Unexpected association between induction of immunity to the universal tumor antigen CYP1B1 and response to next therapy.
OBJECTIVE
The carcinogen activator cytochrome P450 1B1 (CYP1B1) is expressed on almost all human tumors with rare expression on normal tissues. Anti-CYP1B1-specific T cells kill CYP1B1-expressing tumors, providing the rationale to examine CYP1B1 as a target for immunotherapy.


METHODS
ZYC300, a plasmid DNA of CYP1B1 encapsulated in biodegradable poly-DL-lactide-coglycolide microparticles, was used in a phase I clinical trial to treat 17 patients with advanced stage, progressive cancer. ZYC300 was administered i.m. at a fixed dose of 400 microg every other week for up to 12 doses.


RESULTS
Thirteen patients received six vaccinations and five received all 12 doses. No significant adverse events were observed. Six patients developed immunity to CYP1B1, three of whom developed disease stabilization. All but 1 of 11 patients who did not develop immunity to CYP1B1 progressed and did not respond to salvage therapy. Five patients who developed immunity to CYP1B1 required salvage therapy for progressive metastatic disease and showed marked response to their next treatment regimen, most of which lasted longer than 1 year.


CONCLUSIONS
The association between immunity to CYP1B1 and response to next salvage therapy was not expected. Because six of the seven patients who had clinical benefit regardless of the nature of salvage therapy had developed immunity to CYP1B1, it seems highly unlikely that this occurred by chance alone. Regardless of the mechanism(s) that induced tumor regression, these findings force us to rethink how the generation of antitumor immunity might be integrated into the treatment of cancer.
Gribben
John G
JG
Department of Medical Oncology, Dana-Farber Cancer Institute and Division of Medical Oncology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Ryan
David P
DP
Boyajian
Richard
R
Urban
Robert G
RG
Hedley
Mary L
ML
Beach
Kathleen
K
Nealon
Patrick
P
Matulonis
Ursula
U
Campos
Susana
S
Gilligan
Timothy D
TD
Richardson
Paul G
PG
Marshall
Blossom
B
Neuberg
Donna
D
Nadler
Lee M
LM
D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000276:immunology*; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D065633:Cytochrome P-450 CYP1B1; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D010957:Plasmids / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1