Vaccination of fiber-modified adenovirus-transfected dendritic cells to express HER-2/neu stimulates efficient HER-2/neu-specific humoral and CTL responses and reduces breast carcinogenesis in transgenic mice

Sas, S; Chan, Tim; Sami, Amer; El-Gayed, Ali; Xiang, Jim

doi:10.1038/cgt.2008.18

Cited by 24 publications

(14 citation statements)

References 55 publications

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“…Now, DCs can be pulsed with synthetic peptides or proteins derived from known tumor-associated antigens (TAA) such as MUC1 [17], Her-2/neu [18], tyrosinase [19], CEA [20], or Melan-A/MART [21]. However, vaccinating against a single antigen has disadvantages, as it is unknown which of the identified antigens have the potential to induce an effective antitumor immune response [22].…”

Section: Discussionmentioning

confidence: 99%

Tumor cell lysate-pulsed dendritic cells induce a T cell response against colon cancer in vitro and in vivo

Wang

et al. 2009

Med Oncol

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To investigate whether tumor cell lysate-pulsed (TP) dendritic cells (DCs) induce cytotoxic T lymphocyte (CTL) activity against colon cancer in vitro and in vivo. Hematopoietic progenitor cells were magnetically isolated from BALB/c mice bone marrow cells. These cells were cultured with cytokines GM-CSF, IL-4, and TNFalpha to induce their maturation. They were analyzed by morphological observation and phenotype analysis. DCs were pulsed with tumor cell lysate obtained by rapid freezing and thawing at a 1:3 DC:tumor cell ratio. CTL activity and interferon gamma (IFNgamma) secretion was evaluated ex vivo. In order to determine whether or not vaccination with CT26 TP DCs induce the therapeutic potential in the established colon tumor model, CT26 colon tumor cells were implanted subcutaneously (s.c.) in the midflank of naïve BALB/c mice. Tumor-bearing mice were injected with vaccination with CT26 TP DCs on days 3 and 10. Tumor growth was assessed every 2-3 days. Finally, CTL activity and IFNgamma secretion were evaluated in immunized mice. Hematopoietic progenitor cells from mice bone marrow cells cultured with cytokines for 8 days showed the character of typical mature DCs. Morphologically, these cells were large with oval or irregularly shaped nuclei and with many small dendrites. Phenotypically, FACS analysis showed that they expressed high levels of MHC II, CD11b, CD80, and CD86 antigen, and were negative for CD8alpha. However, immature DCs cultured with cytokines for 5 days did not have typical DCs phenotypic markers. Ex vivo primed T cells with CT26 TP DCs were able to induce effective CTL activity against CT26 tumor cells, but not B16 tumor cells (E:T = 100:1, 60.36 +/- 7.11% specific lysis in CT26 group vs. 17.36 +/- 4.10% specific lysis in B16 group), and produced higher levels of IFNgamma when stimulated with CT26 tumor cells but not when stimulated with B16 tumor cells (1210.33 +/- 72.15 pg/ml in CT26 group vs. 182.25 +/- 25.51 pg/ml in B16 group, P < 0.01). Vaccination with CT26 TP DCs could induce anti-tumor immunity against CT26 colon tumor in murine therapeutic models (tumor volume on day 19: CT26 TP DCs 342 +/- 55 mm(3) vs. the other control groups, P < 0.05). In addition, all splenic CD3(+) T cells obtained from mice vaccinated with CT26 TP DCs produced high levels of IFNgamma and shown specific cytotoxic activity against CT26 tumor cells, but no cytotoxic activity when stimulated with B16 tumor cells. Tumor cell lysate-pulsed DCs can induce tumor-specific CTL activity against colon cancer in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

Tumor cell lysate-pulsed dendritic cells induce a T cell response against colon cancer in vitro and in vivo

Wang

et al. 2009

Med Oncol

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“…Similarly, the CTL and humoral responses induced by DCneu2 vaccination were more important than those induced by DCneu1 vaccination. Immunization of FVB mice with the DCneu2-based vaccine protected 100% of the animals that were transplanted with a syngeneic tumor cell line, which over-expresses HER2 [41]. In addition, the same authors previously reported in a sideby-side study that a vaccine based on DCs transfected with an adenovirus encoding HER2 was more efficient than the DNA-based HER2 vaccine [42].…”

Section: Experimental Workmentioning

confidence: 85%

“…The addition of the RGD motif in the construct was reported to efficiently increase expression of HER2/neu. The authors transfected DCs with (RGD) AdVneu [(DCneu2 cells) or AdVneu alone (DCneu1 cells)] and then evaluated the anti-HER2 cellular and humoral responses as well as the anti-tumor effect [41]. In DCneu2 cells, HER2/neu expression was more than eight times higher than in DCneu1 cells.…”

Section: Experimental Workmentioning

confidence: 99%

Anti-HER2 vaccines: new prospects for breast cancer therapy

Ladjemi

Jacot

Chardès

et al. 2010

Cancer Immunol Immunother

118

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Each year, breast cancer accounts for more than 400,000 new cancer cases and more than 130,000 cancer deaths in Europe. Prognosis of nonmetastatic breast cancer patients is directly related to the extent of the disease, mainly nodal spreading and tumor size, and to the molecular profile, particularly HER2 over-expression. In patients with HER2-over-expressing tumors, different studies have shown cellular and/or humoral immune responses against HER2 associated with a lower tumor development at early stages of the disease. These findings have led to the hypothesis that the generation of an anti-HER2 immune response should protect patients from HER2-over-expressing tumor growth. Taken together with the clinical efficiency of trastuzumab-based anti-HER2 passive immunotherapy, these observations allowed to envisage various vaccine strategies against HER2. The induction of a stable and strong immunity by cancer vaccines is expected to lead to establishment of immune memory, thereby preventing tumor recurrence. However, an immunological tolerance against HER2 antigen exists representing a barrier to effective vaccination against this oncoprotein. As a consequence, the current challenge for vaccines is to find the best conditions to break this immunological tolerance. In this review, we will discuss the different anti-HER2 vaccine strategies currently developed; considering the strategies having reached the clinical phases as well as those still in preclinical development. The used antigen can be either composed of tumoral allogenic cells or autologous cells, or specific to HER2. It can be delivered by dendritic cells or in a DNA, peptidic or proteic form. Another area of research concerns the use of antiidiotypic antibodies mimicking HER2.

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“…40 The mouse breast cancer cell line Tg1-1 (H-2K q ) expressing rat HER2/neu was derived from a spontaneous breast cancer in FVBneuN mice. 37,38 Female wild-type C57BL/6 (H-2K b ) mice and transgenic CD11c-diphtheria toxin receptor (DTR) (H-2K b ) and FVB/N-Tg(MMTVneu)202Mul/J (FVBneuN) (H-2K q ) mice were obtained from Jackson Laboratories (Bar Harbor, ME, USA). All animal experiments were carried out in accordance to the Canadian Council for Animal Care guidelines.…”

Section: Reagents Cell Lines and Animalsmentioning

confidence: 99%

“…[32][33][34][35][36] We have previously shown that HER2/neu-specific DC vaccine stimulated more efficient HER2/neu-specific CTL responses and antitumor immunity than DNA vaccine. 37,38 Recently, we have demonstrated that DC vaccine-stimulated CTL responses were derived not only from the stimulation of CD4 þ T-cell-licensed DCs, but also from the stimulation of DC-primed CD4 þ T cells with acquired DC's peptide/MHC-I complexes by trogocytosis. 39 Therefore, we assume that DC vaccine containing the potent CD4 þ Th epitope P30 may stimulate enhanced CD4 þ T-cell responses, leading to more efficient HER2/neu-specific CTL responses and immunity against HER2/neu-positive breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Potent CD4+ T-cell epitope P30 enhances HER2/neu-engineered dendritic cell-induced immunity against Tg1-1 breast cancer in transgenic FVBneuN mice by enhanced CD4+ T-cell-stimulated CTL responses

et al. 2013

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One of the major obstacles in human epidermal growth factor receptor (HER)-2/neu-specific trastuzumab immunotherapy of HER2/neu-positive breast cancer is the development of trastuzumab resistance, warranting the search for other therapeutic strategies. Although dendritic cell (DC) vaccines have been extensively applied in clinical trials for cancer treatment, the vaccination efficacy is still limited, mostly because DC vaccines are not sufficient to break tumor-associated antigen-specific self-immune tolerance in cancer patients. P30 (FNNFTVSFWLRVPKVSASHLE) derived from tetanus toxin is a universally potent CD4(+) T helper epitope capable of enhancing CD8(+) cytotoxic T-lymphocyte (CTL) responses. In this study, we constructed two recombinant adenoviral vectors (AdVs), AdVOVA-P30 and AdVHER2/neu-P30, expressing ovalbumin (OVA)-P30 and HER2/neu-P30. In order to enhance DC vaccine efficacy, we transfected mouse bone marrow (BM)-derived DCs with AdVOVA-P30 and AdVHER2/neu-P30 to generate engineered DCOVA-P30 and DCHER2/neu-P30 vaccines, respectively. We, then, compared CD4(+) and CD8(+) T-cell responses and antitumor immunity derived from DCOVA-P30 and DCHER2/neu-P30 vaccination in wild-type C57BL/6 and transgenic FVBneuN mice, respectively. We demonstrate that engineered DCOVA-P30 vaccine stimulates more efficient CD4(+) and CD8(+) T-cell responses than DCOVA in C57BL/6 mice. Interestingly, the increased DCOVA-P30-induced CTL responses are mainly contributed by enhanced CD4(+) T-cell-stimulated CTL proliferation. We show that DCOVA-P30 vaccine also stimulates more efficient therapeutic immunity against OVA-expressing BL6-10OVA melanoma than DCOVA in C57BL/6 mice. In addition, we demonstrate that DCHER2/neu-P30 vaccine stimulates more efficient CD4(+) and CD8(+) T-cell responses and protective immunity against HER2/neu-expressing Tg1-1 breast cancer than DCHER2/neu in transgenic FVBneuN mice with HER2/neu-specific self-immune tolerance. Therefore, the engineered DCHER2/neu-P30 vaccine may provide a new immunotherapy alternative for women with HER2/neu(+) breast cancer, especially for trastuzumab-resistant HER2/neu(+) breast cancer patients.

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Vaccination of fiber-modified adenovirus-transfected dendritic cells to express HER-2/neu stimulates efficient HER-2/neu-specific humoral and CTL responses and reduces breast carcinogenesis in transgenic mice

Cited by 24 publications

References 55 publications

Tumor cell lysate-pulsed dendritic cells induce a T cell response against colon cancer in vitro and in vivo

Tumor cell lysate-pulsed dendritic cells induce a T cell response against colon cancer in vitro and in vivo

Anti-HER2 vaccines: new prospects for breast cancer therapy

Potent CD4+ T-cell epitope P30 enhances HER2/neu-engineered dendritic cell-induced immunity against Tg1-1 breast cancer in transgenic FVBneuN mice by enhanced CD4+ T-cell-stimulated CTL responses

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