A Case Report of Sequential Use of a Yeast-CEA Therapeutic Cancer Vaccine and Anti-PD-L1 Inhibitor in Metastatic Medullary Thyroid Cancer

Abstract

Medullary thyroid cancer (MTC) accounts for ~4% of all thyroid malignancies. MTC derives from the neural crest and secretes calcitonin (CTN) and carcinoembryonic antigen (CEA). Unlike differentiated thyroid cancer, MTC does not uptake iodine and I-131 RAI (radioactive iodine) treatment is ineffective. Patients with metastatic disease are candidates for FDA-approved agents with either vandetanib or cabozantinib; however, adverse effects limit their use. There are ongoing trials exploring the role of less toxic immunotherapies in patients with MTC. We present a 61-year-old male with the diagnosis of MTC and persistent local recurrence despite multiple surgeries. He was started on sunitinib, but ultimately its use was limited by toxicity. He then presented to the National Cancer Institute (NCI) and was enrolled on a clinical trial with heat-killed yeast-CEA vaccine (NCT01856920) and his calcitonin doubling time improved in 3 months. He then came off vaccine for elective surgery. After surgery, his calcitonin was rising and he enrolled on a phase I trial of avelumab, a programmed death-ligand 1 (PD-L1) inhibitor (NCT01772004). Thereafter, his calcitonin decreased > 40% on 5 consecutive evaluations. His tumor was subsequently found to express PD-L1. CEA-specific T cells were increased following vaccination, and a number of potential immune-enhancing changes were noted in the peripheral immunome over the course of sequential immunotherapy treatment. Although calcitonin declines do not always directly correlate with clinical responses, this response is noteworthy and highlights the potential for immunotherapy or sequential immunotherapy in metastatic or unresectable MTC.

Keywords: CEA; PD-L1 inhibitor; calcitonin; immunotherapy; medullary thyroid cancer.

Copyright © 2020 Del Rivero, Donahue, Marté, Gramza, Bilusic, Rauckhorst, Cordes, Merino, Dahut, Schlom, Gulley and Madan.

Figures

Figure 1

(A) Five consecutive declines in the patient's calcitonin levels while on the immune checkpoint inhibitor, a > 40% decline. (B) Robustly positive PD-L1 staining after surgical resection of a neck lymph node after vaccine (higher power on the right).

Figure 2

Cross sectional imaging studies with computed tomography of the neck (A) prior to PD-L1 administration and (B) after a 40% decrease in calcitonin, showing stable thyroid bed recurrence.

Figure 3

Induction of CEA-specific T cells and changes in peripheral immune cell subsets. (A) Schema showing the timing of sequential immunotherapies and immune assays. (B) CEA-specific T cells were identified in PBMCs by intracellular cytokine staining following a period of in vitro stimulation with overlapping 15-mer peptide pools encoding for the tumor-associated antigen CEA or the negative control peptide pool HLA. Dot plots of IFNγ and TNF production by CD4+ T cells showing induction of multifunctional CEA-specific T cells (producing >1 cytokine) at 3 months. (C–G) PBMCs were assessed for the frequency of 123 immune cell subsets over the course of immunotherapy. The most notable fluctuations were observed after initiation of avelumab (indicated by black arrow). The frequency over time of Tregs (C), cDC (D), pDC (E), MDSC (F), and B cells (G), indicated as a percentage of total PBMCs.