A randomized phase II study of immunization with dendritic cells modified with poxvectors encoding CEA and MUC1 compared with the same poxvectors plus GM-CSF for resected metastatic colorectal cancer

Abstract

Objective: To determine whether 1 of 2 vaccines based on dendritic cells (DCs) and poxvectors encoding CEA (carcinoembryonic antigen) and MUC1 (PANVAC) would lengthen survival in patients with resected metastases of colorectal cancer (CRC).

Background: Recurrences after complete resections of metastatic CRC remain frequent. Immune responses to CRC are associated with fewer recurrences, suggesting a role for cancer vaccines as adjuvant therapy. Both DCs and poxvectors are potent stimulators of immune responses against cancer antigens.

Methods: Patients, disease-free after CRC metastasectomy and perioperative chemotherapy (n = 74), were randomized to injections of autologous DCs modified with PANVAC (DC/PANVAC) or PANVAC with per injection GM-CSF (granulocyte-macrophage colony-stimulating factor). Endpoints were recurrence-free survival overall survival, and rate of CEA-specific immune responses. Clinical outcome was compared with that of an unvaccinated, contemporary group of patients who had undergone CRC metastasectomy, received similar perioperative therapy, and would have otherwise been eligible for the study.

Results: Recurrence-free survival at 2 years was similar (47% and 55% for DC/PANVAC and PANVAC/GM-CSF, respectively) (χ P = 0.48). At a median follow-up of 35.7 months, there were 2 of 37 deaths in the DC/PANVAC arm and 5 of 37 deaths in the PANVAC/GM-CSF arm. The rate and magnitude of T-cell responses against CEA was statistically similar between study arms. As a group, vaccinated patients had superior survival compared with the contemporary unvaccinated group.

Conclusions: Both DC and poxvector vaccines have similar activity. Survival was longer for vaccinated patients than for a contemporary unvaccinated group, suggesting that a randomized trial of poxvector vaccinations compared with standard follow-up after metastasectomy is warranted. (NCT00103142).

Conflict of interest statement

Disclosure: The authors declare no conflicts of interest.

Figures

FIGURE 1

CONSORT diagram. Patient disposition in this clinical trial is described. *Analyzed with DC/PANVAC arm by intention to treat analysis.

FIGURE 2

A, Recurrence-free survival for randomized patients receiving DCs loaded with PANVAC or PANVAC plus GM-CSF measured from the date of metastasectomy, with relapse defined as documented disease recurrence at any site. Median RFS (95% CI) was 22.9 (19.6–49.8) and 28.9 (16.2, not reached), months, respectively. B, OS for randomized patients receiving DCs loaded with PANVAC or PANVAC plus GM-CSF measured from metastasectomy until death from any cause. Patients were censored on the date of last known follow-up. 95% CI indicates 95% confidence interval.

FIGURE 3

ELISpot analysis after vaccinations. Patient PBMCs were analyzed pre- (week 0) and post- (week 13) vaccinations for arm A (+DC) and arm B (no DC) by IFNγ ELISpot. Patient PBMCs were stimulated 20 to 24 hours with PANVAC-F (moi 10) and fowlpox-TRICOM (moi 10) in a standard ELISpot assay. The number of IFNγ-producing cells per 106 PBMCs for each subject analyzed is represented for the response to PANVAC-F minus the fowlpox-TRICOM response (solid black circles for arm A; solid black squares for arm B). The mean response is depicted as a solid black bar pre- and postimmunization for each study arm. The P value reported is based on the Wilcoxon signed rank test calculated by Graph-Pad Prism. moi indicates multiplicity of infection.

FIGURE 4

Recurrence-free survival by ELISpot immune response for patients enrolled and treated on the PANVAC trial (Wilcoxon P = 0.08). IR indicates immune responders; NR, no immune response.

FIGURE 5

A, Recurrence-free survival for vaccinated patients combined versus contemporary, unvaccinated controls. RFS was measured from the date of metastasectomy until documented disease recurrence at any site. Median RFS (95% CI) was 21.9 (16.9–38.8) and 25.7 (20.0–37.2), months, respectively. B, OS for vaccinated patients combined compared with contemporary, unvaccinated controls. OS was measured from metastasectomy until death from any cause. Patients were censored on the date of last known follow-up. Median OS (95% CI) was not reached and 44.1 (36.2–63.4), months, respectively. 95% CI indicates 95% confidence interval.