Background: The use of immune checkpoint inhibitors in the treatments of cancer patients, is a consolidated and effective therapy that has been associated with different toxicities, defined Immune-related Adverse Events (IrAEs). Reports of IrAEs describe symptoms resembling classic rheumatic diseases, most notably associated with cytotoxic T-lymphocyte-associated protein 4 inhibitor blockade. There are fewer reports of rheumatic diseases associated to treatment with programmed cell death protein-1 (PD-1) and its ligand (PD-L1) inhibitors, even if cases have been described. For this reason, the mechanisms associated with this uncommon toxicities are still unknown.
Methods: This is a single-center prospective observational pilot study including cancer patients receiving PD-1/PD-L1 inhibitors alone or in combined treatment.
Inclusion Criteria: Patients that have a diagnosis of cancer undergoing treatment using anti-PD1 or anti-PD-L1 checkpoint inhibitors (melanoma, non small cell lung cancer, renal carcinoma etc.); 18 years of age or over; histologically confirmed cancer diagnosis; mandatory written informed consent.
Exclusion criteria: Patients or family refusal; patients with immunological and/or rheumatological pre-existing disease; patients on immunotherapic treatments.
Enrolled patients will be assessed before the treatment (T0) and after 3 (T1), 6 (T2) and 12 (T3) months, for rheumatic diseases development and/or ocular-releated IrAEs; patients will be also profiled for T helper subpopulations, cytokines/chemokines expression and related microRNAs alterations.
Expected outcomes: The main outcome expected from our study is to demonstrate a possible deregulation in the profile of immune cell populations as well as immune mediators at T0 and/or during the treatment of cancer patients with anti PD1/PD-L1, correlating it with IrAEs onset, the safety and the overall response rate to the treatments.
Data on IrAEs other than rheumatologic (i.e. colitis, hepatitis, pneumonitis, and hypothyroidism) are already reported during ICIs therapy, especially in the case of anti-CTLA-4 but also during administration of anti-PD1/anti PD-L1 therapy whereas rheumatologic adverse effects are still largely missing as described in the Introductory section. In particular, no prospective observational study has systematically assessed musculoskeletal IrAEs. Although some retrospective observational studies have reported the incidence of musculoskeletal IrAEs, detailed clinical, laboratory, and imaging information is limited. Our study is focalized in this setting.
The investigation is designed to test a new approach to monitor and predict immunological and rheumatological IrAEs in cancer patients, using a more rigorous, broader and standardized procedure. Building on these data the present study could include the validation of these new tests as predictive markers for ICI rheumatologic immune-related adverse events. Moreover it allows a critical evaluation of recent protocols in terms of safety and efficacy and to improve patient's Quality of Life (QoL), allowing the early detection of patients at high risk of toxicity.
In light of the increasingly attention to cancer patient's QoL, it is important to identify new useful parameters to monitor and prevent response to treatments and toxicities. The analysis of these data could give a more clear interpretation of the toxicities and response to ICIs, reducing the hospitalization and drugs costs to the National Health Service (Servizio Sanitario Nazionale), in terms of admissions and inappropriate treatments. The originality of this project is to prospectively analyze the possible causes of these invalidating toxicities during these new immunological treatments. This modality has never been previously proposed, and could be important to study this new analysis system for reducing the improper use of ICIs agents and for monitoring the real patient's toxicity state. Moreover, this study could identify more accurate schedules of treatment, analyzing efficacy and safety of current drugs used correlating with laboratory results. Thus allowing the patients to be correctly treated and monitored, sparing them expensive and ineffective treatments.
A better understand of the immunological network subtending the development of IrAEs in these patients and, in particular, their selection, could improve not only the ICIs therapy management but also the possible anti-rheumatologic treatments.