Immune responses in advanced colorectal cancer following repeated intradermal vaccination with the anti-CEA murine monoclonal antibody, PR1A3: results of a phase I study.
OBJECTIVE
The aim was to determine the toxicity, clinical and immune responses to the murine monoclonal anti-carcinoembryonic antigen (CEA) antibody, PR1A3, in patients with advanced colorectal cancer.


METHODS
Fifteen patients with advanced colorectal cancer received either 0.5-, 1.0- or 5.0-mg doses of PR1A3 mixed with 10% w/v Alum adjuvant (Superfos Biosector, Denmark) intradermally at 4-week intervals for 3 months. Patient serum was assessed for anti-idiotypic (Ab2), anti-anti-idiotypic (Ab3) and human anti-mouse antibody (HAMA) reactivity. Peripheral blood mononuclear cell (PBMC) proliferation with phytohaemagglutinin (PHA), CEA and PR1A3, stimulated IL-2, IL-4 and IFN-gamma levels and PR1A3-stimulated IL-2 receptor expression during immunotherapy were determined. Comparisons were made with 16 age-matched controls without malignant disease.


RESULTS
Hyperimmune sera from 12 of the 15 patients showed Ab2 reactivity with no detectable Ab3 responses. Strong HAMA reactivity was recorded in 7 of the 15 cases with no adverse clinical effect. Delayed-type hypersensitivity (DTH) responses developed in 12 of the 15 patients. Pre-treatment PBMC proliferation with PHA was subnormal in each patient compared with controls, becoming normal (or supranormal) in all patients during immunisation (P<0.001). PBMC proliferation with CEA and PR1A3 increased during immunotherapy (P<0.001) along with stimulated production of IL-2, IFN-gamma and IL-2 receptor expression. Progressive disease was observed in 14 of the 15 patients with minimal toxicity.


CONCLUSIONS
PR1A3 generated limited idiotypic responses but robust DTH reactivity in most patients. In vitro PBMC proliferation with mitogens and recall antigens is greatly increased during the course of immunisation, with a shift in stimulated cytokine profile.
Zbar
A P
AP
Academic Department of Colorectal Surgery, Hammersmith Hospital, London, UK. azbar@uwichill.edu.bb
Thomas
H
H
Wilkinson
R W
RW
Wadhwa
M
M
Syrigos
K N
KN
Ross
E L
EL
Dilger
P
P
Allen-Mersh
T G
TG
Kmiot
W A
WA
Epenetos
A A
AA
Snary
D
D
Bodmer
W F
WF
D000368:Aged; D000369:Aged, 80 and over; D000888:Antibodies, Anti-Idiotypic / Q000097:blood / Q000187:drug effects / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D000912:Antibodies, Neoplasm / Q000097:blood / Q000187:drug effects / Q000276:immunology; D000951:Antigens, Neoplasm / Q000097:blood / Q000187:drug effects / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use*; D002272:Carcinoembryonic Antigen / Q000187:drug effects* / Q000276:immunology*; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D016207:Cytokines / Q000097:blood / Q000187:drug effects / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007106:Immune Sera / Q000187:drug effects / Q000276:immunology; D018928:Immunity, Mucosal / Q000187:drug effects; D007271:Injections, Intradermal; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D015375:Receptors, Interleukin-2 / Q000097:blood / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D016207:Cytokines; D007106:Immune Sera; C511152:PR1A3 monoclonal antibody; D015375:Receptors, Interleukin-2