Phase I Study of Recombinant Carcinoembryonic Antigen (CEA) Vaccinia Virus Vaccine With Post Vaccination Carcinoembryonic Antigen Peptide (CAP-1) Boost

Abstract

227 February 2000 Rationale Seventy percent of non–small-cell lung cancers express carcinoembryonic antigen (CEA).1 A direct immunologic approach to CEA-bearing tumors has been recently defined using inoculation with a recombinant vaccinia virus that expresses the human CEA gene.2 Since vaccinia elicits both humoraland cell-mediated immune responses, copresentation of tumor-associated antigen products with vaccinia could enhance cell-mediated immunity against the tumor.3 A preclinical murine model has been established using cDNA coding for CEA inserted into a strain of vaccinia virus (rV-CEA) (Figure 1). Animals inoculated with rVCEA showed inhibition of CEA-positive tumor growth and did not allow tumor growth when rechallenged.4 Safety testing of rV-CEA in the rhesus monkey model noted only local skin reactions, low-grade fever, and lymphadenopathy.5 Based on this preclinical data, an initial phase I study using an escalating dose administration of the rV-CEA vaccine was performed without grade 3 or dose-limiting toxicities.6 A therapeutic immune response was not realized; however, in vitro priming of postvaccination peripheral blood lymphocytes (PBL) with CEA peptide demonstrated specific lytic activity against CEA-expressing tumor cells. Immune recognition, therefore, of the CEA peptide can be induced by the rVCEA vaccine.6,7 The in vitro response of the post-vaccination PBL to peptide stimulation suggests that a CEA-specific T-lymphocyte precursor population is present in vivo as a result of the rV-CEA vaccination. Administration of relevant tumor-associated epitopes with adjuvant to stimulate and significantly expand the number of antigen-specific T-lymphocyte precursor cells present in vivo holds promise.8 A logical next step, therefore, would be post-rV-CEA vaccination administration of CEA peptide with an adjuvant reagent in vivo. An enhanced CEA-bearing tumor T-cell population could then potentially lead to a direct therapeutic antitumor immune response. Furthermore, additional interventions, such as the ex vivo expansion of CEA-specific Tlymphocytes for adoptive immunotherapy, would then be possible. Therefore, we hypothesize that a significant in vivo precursor tumor-specific T-cell population can be established using rV-CEA vaccination and follow-up CEA peptide challenge that could lead to an effective antitumor response. Our objectives are: (1) to determine tolerance/side effects of repeated vaccination with rV-CEA followed by repeated CEA peptide David J. Cole,1 Paul L. Baron,1 Paul O'Brien,1 Carolyn E. Reed,1 Jeffrey Schlom,2 Kwon Y. Tsang2