Cooperative effect between immunotherapy and antiangiogenic therapy leads to effective tumor rejection in tolerant Her-2/neu mice.
Immunotherapy is an attractive strategy for cancer treatment. However, self-tolerance is one of the major mechanisms that dampen immune responses against self-tumor antigens. We have demonstrated that Her-2/neu transgenic mice (neu mice) are tolerant to neu antigens and contain only a low avidity repertoire for neu. However, this repertoire has antitumor activity. Immunizations of neu mice are capable of activating the low-avidity T cells that, at best, retard the tumor growth. To increase the efficacy of the antitumor responses in neu mice, we hypothesized that immunotherapy in combination with antiangiogenic therapy would be a more efficient strategy for tumor eradication. The rationale for using this combination was that by decreasing the growth rate of the tumor with an antiangiogenic therapy, the low-avidity repertoire of neu mice stimulated by immunotherapeutic intervention would be more effective in destroying the slow growing tumor. To test this hypothesis, we stably expressed a soluble form of the Flt-1 vascular endothelial growth factor receptor (sFlt-1) on N202.1A cells, using a retrovirus vector. Expression of sFlt-1 on N202.1A (N202-Flt) cells significantly inhibited the tumor growth compared with N202.1A parental cells. In contrast to the application of immunotherapy alone or antiangiogenic therapy alone, which delayed the tumor growth, the combination of the two therapies provided complete inhibition of tumor growth in Her-2/neu mice. These results indicate that the use of tumor targeting with immunotherapy in simultaneous combination with antiangiogenic therapy provides a more efficient strategy for the treatment of solid tumors.
Cuadros
Camilo
C
Sidney Kimmel Cancer Center, San Diego, California 92121, USA.
Dominguez
Ana Lucia
AL
Frost
Gregory I
GI
Borgstrom
Per
P
Lustgarten
Joseph
J
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000276:immunology*; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D007108:Immune Tolerance; D016219:Immunotherapy, Adoptive / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D018995:Myosin Heavy Chains; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D024501:Nonmuscle Myosin Type IIB; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic; D040281:Vascular Endothelial Growth Factor Receptor-1
D000951:Antigens, Neoplasm; D016326:Extracellular Matrix Proteins; D018995:Myosin Heavy Chains; D024501:Nonmuscle Myosin Type IIB; D018719:Erb-b2 Receptor Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1; C501163:Flt1 protein, mouse; C103815:nonmuscle myosin type IIB heavy chain