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 carcinoma as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown 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 were 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 CEA, remains on study for greater than 1 year with stable disease, evidence of decreased tumor density and decreased serum CEA. This study is the first-in-human to demonstrate the safety and immunogenicity of this therapeutic cancer vaccine and provides rationale for exploration in Phase II studies. A randomized Phase II chordoma study is enrolling.

Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury

“…A prior trial of a recombinant yeast-brachyury-targeting vaccine demonstrated immunogenicity, safety, and generation of brachyury-specific T cells, without evidence of autoimmune toxicity (45). Preclinical murine studies (58) have shown that both the recombinant yeast vaccine (yeast-CEA) and the recombinant poxviral vaccine (CEA-TRICOM) platforms generate immune responses directed against different CEA epitopes, most likely due to differences in antigen processing by the two diverse vaccine platforms.…”

“…Analysis of antigen-specific responses following therapy was assessed by intracellular cytokine staining following a period of in vitro stimulation (IVS) with overlapping 15-mer peptide pools encoding the tumor-associated antigen (TAA) brachyury as previously described (45). The TAA peptide pool was designed to contain a brachyury agonist epitope that had been previously identified (24).…”

“…Cryopreserved PBMCs from patients before therapy and on days 28 (post I cycle of vaccine), 56 (post II cycles of vaccine), 84 (post III cycles of vaccine), and at a late time point (day 168–190, where available) were assayed as previously described (45). Using a BD LSR-II flow cytometer equipped with a UV, violet, blue, and red laser, 3 × 10 5 events in the live gate were acquired.…”

TILGen: A Program to Investigate Immune Targets in Breast Cancer Patients - First Results on the Influence of Tumor-Infiltrating Lymphocytes

“…One such TSA is brachyury, a developmental protein found to be abnormally expressed during the epithelial-mesenchymal transition in chordoma and other cancers [50]. Using a heat-killed yeast platform designed to evade immune neutralization while inducing an immunogenic response against its payload, a phase I trial of yeastbrachyury resulted in specific T-cell immune responses in the majority of the trial's 34 patients despite heavy pretreatment and metastatic disease, and stable disease in 2 chordoma patients and 1 colorectal cancer patient [51]. A randomized phase II study using this platform is ongoing for chordoma patients.…”

Spinal stereotactic body radiotherapy following intralesional curettage with separation surgery for initial or salvage chordoma treatment

“…28 Additionally, interest in radiosensitization, vaccines, and immunotherapies, and with novel mechanistic insight from emerging from epigenetic discovery approaches, may potentially allow for future therapy abrogating the need for strategies emphasizing surgical cure via wide marginal excision. 19,21,26,41,45,48 …”