Abstract
IntroductionNovel adjuvant therapies are needed to prevent metastatic relapses in HER2-expressing breast cancer. Here, we tested whether trastuzumab-selected single-chain Fv (scFv) could be used to develop an anti-idiotype-based vaccine to inhibit growth of HER2-positive tumor cells in vitro and in vivo through induction of long-lasting HER-specific immunity.MethodsBALB/c mice were immunized with anti-trastuzumab anti-idiotype (anti-Id) scFv (scFv40 and scFv69), which mimic human HER2. Their sera were assessed for the presence of HER2-specific Ab1' antibodies and for their ability to reduce viability of SK-OV-3 cells, a HER2-positive cancer cell line, in nude mice. MMTV.f.huHER2(Fo5) transgenic mice were immunized with scFv40 and scFv69 and, then, growth inhibition of spontaneous HER2-positive mammary tumors, humoral response, antibody isotype as well as splenocyte secretion of IL2 and IFN-γ were evaluated.ResultsAdoptively-transferred sera from BALB/c mice immunized with scFv40 and scFv69 contain anti-HER2 Ab1' antibodies that can efficiently inhibit growth of SK-OV-3 cell tumors in nude mice. Similarly, prophylactic vaccination with anti-Id scFv69 fully protects virgin or primiparous FVB-MMTV.f.huHER2(Fo5) females from developing spontaneous mammary tumors. Moreover, such vaccination elicits an anti-HER2 Ab1' immune response together with a scFv69-specific Th1 response with IL2 and IFN-γ cytokine secretion.ConclusionsAnti-trastuzumab anti-Id scFv69, used as a therapeutic or prophylactic vaccine, protects mice from developing HER2-positive mammary tumors by inducing both anti-HER2 Ab1' antibody production and an anti-HER2 Th2-dependent immune response. These results suggest that scFv69 could be used as an anti-Id-based vaccine for adjuvant therapy of patients with HER2-positive tumors to reverse immunological tolerance to HER2.
Highlights
Novel adjuvant therapies are needed to prevent metastatic relapses in Human Epidermal growth factor Receptor 2 (HER2)-expressing breast cancer
In a previous work [21], we reported that two human anti-Id single-chain Fv (scFv) antibody fragments, which were selected by screening a phage-displayed library using the anti-HER2 antibody trastuzumab, induced an anti-HER2 antibody response in sera of immunized BALB/c mice
Anti-Id immunization of BALB/c mice with scFv40 or scFv69 induces anti-HER2 humoral Ab1’ immune response To test whether the trastuzumab-specific anti-Id scFv40 and scFv69 we previously isolated could be used to develop a vaccine to boost anti-HER2 immunity, we immunized six- to eight-week-old BALB/c mice (n = 20 animals/group) with scFv40, scFv69, HER2-Fc fusion protein, or phosphate-buffered saline (PBS)
Summary
Novel adjuvant therapies are needed to prevent metastatic relapses in HER2-expressing breast cancer. Human Epidermal growth factor Receptor 2 (HER2) over-expression is observed in Patients with HER2-expressing tumors show HER2-specific humoral and/or T-cell responses [6,7] Such anti-HER2 immune responses, albeit of low magnitude, indicate that HER2 is a suitable candidate for HER2-targeted vaccine strategies. Anti-Id antibodies have been proposed as vaccines for cancer immunotherapy and significant success has been achieved using anti-Id vaccines mimicking tumor-associated antigens (TAAs) This approach is based on N.K. Jerne’s idiotype network theory about the Ab1-Ab2-Ab3 antibody cascade stimulation, whereby specific anti-Id antibodies (Ab2b induced by immunization with antigen-specific Ab1 antibodies, can serve as an “internal image” of the target antigen and can be used to induce Ab3 ( named Ab1’) antibodies that can bind to the cognate antigen [15]. Available results of treatment of breast cancer patients with anti-Id mAbs are still very preliminary and conclusions go no further than the mere biologic proof of principle [20]
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