Dr Alessandra Curioni-Fontecedro explains recent incredible progress for thoracic cancer treatment with immunotherapy.
Cancer cells can be recognised and controlled by the immune system through antigens expressed on their surface (see Fig. 1). Such antigens can be categorised as oncofetal (typically only expressed in fetal tissues and in cancerous somatic cells), oncoviral (encoded by tumorigenic transforming viruses), overexpressed/accumulated (expressed by both normal and neoplastic tissue, with the level of expression highly elevated in neoplasia), cancer-testis (expressed only by cancer cells and adult reproductive tissues such as testis and placenta) and mutated (only expressed by cancer as a result of genetic mutation or alteration in transcription). Despite the presence of tumour-specific T cells targeting such antigens, the tumour might escape immune control.1 This can be due to a reduced immunogenicity of cancer cells (by lowering the expression of antigens or antigen-presenting molecules) or by a negative modulation of T-cell effector responses.
Immunotherapy: general principles
The immunotherapy of tumours works by enhancing the body’s immune system leading to the control and disruption of tumour cells. Immunotherapy can therefore be categorised in two subgroups: active and passive. The active forms leads to the activation of the patients’ own immune system either in a specific way (as with vaccines) or unspecific (as with cytokines or other immune-modulators). The passive form is based on the use of components of the immune system such as antibodies or immune cells that can be given to restore an immune-response.
The theory of an immune system able to detect and kill cancer cells has his origin in 1893, when Dr Coley et al. as well as Dr Bonn et al. described cases of patients with infections due to Streptococcus pyogenes had a spontaneous remission of their cancers. This allowed to develop and support the theory of an immune phenomenon able to kill cancer. In 1950, Thomas and Burnet presented their immunosurveillance hypothesis and, since then, cancer immunology research continued to evolve and provided the base for the fundamental findings of the 2018 Nobel laureates Allisson’s and Honjo’s research. Their findings about CTLA4 and PD-1 with its ligand (programmed cell death ligand 1 ‘PD-L1’) allowed the development of checkpoints inhibitors.
CTLA4 and PD-1 prevent the immune system from overshooting during infections; blocking them releases the break from the immune system and induces re-activation of T cells to attack tumour cells (see Fig. 1) and is therefore a form of active immunotherapy.
Success of immune checkpoint inhibitors for thoracic malignancies
The development and clinical success of antibodies targeting CTLA-4, PD-1 or its ligands have revolutionised cancer treatment and Science magazine elected immune therapy as ‘breakthrough of the year’ in 2013.2
Current standard of care for advanced NSCLC includes those treatments already in the first line setting. Recent studies in these patients have shown that the addition of an anti PD(L)1 antibody (namely pembrolizumab or atezolizumab) to chemotherapy improved overall survival when compared to chemotherapy alone.3
Moreover, the combination of both immune-checkpoint inhibitors can be superior to chemotherapy based on patients’ selection.4,5 However, when given as a second-line
treatment, such immunotherapies can induce important responses.
These therapies completely changed the way we treat patients with metastatic NSCLC. Until just a few years ago, without access to immunotherapy, less than 3% of patients were surviving at three years from diagnosis; now, such a survival increased to about 20% of patients alive at five years. This is a real revolution for us oncologists, and especially for patients.
Commitment of the Thoracic Cancer Center Zurich on immunotherapy for thoracic malignancies
The University Hospital in Zurich, Switzerland, implemented the use of immunotherapy for NSCLC in early 2014 by the activation of clinical trials that gave access to these drugs about two years before their approval. To date, we have treated more than 100 patients with advanced NSCLC with immune-checkpoint inhibitors, and we have activated more than a dozen studies that used such drugs for thoracic malignancies with different stages.
Our aim is to also provide access to these drugs for a more rare disease, namely mesothelioma. Immunotherapy is not yet approved for mesothelioma in Switzerland, and our institute has initiated and continued to be involved in clinical trials with immunotherapy as checkpoint inhibitors, as well as CAR T-cells. This has been only possible thank to a highly dedicated team of specialists in oncology, surgery, radio-oncology, pathology and radiology, who meet weekly to discuss all new cases with thoracic malignancies and implement the best personalised treatment for each patient.
In the near future, we aim at understanding the mechanisms and molecules related to the response or resistance to treatment through the collection and analysis of patient’s material. Moreover, the research laboratory lead by Emanuela Felley-Bosco developed a mouse model of mesothelioma that closely resembles the human disease.6 This model is ideal to study different treatment approaches and combinations for this disease and to understand the molecular features that characterise the response to treatment.
Thanks to this model, we have discovered a synergistic effect between a chemotherapy named gemcitabine and immune-checkpoint inhibitors. This was proven in a preclinical model and shown also in two patients, treated with this combination of treatments.7
Based on these findings, we designed a clinical trial for solid tumours. Such a trial has been recently submitted to the Swiss Group for Clinical Cancer Research and immediately received first approval.
This represents an ideal situation where preclinical data could be translated to clinical applications.Through patient’s data and material, we will be able to define markers of response and resistance to immunotherapy and will be able to proof those markers in our preclinical model to improve treatment outcome.
1 Schreiber, R.D., Old, L.J. & Smyth, M.J. ‘Cancer immunoediting: integrating immunity’s roles in
cancer suppression and promotion’. Science 331, 1565-1570 (2011)
2 Couzin-Frankel, J. Breakthrough of the year 2013. Cancer immunotherapy. Science 342, 1432-1433 (2013)
3 Gandhi, L. et al. ‘Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer’. N Engl J Med 378, 2078-2092 (2018)
4 Larkin, J. et al. ‘Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma’. N Engl J Med 373, 23-34 (2015)
5 Antonia, S.J. et al. ‘Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial’. Lancet Oncol 17, 883-895 (2016)
6 Blum, W. et al. ‘Establishment of immortalized murine mesothelial cells and a novel mesothelioma cell line’. In Vitro Cell Dev Biol Anim 51, 714-721 (2015)
7 Tallon de Lara, P. et al. ‘Gemcitabine synergizes with immune checkpoint inhibitors and overcomes resistance in a preclinical model and mesothelioma patients’. Clin Cancer Res (2018)