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Targeting of antigens to B lymphocytes via CD19 as a means for tumor vaccine development.

ABSTRACT: Ab therapy against surface Ags on tumor cells has demonstrated significant efficacy for some cancers. However, it is costly and patients frequently develop acquired resistance over time. In cases of Ab therapy resistance, T cell responses have been shown to be essential in controlling disease progression. Thus, vaccination that generates a sustained Ab response as well as a T cell response may be more effective and economical. In this article, we have developed a vaccination strategy by targeting protein Ags to B cells via a CD19 single-chain variable fragment miniAb. Using the tumor-associated Ag her-2/neu extracellular domain, we showed that the coengagement of CD19 and BCR induced full B cell activation to produce a high titer of Abs and enhanced CD4 Th2 response and CD8 T cell activation and differentiation. These Abs competitively inhibited humanized her-2/neu Ab binding and were capable of activating the complement and inhibiting human breast cancer growth in vitro. Therapeutic efficacy was demonstrated in vivo using murine mammary carcinoma models. Furthermore, four different extracellular domains of her-2/neu could be targeted to B cells to generate Abs against particular domains with different antitumor properties. This approach may offer a new avenue for vaccine development with significantly lower cost, which may be of use not only for cancer therapy but also for infectious agents.

SUBMITTER: Ma Y

PROVIDER: S-EPMC3660458 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Targeting of antigens to B lymphocytes via CD19 as a means for tumor vaccine development.

Ma Yunfeng Y Xiang Dong D Sun Jinwen J Ding Chuanlin C Liu Min M Hu Xiaoling X Li Guoxin G Kloecker Goetz G Zhang Huang-Ge HG Yan Jun J

Journal of immunology (Baltimore, Md. : 1950) 20130429 11

Ab therapy against surface Ags on tumor cells has demonstrated significant efficacy for some cancers. However, it is costly and patients frequently develop acquired resistance over time. In cases of Ab therapy resistance, T cell responses have been shown to be essential in controlling disease progression. Thus, vaccination that generates a sustained Ab response as well as a T cell response may be more effective and economical. In this article, we have developed a vaccination strategy by targetin ...[more]

PMID: 23630363

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Project description:Breast cancer vaccines composed of antigens identified by serological analysis of cDNA expression libraries (SEREX) induce antigen specific immune responses in patients but have had disappointing clinical benefits. While many attempts to modify the adjuvants and vaccine method have been tried, one issue not addressed was whether the SEREX tumor-associated antigens identified from late stages of disease were ideal targets. We questioned in the transgenic TgMMTV-neu mouse model whether the antigen repertoire is distinct between early and late stage breast cancer and whether the antigens identified via SEREX from transgenic mice with early or late stage tumors would elicit differential anti-tumor effects to address this question. Three early stage antigens, Pdhx, Stk39, and Otud6B, were identified from a SEREX screen of mice prior to development of palpable lesions. Formulated into a vaccine, each early antigen inhibited tumor growth (p?<?0.0001). The antigens identified from mice with late stage tumors (Swap70, Gsn, and Arhgef2) were unable to inhibit tumor growth when used as vaccines (for example Gsn p?=?0.26). Each of the three early stage antigens were essential for tumor survival in syngeneic mouse tumor cells and in human breast cancer cell lines across breast cancer subtypes. Silencing protein expression of the early antigens increased apoptosis (p?<?0.0001 for all antigens in mouse and p?<?0.05 for all antigens in human triple negative breast cancer) and decreased survival (p?<?0.0001 for all antigens in mouse and human triple negative and HER2 positive breast cancer). Overexpression of the early stage antigens in women with breast cancer predicted worse prognosis (p?=?0.03) while overexpression of late stage antigens did not impact prognosis (p?=?0.09). These data suggest that antigens expressed earlier in breast tumor development and functionally relevant to breast tumor growth may be more effective targets for therapeutic breast cancer vaccines than antigens identified in later disease.

Project description:BackgroundAlthough mRNA vaccines have been efficient for combating a variety of tumors, their effectiveness against glioma remains unclear. There is growing evidence that immunophenotyping can reflect the comprehensive immune status and microenvironment of the tumor, which correlates closely with treatment response and vaccination potency. The purpose of this research was to screen for effective antigens in glioma that could be used for developing mRNA vaccines and to further differentiate the immune subtypes of glioma to create an selection criteria for suitable patients for vaccination.MethodsGene expression profiles and clinical data of 698 glioma samples were extracted from The Cancer Genome Atlas, and RNA_seq data of 1018 glioma samples was gathered from Chinese Glioma Genome Atlas. Gene Expression Profiling Interactive Analysis was used to determine differential expression genes and prognostic markers, cBioPortal software was used to verify gene alterations, and Tumor Immune Estimation Resource was used to investigate the relationships among genes and immune infiltrating cells. Consistency clustering was applied for consistent matrix construction and data aggregation, Gene oncology enrichment was performed for functional annotation, and a graph learning-based dimensionality reduction method was applied to describe the subtypes of immunity.ResultsFour overexpressed and mutated tumor antigens associated with poor prognosis and infiltration of antigen presenting cells were identified in glioma, including TP53, IDH1, C3, and TCF12. Besides, four immune subtypes of glioma (IS1-IS4) and 10 immune gene modules were identified consistently in the TCGA data. The immune subtypes had diverse molecular, cellular, and clinical features. IS1 and IS4 displayed an immune-activating phenotype and were associated with worse survival than the other two subtypes, while IS2 and IS3 had lower levels of tumor immune infiltration. Immunogenic cell death regulators and immune checkpoints were also diversely expressed in the four immune subtypes.ConclusionTP53, IDH1, C3, and TCF12 are effective antigens for the development of anti-glioma mRNA vaccines. We found four stable and repeatable immune subtypes of human glioma, the classification of the immune subtypes of glioma may play a crucial role in the predicting mRNA vaccine outcome.

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Targeting of antigens to B lymphocytes via CD19 as a means for tumor vaccine development.

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Targeting of antigens to B lymphocytes via CD19 as a means for tumor vaccine development.

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