Checkpoint inhibitor (CPI) therapy has transformed treatment of solid tumors. Clinical responses in the range of 20-25%, with prolonged survival, have been reported for tumors, such as malignant melanoma and non- small cell lung cancer, that previously had poor response rates and dismal prognoses. Current therapies block PD-1/PD-L1 and CTLA-4, and there are other targets being developed such as LAG3. However, these immune-based therapies can lead to adverse events. Unrestricted immune activation leads to autoimmunity, in particular endocrinopathies including thyroiditis, hypophysitis, and adrenalitis. We first reported the development of ketosis prone diabetes in elderly individuals treated with inhibitors of the PD-1/PD-L1 axis, and subsequently other studies have identified hyperglycemia as a consequence of CPI therapy with PD-1/PD-L1 antagonists. These hormone deficiencies, however, can result in considerable morbidity and prolonged hospitalization. Therefore, identifying individuals before they present with metabolic syndromes may enable the prevention of morbidity associated with the adverse effects of immune therapy and even open the possibility of selective immune modulation to prevent this occurrence in those at risk. To address this gap we developed assays to measure ? cell death in serum of patients, based on the principle that dying cells release fragments of DNA into the circulation with cell-specific epigenetic patterns. Our preliminary studies from patients with cancers who were treated with CPIs indicated that this measurement may identify individuals who will develop diabetes prior to its clinical onset. Building upon this success, we propose to develop methylation marker specific assays for detecting adrenal and pituitary tissue damage and to further study changes in ? cell derived DNA in patients. A recent review has shown that hypophysitis and adrenal insufficiency may be found in greater than 16% of individuals treated with anti-CTLA-4 mAb and in more than 5% of patients treated with anti-PD-1/PD-L1 blockade. In addition, endocrinopathies such as pituitary or adrenal insufficiency are difficult to diagnose without dynamic endocrine testing, which can only identify the insufficiency after it has led to organ destruction. Our experience with the analysis of the insulin gene and recently the IGRP gene for detection of ? cell death has shown our ability to work with this approach and to use it to find clinically meaningful outcomes. These assays will fulfill an important unmet medical need: to identify patients who are developing endocrine complications from immunotherapy.
The overall objective of this proposal is to develop and test if biomarkers for adrenal and pituitary and ? cell death are able to identify progression to endocrinopathies in cancer patients who are on immunotherapy. A successful project will lead to a diagnostic test that would have widespread use for monitoring all cancer patients who are treated with checkpoint inhibitor immunotherapy.
