Anti-CD3 x anti-HER2 bispecific antibody effectively redirects armed T cells to inhibit tumor development and growth in hormone-refractory prostate cancer-bearing severe combined immunodeficient beige mice.
The bispecific antibody (BiAb) anti-CD3 x anti-Her2/neu (Her2Bi), combines Her2/neu targeting with nonmajor histocompatibility complex-restricted cytotoxicity mediated by activated T cells (ATCs). To evaluate this adaptive immunotherapeutic strategy for augmenting antitumor immune response toward hormone-refractory prostate cancer (HRPC), normal donor or patient T cells were activated with anti-CD3, expanded ex vivo in interleukin-2, and then armed with Her2Bi (5-500 ng per million ATCs). In vitro, arming ATCs with Her2Bi increased the percent specific cytotoxicity toward PC-3 prostate adenocarcinoma cells 2-3 fold and increased the secretion of Th1 cytokines granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, and interferon-gamma when compared with unarmed ATCs or ATCs armed with an irrelevant BiAb. Her2Bi-armed ATCs administered with PC-3 (Winn Assay) or injected intratumorally prevented development or induced remissions, respectively, of PC-3 tumors in severe combined immunodeficient beige mice. Intravenously administered Her2Bi-armed ATCs localized to PC-3 xenografts mediated cytotoxicity toward tumor cells and produced significant tumor growth delay of PC-3 tumors, but not Her2/neu-negative LS174T colon adenocarcinoma xenografts. By flow cytometry analyses, Her2Bi-armed ATCs had a proliferative advantage over unarmed ATCs and persisted in the circulation and tumor tissues longer than unarmed ATCs. These findings suggest that Her2Bi-armed ATC therapy may be an effective, nontoxic, tumor-specific treatment for Her2-positive HRPC.
Cancer Immunotherapy Laboratory, Adele R. Decof Cancer Center, Roger Williams Medical Center, Providence, RI 02908, USA.
Pamela A
PA
Davol
Janelle A
JA
Smith
Nicola
N
Kouttab
Gerald J
GJ
Elfenbein
Lawrence G
LG
Lum
D000704:Analysis of Variance; D000818:Animals; D018033:Antibodies, Bispecific / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015925:Cryopreservation; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D012680:Sensitivity and Specificity; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D018033:Antibodies, Bispecific; D018931:Antineoplastic Agents, Hormonal; D017252:CD3 Complex; D018719:Erb-b2 Receptor Tyrosine Kinases