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Letters to the Editor |
Molecular Targeting Unit Department of Experimental Oncology 20133 Milan, Italy [R.DV., S.P] Institute for Cancer Research University of Bologna 40126 Bologna, Italy [P-L.L.]
DNA immunization has been suggested as the best approach to reproducing antigen overexpression by tumors because it leads to persistent high-level protein expression in vivo by a few cells. (1) Chen et al. (2) recently reported data suggesting that DNA vaccines encoding full-length or truncated neu induce protective immunity against neu-expressing mammary tumors. However, their conclusions are somewhat misleading. Indeed, immunization with neu DNA was performed in the parental FVB mouse strain, which, of course, is not tolerant to the rat neu oncoprotein. In our experience, the growth of transplanted transgenic tumors originated in FVB neu transgenic mice is markedly delayed in parental FVB mice compared to that in transgenic mice and nude mice. Furthermore, immunization of FVB mice with the same tumor cells induces high-titer antibody with anti-neu specificity in 100% of mice, clearly demonstrating the strong immunogenicity of the transgene-coded protein. In the same strain, immunization with full-length plasmid DNA gives inferior results with respect to induction of a humoral immune response and protection from transplanted tumor cells. Thus, in the absence of immune tolerance, the efficacy of DNA vaccination is clearly less than that after immunization with the antigen, whereas it has been suggested to be more effective in overcoming tolerance. FVB neu transgenic mice represent the best possible model for verifying this hypothesis because they express the neu gene product as a self antigen and develop spontaneous mammary tumors overexpressing the oncoprotein (3) , closely resembling the human scenario.
The immunological response of FVB transgenic mice against the neu oncoprotein differs somewhat from that of parental FVB mice; thus far, immunity has not been induced with either irradiated tumor cells or plasmid DNA in the transgenics, suggesting that it is difficult to break immune tolerance against the transgene-coded protein even with DNA vaccine. Unlike the humoral immune response against the c-erbB-2 oncoprotein detected in breast carcinoma patients (4 , 5) , no antibody response against the transgene was detected in more than 100 virgin or multiparous transgenic mice tested with or without spontaneous mammary tumors. These data suggest that breaking tolerance to the oncoprotein is even more difficult in transgenic mice than in humans.
Positive data on the use of DNA vaccines in a mouse strain that is not tolerant to the encoded gene do not demonstrate the potential usefulness of this method in inducing immunity in a tolerant mouse strain.
FOOTNOTES
1 To whom requests for reprints should be addressed. 
1 To whom requests for reprints should be addressed.
Received 7/20/98. Accepted 7/ 2/99.
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Division of Hematology/Oncology UCSD Medical School 9500 Bilman Drive La Jolla, CA 92093
In their letter, De Vecchi et al. (1) take issue with a paper that we published last year in Cancer Research concerning the use of DNA vaccines to induce protective immunity against mammary tumors that overexpress the neu transgene (2) . It is unfortunate that De Vecchi et al. misinterpreted the implications of our paper because this appears to be the basis for much of their critique. In our paper, we did not conclude that DNA immunization was the best approach to reproduce antigen overexpression because we did not compare this approach with other methods of immunization (2) . Furthermore, although the mouse neu and rat neu have 94.8% sequence homology and share many identical peptide motifs that can be presented on mouse class I H-2 molecules (3) , we did not claim that we have overcome self-tolerance to the neu proto-oncogene product. Instead, we reported that DNA immunization could induce protective immunity against Tg1-1, a neu-expressing mammary tumor cell line that rapidly and reproducibly can develop tumors when transplanted to otherwise syngeneic nontransgenic FVB/N mice. This mammary tumor was derived from FVB/N transgenic mice that have the activated neu oncogene under the control of the mouse mammary tumor virus promoter (4) . Such animals develop mammary tumors at a significantly younger age than do FVB/N transgenic mice that have the nonmutated neu proto-oncogene. It is conceivable that De Vecchi et al. used tumors derived from the latter type of transgenic mice in their studies and that this accounts in part for their discrepant results. Finally, we did not discern that DNA immunization consistently induced robust anti-neu antibody responses in FVB/N nontransgenic mice. Nevertheless, animals that did not develop anti-neu antibodies following injection of neu-encoding plasmids still could resist challenge with Tg1-1 at amounts that were capable of inducing tumors in all animals of the control groups. As such, the production of anti-neu antibodies was not required for resistance to challenge with this neu-expressing tumor.
Although De Vecchi et al. claim that the FVB/N neu transgenic mouse model system is one that closely resembles the human scenario, there appear to be some limitations even with this model that will require further study. Analyses of tumors that eventually do develop in such animals have revealed tumor cell acquisition of somatic mutations in the neu transgene itself (5) . Such mutations have not been identified in the human tumors that overexpress the neu homologue, HER-2 (6) . In addition, because the neu transgene is under the control of the mouse mammary tumor virus promoter it is expressed at different levels and at different stages of development than the wild-type neu or HER-2 in humans. Conceivably, this altered expression could make the neu transgene less immunogenic in neu transgenic animals than is the self-homologue in nontransgenic animals or humans. As such, if strategies for inducing immune responses against neu-expressing tumors are not effective in neu transgenic mice, one should not necessarily conclude that such strategies would not be effective in patients with HER-2 overexpressing tumors.
Received 5/19/99. Accepted 7/ 2/99.
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