Cure Alveolar Soft Part Sarcoma International (iCureASPS)

PD-1 Inhibitor Immune-Related Adverse Events in Patients With Preexisting Endocrine Autoimmunity


Abstract

Context

Immune checkpoint inhibitors, including monoclonal antibodies directed against programmed cell death protein 1 (PD-1) and its ligand, have emerged as beneficial cancer immunotherapies. These therapies are known to cause immune-related side effects; however, their role in patients with a preexisting autoimmune disease is not clear.

Case Description

We describe two cases of anti-PD-1 immune-related adverse events. A 52-year-old male with longstanding type 1 diabetes (T1D), long-term stable kidney transplant, and hypothyroidism received two separate anti-PD-1 monoclonal antibodies for metastatic melanoma. The patient developed acute kidney graft rejection requiring hemodialysis and worsening of autoimmune hypothyroidism 3 weeks after starting treatment. He continued anti-PD-1 treatments and remained on hemodialysis and increased levothyroxine dosage. The second case is a 62-year-old male with no previous history of diabetes who received anti-PD-1 treatment and developed severe diabetic ketoacidosis (DKA) 5 days following the start of therapy. Further laboratory testing revealed high titer antibodies directed against glutamic acid decarboxylase. These antibodies, which were of the IgG isotype and involved in memory immune responses, were likely present before anti-PD-1 treatment. He also had human leukocyte antigen genes that confer T1D genetic risk. Despite normal pretreatment blood glucose levels and HbA1c, the patient requires permanent exogenous insulin treatment.

Conclusion

Patients with preexisting endocrine autoimmunity may have more frequent and severe immune-related side effects with anti-PD-1 treatment. Given the morbidity and mortality associated with solid organ transplant rejection and DKA, clinicians caring for patients receiving these state-of-the-art therapies need to be aware of the potential adverse events.

Immunotherapy, including immune checkpoint blockade, is becoming a highly effective treatment of multiple malignancies refractory to conventional chemotherapies. Programmed cell death protein 1 (PD-1) inhibitors inhibit the interaction between PD-1 and its ligand, thereby activating immune responses toward cancer cells. In a normal adaptive immune response, immune checkpoint inhibition is in place to ensure that immune cells do not harm the host when responding to a foreign antigen. Interfering with this mechanism can cause immune-related adverse events directed against self-tissues (1). Pembrolizumab and nivolumab are two of the most commonly used human monoclonal antibodies directed against PD-1 and are approved by the US Food and Drug Administration to be used in several stage IV cancers, including melanoma.

Clinical trials that led to the US Food and Drug Administration approval of these agents often excluded patients with a known autoimmune disease such as type 1 diabetes (T1D) or an organ transplant (1, 2). Thus, in clinical practice, the potential exists to encounter immune-related adverse events more often than registration trials. Currently, there are no guidelines for the treatment of patients with immune checkpoint inhibitors in the setting of preexisting autoimmunity or a prior organ transplant. We report cases of acute kidney transplant rejection and worsening of autoimmune hypothyroidism in a patient with longstanding T1D having previously stable kidney and thyroid function and a second case of autoimmune diabetes as a rapid consequence of anti-PD-1 treatment of metastatic melanoma.



https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179163/

“Case 2

A 62-year-old white male with no previous history of diabetes presented with abdominal pain, confusion, nausea, and vomiting for 5 days after receiving a single IV infusion of nivolumab for metastatic melanoma. His laboratories upon hospital admission showed substantial hyperglycemia, a metabolic acidosis with an increased anion gap, and the presence of serum and urine ketones consistent with severe diabetic ketoacidosis (DKA) (Table 2). One week prior to starting anti-PD-1 therapy, he had normal blood glucose and HbA1c values. He was admitted to the intensive care unit for DKA management, discharged on multiple daily insulin injections, and continues exogenous insulin treatment 6 months later. We evaluated T1D-associated autoantibodies at the time of his DKA presentation, which revealed high levels of antibodies directed against glutamic acid decarboxylase (GAD65), which is a major autoantigen in T1D. The antibody measurements were done with highly sensitive and specific fluid-phase radioimmunoassay, which measure IgG antibody isotypes. Because IgG antibodies are involved in memory immune responses and the short interval from anti-PD-1 treatment to DKA presentation, these antibodies directed against GAD65 were likely present in the patient before treatment. Further phenotyping indicated that these antibodies were polyclonal and predominantly of the IgG1 (56%) and IgG2 (35%) subclasses. In addition to T1D-associated antibodies, HLA genes, especially the class II molecules DR and DQ, confer substantial genetic risk for prototypical childhood-onset T1D, and our patient was homozygous for the high-risk HLA-DR3/DQ2 (DRB*0301, DQA*0501, DQB*0201) haplotype. Autoantibodies for celiac and autoimmune Addison disease were negative. The patient continued nivolumab therapy, receiving 11 additional infusions over 6 months, with a good response to his tumor burden.“

“Addison's disease occurs more frequently in patients with type 1 diabetes mellitus as part of the autoimmune polyendocrine syndromes. The diagnosis of Addison's disease is, however, often delayed because the onset of diabetes mellitus usually precedes the diagnosis of Addison's disease.”

“Subjects with celiac disease were at an 11-fold increased risk of subsequent Addison's disease. The incidence rate for Addison's disease was 15 per 191,780 person-years in individuals with celiac disease and nine per 971,639 person-years in reference individuals.”