The Promise of Tumour-Infiltrating Lymphocytes for Cancer Treatment and as Prognostic/Predictive Indicators
Solid tumours are made up of a variety of components, including malignant cells and endothelial, structural and immune cells. Cancer cells are able to shape the microenvironment to satisfy their own metabolic and immunological needs.
In opposition to this, tumour-infiltrating lymphocytes (TILs) are recruited into the tumour in an attempt to control its growth. Therefore, some patients may obtain the most benefit from some given treatments according to the expression of TILs (e.g. chemotherapy and/or trastuzumab in breast cancer). Evidence is also accumulating to show that the quantity of TILs at diagnosis is associated with prognosis. TILs from a patient can be manipulated to be used as treatment for that patient’s cancer.
Low-dose interleukin-2 is feasible with TILs in the treatment of patients with metastatic melanoma
Adoptive cell therapy (ACT) with TILs is an effective strategy for the treatment of metastatic melanoma. The technique involves the generation of TIL cultures from a patient’s melanoma biopsy and the rapid expansion in an interleukin-2 (IL-2)-containing medium of lymphocytes displaying high antitumour activity. The TILs are subsequently reintroduced into the same patient following lymphodepletion and in the presence of high-dose IL-2. Despite having been described over a decade ago, ACT with TILs using lymphodepletion has not been as widely adopted as might be expected given its apparent efficacy. A contributing factor to this may be the toxicity associated with high-dose IL-2 which, although generally transient, can be severe.
In yesterday’s Proffered Paper Session on Immunotherapy of Cancer, Dr Rikke Andersen from Herlev Hospital, Denmark, reported the results from a phase II trial investigating the use of an attenuated regimen of low-dose IL-2 in patients receiving TILs for metastatic melanoma. Among the first 20 patients, toxicity was much lower than could be expected with high-dose IL-2 and there were 2 complete and 7 partial responses, 2 of which persisted beyond 2 years (overall response rate was 45%). Importantly, ACT with TILs was associated with the induction and persistence in peripheral blood of T cells with in-vitro activity against melanoma cells. These results demonstrate that the use of a lower dose of IL-2 in the context of ACT with TILs is well tolerated and clinically effective.
Low-dose IL-2-associated TILs infusion was associated with good clinical activity and tolerability
The future of TILs therapy will be expanded by mapping the mutational sequencing of specific genes supposed to be oncodrivers in human cancers to demonstrate if the immune system can mount a T helper 1 (Th1) cell response against the mutation expressed by an epithelial cancer. Given that a major hurdle for the success of immunotherapies is the apparent low frequency of tumour-reactive T cells, the strategies reported here could be used to generate a T cell product that is highly enriched in mutation-reactive T cells for use in ACT. The ability to immunologically target unique mutations in cancers can potentially extend highly personalised immunotherapies to patients with solid tumours.
The prognostic and predictive potential of TILs in breast cancer
Data from large clinical studies in several types of cancer have demonstrated that marked infiltration of tumours by specific immune cell populations, including (but not limited to) CD8(+) cytotoxic T lymphocytes, Th1 and Th17 CD4(+) T cells, natural killer cells, dendritic cells and M1 macrophages, is an independent indicator of good prognosis. On the other hand, high levels of intratumoural CD4(+)CD25(+)FOXP3(+) regulatory T cells, Th2 CD4(+) T cells, myeloid-derived suppressor cells, M2 macrophages and neutrophils have frequently been associated with a poor prognosis.
Cancer cells express antigens that differentiate them from their healthy cells. Tumour-associated antigens, like HER2, MAGE1 or NY-ESO-1, are normal proteins that are overexpressed and they are therefore tolerated by the immune system. Experiments in mice show that tumours formed in those without an intact immune system are more immunogenic than tumours from immunocompetent mice. This is due partly to the immune selection pressure on genetically unstable tumour cells, which leads to the selection of tumour cell variants. These variants are no longer recognised by adaptive immunity, for example due to antigen loss or defects in antigen processing or presentation, and they become insensitive to immune effector mechanisms, or induce tolerance within the tumour microenvironment. Eventually, these tumour cells may enter an escape phase in which their outgrowth is no longer blocked by immunity. Such cells can re-emerge after adjuvant therapy to cause metastatic disease.
Several studies support the suggestion that breast cancer is immunogenic. Data from an adjuvant trial in triple-negative breast cancer (TNBC) were used to investigate the prognostic implications of TILs in TNBC and associations with trastuzumab benefit in HER2-overexpressing disease.1 There was a positive association between the amount of TILs present at diagnosis and prognosis in TNBC, but not in luminal or HER2-positive subtypes.
There was also an interaction between higher levels of TILs and increased benefit from trastuzumab: for each 10% increase in lymphocyte infiltrate, there was an 18% reduction in the relative risk of distant recurrence. The prognostic role of TILs in TNBC has been demonstrated previously, and may result from a number of factors. The genetic instability and heterogeneity of these tumours leads to the selection of variants that can more strongly stimulate a host immune response against the tumour. Better prognosis in patients with TNBC and higher TILs is also the result of an immunoediting process induced by chemotherapy. The response to chemotherapy is at least partly dependent on an immunological reaction against tumour cells that are dying during chemotherapy. Also, chemotherapy can stimulate the immune system to recognise and destroy malignant cells.
A wealth of data has been produced on the genes and proteins associated with the immune system (immunome) over the last few years. A number of issues remain to be addressed:
- Validation of whether TILs are prognostic or predictive in HER2-positive breast cancer, preferably in a large population set with an appropriate follow-up time
- Validation of immune genomic signatures that may be predictive and prognostic in patients with TNBC and HER2-positive disease
- Development and incorporation of an immunoscore into the traditional classification of breast cancer, thus providing an essential prognostic and potentially predictive tool in the pathology report. Similar immunoscores are under development in other solid tumours (melanoma, colorectal and ovarian cancer)
- Implementation of clinical trials with drugs targeting immune checkpoints for metastatic TNBC and HER2-positive disease. Blockade of one of these checkpoints, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) or the programmed death 1 (PD-1) receptor may provide proof of concept for an immune modulation approach in the treatment of a breast cancer
The immune system remembers what it targets, so once the system is correctly activated, it may mediate a durable tumour response.4
1. Loi S, et al. Ann Oncol 2014;25:1544–50
2. Denkert C, et al. J Clin Oncol 2010;28:105–13
3. Loi S, et al. J Clin Oncol 2013;31:860–7
4. Curigliano G, et al. Ann Oncol 2014;25:1455–6