VRP immunotherapy targeting neu: treatment efficacy and evidence for immunoediting in a stringent rat mammary tumor model

Abstract

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.

Acute Infection with Venezuelan Equine Encephalitis Virus Replicon Particles Catalyzes a Systemic Antiviral State and Protects from Lethal Virus Challenge

“…It is important to note that these distal tissues were analyzed for the presence of VRP message and subsequently found to be completely devoid of replicon RNA, as measured by real-time PCR for VEE nsP1 message (data not shown). Lymph nodes other than the popliteal DLN are also consistently absent of viral antigen following VRP infection of mice, including the contralateral DLN (40,44).…”

“…Following footpad inoculation, Langerhans cells at the site of inoculation are the initial cells infected, rapidly migrating to the lymph node draining the injection site. As such, it is the DLN that serves as the earliest site for viral replication, not the tissue surrounding the inoculation site (40,44). Consequently, the earliest host response to VEE infection is established within the DLN, as demonstrated by the robust induction of the host antiviral gene response within the infected cells of the DLN (26,39).…”

Longitudinal Raman Spectroscopic Observation of Skin Biochemical Changes due to Chemotherapeutic Treatment for Breast Cancer in Small Animal Model

“…During the experimental period, the tumor size was measured by a caliper. The breast cancer animal model was chosen since the model is a well-established animal model in breast cancer study (13762 MAT B-III breast cancer cell line is highly tumorigenic in Fischer 344 since the cell line is derived from the strain of Fischer 344 itself) [12][13][14]. Cyclophosphamide was used because the chemical has been used as a chemotherapeutic agent for treating human [15][16][17] and rat [14,18] breast tumors in previous researches.…”

HER2/neu: an increasingly important therapeutic target. Part 1: basic biology & therapeutic armamentarium

“…The high degree of homology with other receptor tyrosine kinases, including other members of the HER family, and the expression of HER2/neu in normal tissues, pose significant challenges that need to be addressed, including overcoming the anticipated immunological tolerance while maintaining specificity of the elicited immune response. Much of the preclinical work was performed in HER2/neu transgenic mouse models due, in part, to the fact that a murine homolog was not confirmed until the early 2000s [14][15][16], although other models were also employed (dog, guinea pig, rat, primate) [209][210][211][212][213][214]. The majority of these have focused on the extracellular domain of HER2/neu due, in large part to the high degree of homology of the intracellular kinase domain with other receptor tyrosine kinases both in and outside of the HER family [209,[215][216][217][218][219], although some strategies have included elements from the intracellular domain [213][214][215].…”

“…Viral vector vaccine strategies using adenovirus vectors [257][258][259][260], alphavirus vectors [212,213,261], vaccinia virus vectors (NCT00485277 and NCT01152398), vesicular stomatitis virus [262] and polyoma virus systems [263,264] have all been used to elicit anti-HER2/neu immune responses. The intracellular bacteria Listeria monocytogenes has also been adapted as an immunotherapeutic vector system and studied in strategies to elicit anti-HER2/neu immune responses [215,265].…”