Use of the humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 in combination with radiotherapy in the treatment of locally advanced head and neck cancer patients.
OBJECTIVE
To evaluate safety and preliminary efficacy of the humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 in combination with radiotherapy (RT) in unresectable head and neck cancer patients. Secondary end points were the measurement of h-R3 serum levels and the assessment of the potential mechanisms of antitumor effect on patient biopsies. Anti-idiotypic response to h-R3 was assessed. To predict pharmacologic effect, a mathematical model for antibodies recognizing antigens expressed in tumors and normal tissues was built.


METHODS
Twenty-four patients with advanced carcinomas of the head and neck received six once-weekly infusions of h-R3 at four dose levels in combination with RT. Pretreatment tumor biopsies were obtained to evaluate epidermal growth factor receptor expression as an enrollment criterion. Second biopsies were taken to evaluate the proliferative activity and angiogenesis in comparison with the pretreatment samples. Patient serum samples were collected to measure h-R3 levels and anti-idiotypic response.


RESULTS
The combination of h-R3 and RT was well tolerated. Antibody-related adverse events consisted in infusion reactions. No skin or allergic toxicity appeared. Overall survival significantly increased after the use of the higher antibody doses. Immunohistochemistry studies of tumor specimens before and after treatment revealed that antitumor response correlated with antiproliferative and antiangiogenic effect. One patient developed antibodies to h-R3. The mathematical model predicted that the maximum difference between the area under the curve in tumors and normal tissues is reached when the antibody has intermediate affinity.


CONCLUSIONS
h-R3 is a well-tolerated drug that may enhance radiocurability of unresectable head and neck neoplasms.
Crombet
Tania
T
Center of Molecular Immunology, Clinical Immunology Department, PO Box 16040, Havana 11600, Cuba. Taniac@ict.cim.sld.cu
Osorio
Marta
M
Cruz
Teresa
T
Roca
Carlos
C
del Castillo
Ramón
R
Mon
Rosa
R
Iznaga-Escobar
Normando
N
Figueredo
René
R
Koropatnick
James
J
Renginfo
Enrique
E
Fernández
Eduardo
E
Alvárez
Daniel
D
Torres
Olga
O
Ramos
Mayra
M
Leonard
Idrissa
I
Pérez
Rolando
R
Lage
Agustín
A
D000368:Aged; D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000912:Antibodies, Neoplasm / Q000032:analysis / Q000276:immunology*; D001706:Biopsy; D002277:Carcinoma / Q000276:immunology* / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D066246:ErbB Receptors / Q000276:immunology* / Q000627:therapeutic use*; D005260:Female; D006258:Head and Neck Neoplasms / Q000276:immunology* / Q000532:radiotherapy*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D066246:ErbB Receptors