Abstract
BACKGROUND: Immune checkpoint inhibitors (ICIs) have dramatically improved the prognosis of metastatic cancer patients. Along with observed durable responses, a considerable rate of immune related adverse events (ir-AEs) is often registered, particularly with the combination of anti-programmed cell death 1 (PD-1) and anti-CTLA-4, probably caused by the loss of immune tolerance under the effects of these ICIs. Considering the key role of the thymus in the development of immune tolerance, it is legit to hypothesize that a possible correlation between the rebound thymic hyperplasia during ICIs and the onset of some ir-AEs may exist. CASE DESCRIPTION: The first patient is a 42-year-old woman with programmed death-ligand 1 (PD-L1) negative metastatic melanoma, who developed, after 2 cycles of nivolumab plus ipilimumab, a persistent fever, shortly followed by grade 4 (CTCAE v. 5.0) ir-hepatitis treated with high dose steroids. During steroids tapering, grade 2 ir-histologically confirmed colitis manifested. After adequate immune suppressive treatment all the ir-AEs resolved and computed tomography (CT) scan showed radiological complete response (CR), persistent so far. The second patient, a 25-year-old man, was also diagnosed with PD-L1 negative metastatic melanoma. As the previous case, after 2 cycles of Nivolumab plus Ipilimumab a persistent fever occurred, followed by grade 4 ir-hepatitis. During the steroids tapering, grade 4 colitis occurred and treatment with anti-TNF-alfa was promptly administered. The subsequent CT scan showed CR. The third patient, a 17-year-old man, was diagnosed with stage IIIB spitzoid melanoma. After 7 cycles of adjuvant anti-programmed cell death 1 (PD-1), he presented grade 2 ir-hepatitis, followed by grade 3 diarrhea. After immune suppressive treatment with steroids, all ir-AEs resolved, however after 3 years from the last dose a histologically ir-hepatitis was again diagnosed. All the CT scans did not show signs of disease recurrence so far. CONCLUSIONS: At the basal CT scan, all the patients presented a thymic hyperplasia, that underwent a radiological evident rebound after ir-AE development. They all manifested similar multiple toxicities managed with immunosuppressive treatments; nevertheless, brilliant responses to treatment were reported. The relation between thymic hyperplasia and ir-AEs onset is still unclear, but taking into account its crucial role in the development of immune tolerance it definitely deserves to be deepened.