Immune Adverse Events Registry in Onco-Hematologic Patients Treated With Immunotherapy

Immunotherapy is a therapeutic strategy aimed at inducing the immune system to identify and combat cancer cells. The rationale behind immunotherapy lies in the context of an altered homeostasis between the immune system and cancer, where the latter prevails. The goal of this type of therapy is to initiate or restore a cycle in which immunity against the tumor is maintained and can be amplified and propagated to achieve good control over the disease. Immune Checkpoint Inhibitors (ICIs) are monoclonal antibodies used in cancer therapy designed to remove the inhibitory brake imposed on T cells, thereby allowing a robust activation of the immune system against the tumor. Over time, the use of ICIs has become increasingly widespread, and alongside the evident clinical success observed in many patients, a specific toxicity profile has emerged, associated with the modulation of the immune system achieved with this type of drugs, known as Immune-Related Adverse Events (irAEs). irAEs encompass a highly heterogeneous spectrum of autoimmune manifestations that can potentially involve any organ or system. By releasing the brakes on checkpoint controls, monoclonal antibodies targeting CTLA-4 (Cytotoxic T Lymphocyte Antigen - 4) and the PD-1 (Programmed cell Death Protein 1) / PD-L1 (Programmed Death-Ligand 1) axis can activate pre-existing autoreactive T-cells or generate novel autoreactive T-cell clones, triggering immune-related adverse events (irAEs) of various types and severity. IrAEs are common occurring in ~ 80% of patients treated with anti-CTLA-4 agents and in ~ 60-70% of patients treated with PD-1/PD-L1 inhibitors. However, severe (grade 3-4) irAEs affect only ~ 15% of patients treated with CTLA-4 inhibitors and ~ 5-10% of patients receiving anti-PD-1/PD-L1 agents, with a mortality rate ranging from 0.36% to 1.23%. The most common irAEs are those affecting the skin, gastrointestinal tract, and endocrine glands. From a rheumatological perspective, inflammatory arthritis and polymyalgia-like syndromes are the most prevalent forms, while the more severe cases include myositis, which may also involve myocardial complications. The main characteristic of irAEs is their unpredictability in terms of time of onset, severity and responsiveness to immunosuppressive agents . Therefore, the management of irAEs often requires clever interpretation of clinical symptoms, proper choice of laboratory tests and imaging tools, and ability to perform differential diagnosis with other condition associated to tumour itself or to unrelated concomitant events (i.e., infections). Although international societies (i.e.; ESMO) have provided detailed guidelines for the management of irAEs or algorithms for the administration of ICI in patients with pre-existing autoimmune disease , they are sometimes difficult to be applied to certain complex situations. Furthermore, given the scarcity of data from clinical trials, some of these recommendations are mainly based on highly heterogeneous patients' population included in relatively small real word studies. Therefore, recommendations should always be adapted to specific clinical conditions and challenges. As an example, although most of the current international guidelines recommend steroid treatment and permanent discontinuation of ICI after a grade 3 irAEs, retrospective studies have reporting spontaneous resolution of grade 3 immune related hepatitis in up to 50% of patients who temporary withhold ICI without receiving any immunosuppressive treatment . A similar "grey area" in the management of irAEs deals with the impact of steroid sparing strategies such as disease-modifying antirheumatic drugs (DMARDs) on the oncological outcome of cancer patients experiencing irAEs. In fact, while some studies suggested a potential detrimental effect of DMARDs on response with ICI in patients with melanoma and irAEs, the investigators and other groups have reported that tailoring immunosuppression using DMARD in steroid-refractory patients is associated with a good remission rate of irAEs and no negative impact on the oncological outcomes. In addition, the investigators have identified a panel of autoantibodies able to predict the emergency of steroid refractory irAEs, which could help to better select patients for whom an earlier upfront tailored management of irAEs could be required.

Despite recommendations from major European and American rheumatology and oncology societies regarding the management of irAEs, these guidelines are largely based on expert opinion, and this complex group of manifestations remains challenging to treat. In recent years, potential predictors have been identified, both in terms of the likelihood of developing irAEs and concerning clinical characteristics and responses to available therapies. Studies investigating these aspects have particularly focused on the autoimmune antibody response, correlating its positivity in various ways with clinical outcomes. However, the results across different studies are not consistent. Additionally, both prospective and retrospective studies have led to very different conclusions, and these predictive factors have not yet been implemented in clinical practice . As a result, the therapeutic algorithm in this clinical scenario remains highly variable and often unsatisfactory. Furthermore, it has not yet been conclusively determined whether immunosuppressive therapies administered to patients with irAEs have a negative impact on oncological prognosis. In this regard, there is also a lack of data on the role of continuing immunotherapy in patients with irAEs and whether this strategy could mitigate the aforementioned impact.

A multidisciplinary case-by-case approach involving oncologist and organ-specialists is likely to lead to an optimal tailored decision for each patient. Several published experiences from the Gustave Roussy Cancer Campus, the Johns Hopkins University School of Medicine and the Belgian Society of Medical Oncology have reported that multidisciplinary managements of irAEs are feasible, could facilitate a prompt resolution of irAEs and could generate knowledge in the field (i.e.; ~ 6% of irAEs discussed at multidisciplinary level were classified as novel and unexpected events). In this regard, multidisciplinary management of irAEs could constitute a forum with a high educational value deriving from a cross-fertilization between different fields of medicine. As an example, attendance by organ specialists could provide them new insights into the pathophysiological features of autoimmune diseases in non-cancer patients Therefore, additional prospective data are needed to confirm which information can guide the management of irAEs in order to optimize therapy and improve prognosis without negatively impacting oncological outcomes. The adoption of a therapeutic strategy tailored to irAEs is essential for improving both the immunological and oncological prognosis of patients affected by this group of manifestations. A prospective and cross-sectional observational approach to studying irAEs is fundamental to the development of such therapeutic innovation. This study approach must be based not only on monitoring patients who have already developed irAEs but also on profiling patients even before the development of irAEs to determine which factors are associated with this group of pathologies and the different characteristics they may assume once they arise. However, this study approach requires the integration of multiple clinical competencies to cover the extensive clinical-pathological spectrum that characterizes irAEs, as well as the complexity of concomitant neoplastic diseases and oncological pharmacology.

Such a process is potentially easier to implement in clinical settings like the Units of Immunology, Rheumatology, Allergy and Rare Diseases (UniRAR), Oncology, Urology, and Gynecology at San Raffaele Hospital, where the concurrent presence of expertise in both immuno-rheumatology and oncology-supported by constant interdisciplinary dialogue-is a structural reality.

The results generated by this complex experimental strategy could lead to a redefinition of the current diagnostic and therapeutic paradigm for irAEs.