Recent accomplishments of our immunotherapy clinical trials include the following: [] PHASE I TRIAL OF M7824 (MSB0011359C), A BIFUNCTIONAL FUSION PROTEIN TARGETING PD-L1 AND TGFbeta, IN ADVANCED SOLID TUMORS. M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a monoclonal antibody against programmed death ligand 1 (PD-L1) fused to a TGFbeta trap. In the 3+3 dose-escalation component of this phase I study (NCT02517398), eligible patients with advanced solid tumors received M7824 at 1, 3, 10, or 20 mg/kg once every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal; in addition, a cohort received an initial 0.3 mg/kg dose to evaluate pharmacokinetics/pharmacodynamics, followed by 10 mg/kg dosing. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include pharmacokinetics, immunogenicity, and best overall response. Nineteen heavily pretreated patients with ECOG 0-1 have received M7824. Greater than or equal to grade 3 treatment-related adverse events occurred in four patients (skin infection secondary to localized bullous pemphigoid, asymptomatic lipase increase, colitis with associated anemia, and gastroparesis with hypokalemia). The MTD was not reached. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGF-beta1, -beta2, and -beta3 throughout the dosing period at greater than 1 mg/kg. There were signs of efficacy across all dose levels, including one ongoing confirmed complete response (cervical cancer), two durable confirmed partial responses (PR; pancreatic cancer; anal cancer), one near-PR (cervical cancer), and two cases of prolonged stable disease in patients with growing disease at study entry (pancreatic cancer; carcinoid). M7824 has a manageable safety profile in patients with heavily pretreated advanced solid tumors. Early signs of efficacy are encouraging, and multiple expansion cohorts are ongoing in a range of tumors. [] ANTI-PD-L1 TREATMENT INDUCED CENTRAL DIABETES INSIPIDUS. Immune checkpoint inhibitors, including anti-programmed cell death protein 1 (PD-1), anti-programmed cell death protein ligand 1 (PD-L1), and anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) monoclonal antibodies, have been widely used in cancer treatment. They are known to cause immune-related adverse events (irAEs), which resemble autoimmune diseases. Anterior pituitary hypophysitis with secondary hypopituitarism is a frequently reported irAE, especially in patients receiving anti-CTLA4 treatment. In contrast, posterior pituitary involvement, such as central diabetes insipidus (DI), is relatively rare and is unreported in patients undergoing PD-1/PD-L1 blockade. This case describes the treatment of a 73-year-old man with Merkel cell carcinoma who received the anti-PD-L1 monoclonal antibody avelumab and achieved partial response. The patient developed nocturia, polydipsia, and polyuria 3 months after starting avelumab. Further laboratory testing revealed central DI. Avelumab was held and he received desmopressin for the management of central DI. Within 6 weeks after discontinuation of avelumab, the patient's symptoms resolved and he was eventually taken off desmopressin. The patient remained off avelumab and there were no signs or symptoms of DI 2 months after the discontinuation of desmopressin. This is the first report (to our knowledge) of central DI associated with anti-PD-L1 immunotherapy. The patient's endocrinopathy was successfully managed by holding treatment with the immune checkpoint inhibitor. This case highlights the importance of early screening and appropriate management of hormonal irAEs in subjects undergoing treatment with immune checkpoint inhibitors to minimize morbidity and mortality.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Basic Sciences
Zip Code
Zhao, Chen; Tella, Sri Harsha; Del Rivero, Jaydira et al. (2018) Anti-PD-L1 Treatment Induced Central Diabetes Insipidus. J Clin Endocrinol Metab 103:365-369
Strauss, Julius; Madan, Ravi A (2016) Therapeutic vaccines for prostate cancer: recent advances and future directions. Expert Rev Vaccines 15:907-14
Heery, Christopher R; Madan, Ravi A; Stein, Mark N et al. (2016) Samarium-153-EDTMP (Quadramet®) with or without vaccine in metastatic castration-resistant prostate cancer: A randomized Phase 2 trial. Oncotarget 7:69014-69023
Fenerty, Kathleen E; Patronas, Nicholas J; Heery, Christopher R et al. (2016) Resources Required for Semi-Automatic Volumetric Measurements in Metastatic Chordoma: Is Potentially Improved Tumor Burden Assessment Worth the Time Burden? J Digit Imaging 29:357-64
Strauss, Julius; Madan, Ravi A; Gulley, James L (2016) Considerations for the combination of anticancer vaccines and immune checkpoint inhibitors. Expert Opin Biol Ther 16:895-901
Rajan, Arun; Kim, Chul; Heery, Christopher R et al. (2016) Nivolumab, anti-programmed death-1 (PD-1) monoclonal antibody immunotherapy: Role in advanced cancers. Hum Vaccin Immunother 12:2219-31
Fenerty, Kathleen E; Folio, Les R; Patronas, Nicholas J et al. (2016) Predicting clinical outcomes in chordoma patients receiving immunotherapy: a comparison between volumetric segmentation and RECIST. BMC Cancer 16:672
Heery, Christopher R; Ibrahim, Nuhad K; Arlen, Philip M et al. (2015) Docetaxel Alone or in Combination With a Therapeutic Cancer Vaccine (PANVAC) in Patients With Metastatic Breast Cancer: A Randomized Clinical Trial. JAMA Oncol 1:1087-95
Heery, Christopher R; Singh, B Harpreet; Rauckhorst, Myrna et al. (2015) Phase I Trial of a Yeast-Based Therapeutic Cancer Vaccine (GI-6301) Targeting the Transcription Factor Brachyury. Cancer Immunol Res 3:1248-56
Gulley, James L; Marté, Jennifer; Heery, Christopher R et al. (2015) The impact of leukapheresis on immune-cell number and function in patients with advanced cancer. Cancer Immunol Immunother :

Showing the most recent 10 out of 15 publications