A randomized pilot phase I study of modified carcinoembryonic antigen (CEA) peptide (CAP1-6D)/montanide/GM-CSF-vaccine in patients with pancreatic adenocarcinoma

Abstract

Background: CEA is expressed in >90% of pancreatic cancers (PC) and may be an appropriate immunotherapy target. CEA is poorly immunogenic due to immune tolerance; CAP1-6D, an altered peptide ligand can help bypass tolerance. We conducted a pilot randomized phase I trial in PC patients to determine the peptide dose required to induce an optimal CD8(+) T cell response.

Methods: Patients with a PS 0-1, HLA-A2+ and CEA-expressing, previously-treated PC were randomized to receive 10 μg (arm A), 100 μg (arm B) or 1000 μg (arm C) of CEA peptide emulsified in Montanide and GM-CSF, given every 2 weeks until disease progression.

Results: Sixty-six patients were screened and 19 enrolled of whom 14 received at least 3 doses of the vaccine and thus evaluated for the primary immunologic endpoint. A median of 4 cycles (range 1-81) was delivered. Median and mean peak IFN-γ T cell response by ELISPOT (spots per 10(4) CD8(+) cells, Arm A/B/C) was 11/52/271 (A vs. C, p = 0.028) for medians and 37/148/248 (A vs. C, p = 0.032) for means. T cell responses developed or increased in 20%/60%/100% of pts in Arms A/B/C. Seven of the 19 patients remain alive at a minimum 32 months from trial initiation, including three with unresectable disease.

Conclusions: The T cell response in this randomized phase I trial was dose-dependent with the 1 mg CEA peptide dose eliciting the most robust T cell responses. A signal of clinical benefit was observed and no significant toxicity was noted. Further evaluation of 1 mg CEA peptide with stronger adjuvants, and/or combined with agents to overcome immune inhibitory pathways, may be warranted in PC pts.

Trial registration: ClinicalTrials.gov NCT00203892.

Keywords: CEA; Immunization; Pancreatic Cancer; Vaccine.

Figures

Figure 1

Study Enrollment and Treatment. CONSORT Diagram.

Figure 2

Baseline and Peak ELISPOT results for 14 evaluable patients and median and mean CAP1-6D (Panel A) and wild-type (Panel B) T Cell response per dose level. Baseline (blue diamond) and peak (green triangle) T cell responses by ELISPOT for each of the 14 evaluable patients. Median and mean T cell response by ELISPOT (spots per 104 CD8+ cells) measured after at least 3 cycles is indicated by the orange bars per each arm. For CAP1-6D (Panel A) median/mean Arm A (0.01 mg) response = 10.5/36.5; median/mean Arm B (0.1 mg) response = 51.75/148.45; median/mean Arm C (1 mg) response = 270.63/247.69. P = 0.028 as measured by Mann–Whitney Rank Sum Test comparing medians. For wild-type (Panel B) median/mean Arm A (0.01 mg) response = 3/22.05; median/mean Arm B (0.1 mg) response = 81/120.5; median/mean Arm C (1 mg) response = 222.5/188.5. P = 0.028 as measured by Mann–Whitney Rank Sum Test comparing medians.

Figure 3

ELISPOT kinetics of in vitro primed CAP-1 peptide specific-CD8+ T cell responses. T cell responses for all 14 patients at various time points on the trial are presented and stratified by treatment arm. Day 1 is first day of vaccination.