Until 2011 no therapy with proven overall survival benefit was Food and Drug
Administration (FDA) approved for the treatment of stage IV (disseminated) melanoma. In
2011 ipilimumab, an inhibitor of CTLA-4, was FDA approved for the treatment of stage IV
melanoma representing the first immunotherapy to confer an increase in overall survival.
CTLA-4 is expressed on the surface of activated T cells and binds to B7 on
antigen-presenting cells with higher affinity than the co-stimulatory protein CD28. By
competing for and disrupting the binding of CD28 to B7, CTLA-4 prevents T-cell
co-stimulation which leads to a dampening of the immune response. Ipilimumab is an IgG1
monoclonal antibody that binds CTLA-4 in an inhibitory manner. Treating stage IV melanoma
with ipilimumab confers an overall survival benefit when compared in randomized fashion
to peptide vaccine treatment, with median survival increasing from 6 to 10 months and
2-year survival increasing from 14% to 24%. Benefit is durable as the overall survival
rate plateauing at 21% by year 3 with follow-up extending up to 10 years.
The regulation of immune T-cell activity is complex involving multiple activating and
inhibitory protein interactions with antigen presenting cells. T-cells express the
protein programmed death-1 (PD-1) which when bound to its ligand PD-L1 normally expressed
on peripheral tissues inhibits T-cell activity. Many melanomas select for aberrant
expression of PD-L1. When T-cells infiltrate the melanoma metastasis tumor
microenvironment the PD-1 on the infiltrating T-cells binds the tumor expressed PD-L1
leading to inhibition of T-cell activity. Blocking the interaction of PD-1 to PD-L1 in
stage IV melanoma leads to clinical efficacy. Two inhibitors of PD-1, nivolumab and
pembrolizumab, were FDA approved in 2014 for the treatment stage IV melanoma with
response rates approximating 40% and 5-year survival post-nivolumab treatment of 35%. In
2015 concurrent treatment with ipilimumab and nivolumab was FDA-approved on the basis of
a 57.6% response rate.
Ipilimumab is infused intravenously as a single agent every 3 weeks for a total of four
treatments. Nivolumab is administered intravenously every two weeks at dose of 240 mg or
every four weeks at a dose of 480 mg while pembrolizumab is infused every three weeks at
dose of 200 mg or every 6 weeks at 400 mg per dose. With concurrent ipilimumab and
nivolumab treatment the combination is administered every three weeks for 4 doses and
then nivolumab is infused as a single agent every two weeks.
The inhibition of immune cell activity in the tumor microenvironment through the
selection of PD-L1 expression on tumor cells is not specific to melanoma. Clinical
efficacy has been appreciated in a range of malignancies leading to multiple FDA
approvals for stage IV disease. Specifically pembrolizumab is also FDA approved for
treatment of stage IV non-small cell lung cancer and recurrent or metastatic HNSCC.
Nivolumab is also FDA approved for the treatment of metastatic non-small cell lung
cancer, advanced renal cell carcinoma, classical Hodgkin lymphoma, and recurrent or
metastatic squamous cell carcinoma of the head and neck.
Given the mechanism of action of CTLA-4 and PD-1 inhibitors toxicity is largely immune
mediated. The incidence of grade3 or higher immune mediated toxicity following single
agent ipilimumab treatment is approximately 25%. Following nivolumab or pembrolizumab
treatment the risk of such toxicity is 17-20% while following combined ipilimumab and
nivolumab treatment the risk is 55-59%. Toxicity can manifest based on organ or tissue
involved such as rash, colitis, hepatitis, nephritis, pancreatitis, myocarditis,
pneumonitis uveitis, neurologic or endocrine.
Autoimmune endocrinopathies (thyroid disease, hypophysitis, adrenal failure and diabetes)
have been reported in 6-25% of patients on anti-PD-1 therapies in different case series.
With concurrent CTLA-4 and PD-1 inhibition the rate of thyroid immune mediated toxicity
is approximately 15%. Autoimmune thyroid disease can easily be detected on routine blood
tests before the patient develops symptoms, is associated with known autoantibodies that
have clinical assays, and autoimmune thyroid disease can be treated with thyroid hormone
replacement, if needed.
Serum 25-hydroxyvitamin D levels have been inversely correlated with the levels of
anti-thyroperoxidase (TPO) antibodies in some cohorts. Vitamin D deficiency has also been
linked to an increased risk of autoimmune thyroid disease. Vitamin D supplementation has
been reported to suppress CD4+ T cell and NK cell function in pre-clinical and clinical
studies. It is not known whether vitamin D deficiency plays a role in the development of
the irAEs in patients treated with immune checkpoint inhibitors. Furthermore, it is not
known if vitamin D deficiency or supplementation alters the rate of response to immune
checkpoint inhibitors.
PD-1/PD-L1 inhibition has demonstrated clinical efficacy in a range of malignancies with
treatment leading to durable benefit. However this type of treatment can lead to immune
mediated toxicity that if high grade can necessitate interventions or management with
high dose steroids. As such identifying biomarkers for toxicity and strategies to
minimize toxicity risk are very important. Serum 25-hydroxyvitamin D levels have been
inversely correlated with the levels of anti-thyroperoxidase (TPO) antibodies in some
cohorts. Vitamin D deficiency has also been linked to an increased risk of autoimmune
thyroid disease. This study plans to determine if baseline deficiency in serum 25-hydroxy
vitamin D levels correlates with altered risk of developing immune mediated toxicity of
the thyroid gland in patients being treated with anti-PD1/PD-L1 immunotherapy.
