Phase I Trial of a Yeast-Based Therapeutic Cancer Vaccine (GI-6301) Targeting the Transcription Factor Brachyury

Abstract

The nuclear transcription factor brachyury has previously been shown to be a strong mediator of the epithelial-to-mesenchymal transition (EMT) in human carcinoma cells and a strong negative prognostic factor in several tumor types. Brachyury is overexpressed in a range of human carcinomas as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown that a recombinant Saccharomyces cerevisiae (yeast) vaccine encoding brachyury (GI-6301) can activate human T cells in vitro. A phase I dose-escalation (3+3 design) trial enrolled 34 patients at 4 dose levels [3, 3, 16, and 11 patients, respectively, at 4, 16, 40, and 80 yeast units (YU)]. Expansion cohorts were enrolled at 40- and 80-YU dose levels for analysis of immune response and clinical activity. We observed brachyury-specific T-cell immune responses in the majority of evaluable patients despite most having been heavily pretreated. No evidence of autoimmunity or other serious adverse events was observed. Two chordoma patients showed evidence of disease control (one mixed response and one partial response). A patient with colorectal carcinoma, who enrolled on study with a large progressing pelvic mass and rising carcinoembryonic antigen (CEA), remains on study for greater than 1 year with stable disease, evidence of decreased tumor density, and decreased serum CEA. This is the first-in-human study to demonstrate the safety and immunogenicity of this therapeutic cancer vaccine and provides the rationale for exploration in phase II studies. A randomized phase II chordoma study is now enrolling patients.

©2015 American Association for Cancer Research.

Figures

Figure 1

A 48-year-old female with metastatic colorectal cancer after disease progression through three prior lines of standard therapy enrolled on study with a rising CEA in January 2014. Her main site of disease was a very large pelvic mass, which caused compression of the ureters and the rectum, resulting in the need for colostomy and bilateral nephrostomy tubes. A, Baseline CT scan of the chest, abdomen and pelvis demonstrating large (approximately 14 cm) pelvic mass with compression of ureters and rectum. Note the lack of contrast enhancing vasculature within the tumor and lack of central necrosis (gas). B, Restaging CT scan at 1-year follow-up demonstrating similar size pelvic mass with increased perfusion demonstrated by contrast enhanced vasculature (white arrows) and central gaseous necrosis (white arrow). C, CEA was rising prior to enrollment and declined after enrollment (arrow indicates time of enrollment and first vaccine).

Figure 2

Mixed response in a patient with chordoma. A 61-year-old male with a sacral chordoma underwent surgery, radiation and multiple systemic therapies with continued progressive disease. His right iliac mass (A) was irradiated approximately 3.5 months prior to enrollment. A, C, and E, Baseline, first restaging, and most recent restaging MRI of the right iliac mass, which was previously irradiated. Mass decreased from 5.9 to 4.4 to 2.6 cm. B, D, and F, Baseline, first restaging, and most recent restaging CT scan of left paraspinal mass, which was not previously irradiated. This mass increased in size from 5.5 cm to 6.9 cm at first restaging, and growth was halted after radiation was given (6.9 to 6.6 cm on follow-up scan) while patient remained on study.

Figure 3

Partial response in a patient with chordoma. A 47-year-old male was diagnosed in 2004 with a large sacral chordoma (12 cm). He underwent surgery followed by radiation with recurrent disease within 1 year. The patient subsequently underwent multiple surgical resections and further courses of radiation, with no response. He was treated with 30 and 36 Gy (in 3 fractions; 10 and 12 Gy fractions), to the anterior and posterior pelvic masses, respectively, about 3.5 months prior to enrollment. A and B, Baseline MRI with right anterior pelvic mass, and left posterior pelvic mass. C and D, After 8 doses of vaccine, both masses decreased in size, constituting a partial response. E and F, The patient had a continued response with a 42% decrease in overall size of tumors up to 9 months after the partial response.