Phase I trial of a recombinant yeast-CEA vaccine (GI-6207) in adults with metastatic CEA-expressing carcinoma

Abstract

Yeast-CEA (GI-6207) is a therapeutic cancer vaccine genetically modified to express recombinant carcinoembryonic antigen (CEA) protein, using heat-killed yeast (Saccharomyces cerevisiae) as a vector. In preclinical studies, yeast-CEA induced a strong immune response to CEA and antitumor responses. Patients received subcutaneous vaccines every 2 weeks for 3 months and then monthly. Patients were enrolled at 3 sequential dose levels: 4, 16, and 40 yeast units (10(7) yeast particles/unit). Eligible patients were required to have serum CEA > 5 ng/mL or > 20 % CEA(+) tumor block, ECOG PS 0-2, and no history of autoimmunity. Restaging scans were performed at 3 months and then bimonthly. Peripheral blood was collected for the analysis of immune response (e.g., by ELISPOT assay). Twenty-five patients with metastatic CEA-expressing carcinomas were enrolled. Median patient age was 52 (range 39-81). A total of 135 vaccines were administered. The vaccine was well tolerated, and the most common adverse event was grade 1/2 injection-site reaction. Five patients had stable disease beyond 3 months (range 3.5-18 months), and each had CEA stabilization while on-study. Some patients showed evidence post-vaccination of increases in antigen-specific CD8(+) T cells and CD4(+) T lymphocytes and decreases in regulatory T cells. Of note, a patient with medullary thyroid cancer had substantial T cell responses and a vigorous inflammatory reaction at sites of metastatic disease. Yeast-CEA vaccination had minimal toxicity and induced some antigen-specific T cell responses and CEA stabilization in a heterogeneous, heavily pre-treated patient population. Further studies are required to determine the clinical benefit of yeast-CEA vaccination.

Fig. 1

A patient (#16) with colon cancer with CEA decline/stabilization after treatment with yeast-CEA vaccine GI-6207. The figure shows the log of CEA values for a 67-year-old man initially diagnosed with stage IIIC colon cancer in January 2007 who was treated with surgery and adjuvant FOLFOX. When he developed metastatic disease, treatments included metastasectomy, FOLFIRI with bevacizumab, then cetuximab, and lastly another regimen of FOLFIRI with bevacizumab. His disease progressed and CEA continued to rise through the last 2 chemotherapy regimens prior to enrollment. At the time of enrollment, he had relatively small disease burden (4 mesenteric lymph nodes measuring ≤ 2.5 cm). He remained on-study at dose level 3 for 17.4 months with stable disease and CEA levels, and tolerated treatment without any adverse effects

Fig. 2

Five patients on study were stable beyond the 3-month staging. PBMCs from 4 of these 5 patients were available for the comparison of immune-cell subsets to the other 20 patients receiving vaccine at baseline and on day 29. a Frequency of CD4⁺ T cells at baseline for the 4 stable patients compared to the other 20 patients. There was no difference between the 2 groups at baseline. b Frequency of CD4⁺ T cells on day 29 for the 4 stable patients compared to the other 20 patients. There was a trend (P > 0.04) in the frequency of CD4⁺ T cells in the stable patients on day 29 after vaccine therapy. c Frequency of CTLA-4⁺ Tregs at baseline for the 4 stable patients compared to the other 20 patients. There was no difference between the 2 groups at baseline. d Frequency of CTLA-4⁺ Tregs on day 29 for the 4 stable patients compared to the other 20 patients. There was a trend (P = 0.098) toward a lower frequency of highly suppressive Tregs in the stable patients on day 29. Dot plots with the median and interquartile range are shown

Fig. 3

Inflammatory response in a patient with medullary thyroid cancer who was treated with vaccine. a, b Baseline computed tomography (CT) of a patient with medullary thyroid cancer who had a pericardial-based lesion (a, arrow) and a right-sided pleural-based lesion (b, arrow). c Six days after the seventh vaccine (approximately 13 weeks after initiating therapy), the patient developed shortness of breath and was admitted to a local hospital. CT showed a right-sided pleural effusion and a pericardial effusion. A biopsy evaluating lymphangitic spread, bronchoscopy with lavage, and empiric antibiotic therapy yielded no clear etiology. With no clear diagnosis, high-dose steroids were started to treat a potential immune-related reaction. The patient’s symptoms resolved within 48 h. d CT image obtained 18 days after the image in (c) and approximately 2 weeks after starting steroids. Notably, this patient was re-evaluated for yeast allergies and found to be negative, and the magnitude of antigen-specific T cell response to multiple tumor antigens increased 10- to 20-fold after vaccine. Based on the clinical course and absence of an alternative diagnosis, it is possible that this was a vigorous immune-mediated antitumor response. Interestingly, in image (c), the effusion was only on the right side (arrow), the same location of the pleural-based lesion seen in (b)