Pilot study of vaccination with recombinant CEA-MUC-1-TRICOM poxviral-based vaccines in patients with metastatic carcinoma

Abstract

Purpose: Poxviral vectors have a proven safety record and can be used to incorporate multiple transgenes. Prior clinical trials with poxviral vaccines have shown that immunologic tolerance to self-antigens can be broken. Carcinoembryonic antigen (CEA) and MUC-1 are overexpressed in a substantial proportion of common solid carcinomas. The primary end point of this study was vaccine safety, with immunologic and clinical responses as secondary end points.

Experimental design: We report here a pilot study of 25 patients treated with a poxviral vaccine regimen consisting of the genes for CEA and MUC-1, along with a triad of costimulatory molecules (TRICOM; composed of B7.1, intercellular adhesion molecule 1, and lymphocyte function-associated antigen 3) engineered into vaccinia (PANVAC-V) as a prime vaccination and into fowlpox (PANVAC-F) as a booster vaccination.

Results: The vaccine was well tolerated. Apart from injection-site reaction, no grade > or =2 toxicity was seen in more than 2% of the cycles. Immune responses to MUC-1 and/or CEA were seen following vaccination in 9 of 16 patients tested. A patient with clear cell ovarian cancer and symptomatic ascites had a durable (18-month) clinical response radiographically and biochemically, and one breast cancer patient had a confirmed decrease of >20% in the size of large liver metastasis.

Conclusions: This vaccine strategy seems to be safe, is associated with both CD8 and CD4 immune responses, and has shown evidence of clinical activity. Further trials with this agent, either alone or in combination with immunopotentiating and other therapeutic agents, are warranted.

Fig. 1

Identification of CEA-specific T cells in patients pre- and postvaccination by ELISPOT assay, CEA-MHC-tetramer binding, and intracellular cytokine (ICC) analysis. Effectors were used at IVS-2 (see Patients and Methods). Results are expressed as frequency of IFN-γ-producing cells (ELISPOT assay), % of tetramer binding cells (tetramer binding assay), or % intracellular IFN-γ-positive cells (ICC staining assay), respectively.

Fig. 2

Serum CA-125 levels from a 42-year-old patient (# 22) with platinum-refractory clear cell ovarian cancer who received PANVAC-V on day 1, followed by multiple boosts with PANVAC-F (vaccinations designated by arrows). The CA-125 level decreased from a peak of 351 U/mL to less than 10 U/mL out to 18 months on study.

Fig. 3

Representative sections (A and B) from a CT scan on baseline and day 71 after initiation of vaccination for patient 22 (ovarian cancer). Baseline study reveals ascites (arrows) and mesenteric stranding, both of which are absent at day 71 and all subsequent restagings.

Fig. 3

Representative sections (A and B) from a CT scan on baseline and day 71 after initiation of vaccination for patient 22 (ovarian cancer). Baseline study reveals ascites (arrows) and mesenteric stranding, both of which are absent at day 71 and all subsequent restagings.