A Phase I/II Study of Active Immunotherapy With CEA(6D)VRP Vaccine(AVX701)in Patients With Advanced or Metastatic Malignancies Expressing CEA or Stage III Colon Cancer
CEA represents an attractive target antigen for immunotherapy since it is over expressed in
nearly all colorectal cancers and pancreatic cancers, and is also expressed by some lung and
breast cancers, and uncommon tumors such as medullary thyroid cancer, but is not expressed
in other cells of the body except for low-level expression in gastrointestinal epithelium
[1]. That CEA is a potential target for T cell mediated immune responses in humans is
demonstrated by the observation that CEA contains epitopes that may be recognized in an MHC
restricted fashion by T cells [2-11]. Specifically, there is support for the existence of
human cytolytic T cells (CTLs) that recognize CEA epitopes that bind to MHC molecules HLA-
A2, A3, and A24. For the most part, these T cells have been generated by in vitro cultures
using antigen-presenting cells pulsed with the epitope of interest to stimulate peripheral
blood mononuclear cells. In addition, T cell lines have been generated after stimulation
with CEA latex beads, CEA protein-pulsed plastic adherent peripheral blood mononuclear
cells, or DCs sensitized with CEA RNA. T cells have also been generated from patients
immunized with a vaccinia vector encoding CEA immunogen (discussed below). Using
high-performance liquid chromatography mass-spectrometry-based approaches, HLA A2-presented
peptides from CEA have been identified in primary gastrointestinal tumors [12]. Of the HLA
A2 restricted epitopes of CEA, CAP-1, a nine amino acid sequence, has been shown to
stimulate CTLs from cancer patients immunized with vaccinia-CEA. Cap-1(6D) is a peptide
analog of CAP-1. Its sequence includes a heteroclitic (nonanchor position) mutation,
resulting in an amino acid change from Asn to Asp, to enhance recognition by the T-cell
receptor without any change in binding to HLA A2. Compared with the non mutated CAP-1
epitope, Cap-1(6D) has been shown to enhance the sensitization of CTLs by 100 to 1,000 times
[3, 5, 13]. CTL lines could be elicited from peripheral blood mononuclear cells of healthy
volunteers by in vitro sensitization to the Cap-1(6D) peptide but not to the CAP-1 peptide.
These cell lines can lyse human tumor cells expressing endogenous CEA.
Interventional
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
determine the safety of immunization with CEA(6D) VRP
2.5 years
No
Michael Morse, M.D.
Principal Investigator
Duke University
United States: Institutional Review Board
AVX701
NCT00529984
September 2007
May 2010
Name | Location |
---|---|
Duke University Medical Center | Durham, North Carolina 27710 |