Abstract PL02-01: What we learned from immunotherapy in previous years
Authors: Ascierto Paolo A. 
Published: May 2016

Abstract
Until recently, most immunotherapeutic approaches used to combat cancer were ineffective, counteracted by the tumour's ability to evade immune attack. However, extensive research has improved our understanding of tumour immunology and enabled the development of novel treatments that can harness the patient's immune system and prevent immune escape. Over the last few years, through numerous clinical trials and real-world experience, we have accumulated a large amount of evidence regarding the potential for long-term survival with immunotherapy agents in various types of malignancy. In 2011, the approval of ipilimumab, an anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4 monoclonal antibody, for the treatment of metastatic melanoma represented the first step in a new era for immunotherapy. Subsequently, promising survival results have been achieved with the anti-programmed death (PD)-1 antibodies nivolumab and pembrolizumab in patients with various cancers that, as well as advanced melanoma, include non-small-cell lung cancer and renal cell cancer. These and other immunotherapy agents in development have been heralded as potential turning point in the treatment of cancer.
Indeed, the characteristics of adaptability and “memory” of the immune system provides the opportunity for long-term survival, with one-fifth of metastatic melanoma patients treated with ipilimumab still alive after 10 years. This observation allows us to state that ipilimumab has the ability to transform melanoma into a chronic disease in 20% of patients. Regarding the anti-PD-1 agents, we currently have no comparable long-term follow-up but data from a phase I study of nivolumab has shown that almost one-third of patients were alive after four years. Moreover, immunotherapy slows the tumor progression process while avoiding the selection of faster progression, as can happen during treatment with tyrosine kinase inhibitors (TKIs).
The results of these studies have also highlighted a number of recurring observations with immuno-oncology agents, including their potential for clinical application across a broad patient population with various tumor types, regardless of patient characteristics (e.g. age, gender, performance status, prior therapies) and tumor characteristics (e.g. histology, mutation status). However, defining predictive biomarkers in order to better identify those patients most likely to benefit from treatment is currently a major focus of investigation. Given that immunotherapies are designed to work with the patient's own immune system rather than targeting the tumor directly, a different approach to identifying biomarkers to that which is typically used may be needed. Various approaches to identify potential biomarkers for immunotherapies are being evaluated, including expression of markers related to the target molecule or pathway (e.g. PD-L1 for therapies directed at the PD-1 pathway), treatment-emergent changes to the immune system or tumor microenvironment (e.g. absolute lymphocyte count, antibody responses to tumor antigens or change in tumor-infiltrating lymphocytes) and gene expression profiling of the patient or tumor (e.g. differential tumor expression of immune-related genes).
Immunotherapy agents may also be associated with both conventional and unconventional response patterns that may differ from those seen with other treatment modalities (i.e. chemotherapy) and so their use may require the development of different response criteria. For example, treatment response may be observed after an initial increase in tumor volume, since stimulation of immunocompetent cells may produce an infiltration of tumor masses that tend to increase the volume of the lesion, thereby counterbalancing the reduction in tumor cells. In addition, reduction in tumor burden has been observed after the appearance of new lesions. These observations suggest that the planned immuno-treatment should be continued regardless of an increase in volume of existing lesions or the early appearance of new lesions. Moreover, durable responses may be observed even after cessation of treatment, suggesting an ability of immunotherapy to reset the equilibrium between host and tumor. Current RECIST and WHO criteria might not be appropriate to asses these types of responses and there is a need for new immune-related response criteria to evaluate these treatments.
The novel modes of action of immunotherapeutic agents can also mean that they are associated with unique safety profiles that are related to immune-system hyper-activity. Typical adverse events (AEs) may differ from those seen with chemotherapy or targeted agents or, even if the same (e.g. pruritus, diarrhea), their etiology may be different. Immuno-related adverse events can be adequately managed through specific treatment guidelines, such as those developed for ipilimumab. However, early diagnosis of these AEs and early treatment with steroids is important in order to prevent potentially life-threatening complications.
Furthermore, given the numerous immune checkpoints that exist and the multiple mechanisms used by tumours to escape the immune system, targeting distinct checkpoint pathways using various combination approaches is an attractive therapeutic strategy with the potential to further enhance the antitumour immune response. Several clinical studies have shown that combining different immunotherapies can improve outcomes and look likely to offer additional clinical benefit compared with single-agent therapies. Immunotherapies are also being assessed in combination with other treatment modalities, including chemotherapy, targeted agents and radiation.
Although the research focus and main advances have to date been largely in melanoma, immunotherapies are being actively investigated in many other cancer types, including those where treatment options for patients are limited. Currently ongoing and planned studies should help bring the benefits of these novel immunotherapies within the reach of patients with a wide range of cancers.
Citation Format: Paolo A. Ascierto. What we learned from immunotherapy in previous years. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL02-01.