VRP immunotherapy targeting neu: treatment efficacy and evidence for immunoediting in a stringent rat mammary tumor model.
The ability to overcome intrinsic tolerance to a strict "self" tumor-associated antigen (TAA) and successfully treat pre-existing tumor is the most stringent test for anti-tumor immunotherapeutic strategies. Although this capacity has been demonstrated in various models using complicated strategies that may not be readily translated into the clinical arena, straightforward antigen-specific immunotherapeutic strategies in the most stringent models of common epithelial cancers have largely failed to meet this standard. We employed an immunotherapeutic strategy using an alphavirus-based, virus-like replicon particle (VRP), which has in vivo tropism for dendritic cells, to elicit immune responses to the non-mutated TAA rat neu in an aggressive rat mammary tumor model. Using this VRP-based immunotherapeutic strategy targeting a single TAA, we generated effective anti-tumor immunity in the setting of pre-existing tumor resulting in the cure of 36% of rats over multiple experiments, P = 0.002. We also observed down-regulation of rat neu expression in tumors that showed initial responses followed by tumor escape with resumption of rapid tumor growth. These responses were accompanied by significant anti-tumor proliferative responses and CD8+ cellular tumor infiltrates, all of which were restricted to animals receiving the anti-neu immunotherapy. Together these data, obtained in a stringent "self" TAA model, indicate that the VRP-based antigen-specific immunotherapy elicits sufficiently potent immune responses to exert immunologic pressure, selection, and editing of the growing tumors, thus supporting the activity of this straightforward immunotherapy and suggesting that it is a promising platform upon which to build even more potent strategies.
Laust
Amanda K
AK
Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, CA 92697, USA.
Sur
Brandon W
BW
Wang
Kehui
K
Hubby
Bolyn
B
Smith
Jonathan F
JF
Nelson
Edward L
EL
D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D004666:Encephalitis Virus, Venezuelan Equine / Q000235:genetics*; D005260:Female; D005822:Genetic Vectors / Q000276:immunology / Q000627:therapeutic use; D015395:Histocompatibility Antigens Class I / Q000032:analysis; D007114:Immunization; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D008969:Molecular Sequence Data; D051381:Rats; D011916:Rats, Inbred F344; D012093:Replicon / Q000276:immunology*
D000951:Antigens, Neoplasm; D015395:Histocompatibility Antigens Class I