"Induction of Tumor Antigen-Specific Immunity In Vivo by a Novel Vaccinia Vector Encoding Safety-Modified Simian Virus 40 T Antigen". Xie, Hwang, Overwijk, et. al, Jrnl Natl Can Inst., Vol. 91, Jan. 20, 1999, p. 169.

Background: Evidence that simian virus 40 (SV40) is associated with human mesotheliomas, osteosarcomas, and brain tumors suggests that a recombinant vaccine directed against lethal cancers expressing SV40 T antigen (Tag) could have clinical utility. To address this potential need, we designed a novel vaccinia virus construct that encodes an SV40 Tag in which oncogenic domains were excluded and immunogenic domains were preserved. We named this recombinant construct vaccinia-encoding safety-modified SV40 Tag (vac-mTag). . . . .

Results: The immune response elicited by vac-mTag in C57BL/6 and BALB/c included an SV40 Tag-specific cytolytic T-lymphocyte activity against syngeneic (identical genetic back ground) SV40 Tag-expressing tumor targets. Immunization of mice with a single dose of vac-m Tag resulted in potent protection against subsequent challenge with a lethal mouse cancer expressing SV40 Tag. In addition, single-dose vac-m Tag immunization coadministered with interleukin 2 produced a possible therapeutic effect against a preadministered microscopic (but lethal) burden of Tag-expressing tumor cells in vivo. . . . .

Recent developments support the hypothesis that simian virus 40 (SV40) T antigen (Tag) is a relevant target for immunotherapy for human cancers. Contemporary assays for DNA sequences have found SV40 DNA in a majority of human osteosarcomas, bone tumors, epdnymomas, choroid plexus tumors, and mesotheliomas that have been evaluated (1 - 5). Expression of SV40 Tag protein in mesotheliomas and brain tumors has been demonstrated, and functional studies (6, 7) have shown that SV40 Tag can interfere with the functions of p53 and retinoblastoma protein in human mesotheliomas. The possible relationship between polio vaccines contaminated with SV40, which were administered to more than 98 million subjects from 1955 to 1963, and the oncogenesis of these cancers remains controversial (8). Nonetheless, the subsequently increasing occurrence that commonly express SV40 Tag and that has limited treatment options, is disconcerting (9). Strategies targeting SV40 Tag represent a rational avenue for developing new therapies for such SV40 Tag expressing cancers. (Emphasis added)

SV40 Tag has several attributes that make it potentially useful in recombinant vaccine strategies.

First, because SV40 Tag is genuine tumor-associated antigen that is not present in normal host cells, vaccine therapies targeting this antigen need not overcome tolerance to achieve efficacy and circumvent the potential hazard of autoimmune responses against tumor-associated antigens coexpressed by tumor and normal tissue.

Second, apart from its association with certain human cancers, SV40 is also pathogenic in rodent models, providing a unique setting for optimizing potentially clinically relevant recombinant vaccines in animal modes (10).

Third, the immuogenicity of SV40 Tag has been studied extensively (11-13), providing insight for rational approaches to the development of new therapeutic vaccine strategies targeting this tumor-associated antigen.

Despite these attributes of SV40 Tag, a cancer vaccine strategy providing safe and effective therapy for pre-established SV40 Tag-expressing tumors has previously been elusive. To determine whether recombinant poxvirus vaccines targeting SV40 Tag would provide an avenue for unprecedented therapeutic efficacy against establish SV40 Tag-expressing tumors, we have made a novel recombinant vaccinia construct. This vector encodes a safety-modified SV40 Tag sequence (mTag) that excludes retinoblastoma protein binding site, p53 binding site, and the amino-terminal oncogenic CRI and J domains to optimize potential clinical safety but that preserves immunogenic domains. After confirming expression of the expected SV40 Tag fragment by this novel recombinant vaccinia construct termed recombinant vaccinia-encoding mTag (vac-mTag), studies were undertaken to evaluate its efficacy against SV40 Tag-expressing tumors in vivo. These studies provide evidence that vac-mTag can efficiently prime the immune response to provide effective antigen specific protection and therapy against SV40 Tag-expressing lethal tumors. . . .

Conculsion....

Accumulating evidence that there is an association between SV40 Tag and human mesotheliomas, osteosarcomas, epdnymomas, and choroid plexus tumors indicates potential clinical utility for a SV40 Tag-specific recombinant vaccine that can be administered practically and safely to human subjects. (Emphasis added)

As many as 60% of these human tumors have been found to carry SV40 sequences in contemporary studies (1-7, 9) and up to two thirds of evaluable specimens have been found to express SV40 Tag messenger RNA or protein (7). In this paper, we have demonstrated that vac-mTag, a novel recombinant vaccinia construct encoding mTag DNA, can induce a potent SV40 Tag-specific immune response in vivo, suggesting a possible therapeutic effect in a lethal SV40 Tag-associated murine cancer model and providing evidence of a potentially preventive and therapeutic approach for treating SV40-associated human cancers.

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** POSTED MARCH 4, 1999 **

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