration used in the study is interesting and translational data will be important in determining the optimal approach. In pre-clinical models, a key mechanism co-defining the activity of anti-CTLA-4 antibodies is depletion of regulatory T cells. Whether this mechanism is relevant also in the human setting is less clear; this study may shed further light on this via analysis of TIL isolates following a single cycle of ipilimumab. Both ipilimumab and nivolumab have the potential to increase the yield of harvested neoantigen-reactive TIL and, depending on expansion, generate a final cell product with greater enrichment for bona fide tumour-reactive T cells.
In terms of future research, we need to know whether this combined approach yields a greater proportion of responders compared with checkpoint inhibitors or TIL therapy alone. To this end, investigations in tumour subtype(s) with known response rates to checkpoint inhibitors are urgently required. We also need to identify those patients most likely to respond to this type of treatment and this will require a better understanding of the biology and dynamics of the immune response, in the context of response and resistance, before, during and after therapy.
We are still at the very beginning of cell therapy for solid tumours but the provocative data from this study presented at ESMO help to further our understanding of the safety of combining checkpoint inhibitors with TILs therapy and IL-2 in this setting.