Development of immunogenic colorectal cancer cell lines for vaccination: Expression of CD80 (B7.1) is not sufficient to restore impaired primary T cell activation in vitro

Habicht, A.; Lindauer, Markus; Galmbacher, Petra; Rudy, Wolfgang; Gebert, Johannes; Schackert, Hans K.; Meuer, Stefan; Moebius, Ulrich

doi:10.1016/0959-8049(95)00435-1

Cited by 23 publications

(18 citation statements)

References 28 publications

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“…However, as shown in Table 1, no large differences in the binding of the anti-CD28 scFv were observed between the anti-c-myc and the anti-CD3 SkMel63 transfectants. Because the human melanoma cell line SkMel63 used in these studies expresses little, if any, CD80 (B7.1) and CD86 (B7.2) ligands to the CD28 receptor, 10,15 these results probably reflect a low expression level of anti-c-myc scFv molecules on the tumor cell surface together with some unspecific binding and lack of binding of the anti-CD28 scFv to CD28 ligands.…”

Section: Discussionmentioning

confidence: 96%

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A cell surface-displayed anti-c-myc single-chain antibody: new perspectives for the genetic improvement of cellular tumor vaccines

et al. 2000

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We have shown recently that cell surface-bound, single-chain Fv antibodies (scFv) are a powerful tool for the improvement of cellular tumor vaccines. To simplify this approach and to develop a general tool for the generation and improvement of cellular tumor vaccines, we chose an scFv against a peptide from the human proto-oncogene c-myc that could anchor any c-myc-tagged protein to the cell surface. The retroviral vector p50-Mx-neo (pMESV) was used to express scFv on the surface of the human melanoma line SkMel63. The cell-bound anti-c-myc scFv bound specifically to a soluble purified anti-CD28 scFv carrying a c-myc peptide-tag at its C terminus. Proof of principle was determined by incubating human peripheral blood lymphocytes with a mixture of (a) anti-c-myc-transfected SkMel63 cells binding the anti-CD28 scFv and (b) SkMel63 cells transfected with an anti-CD3 scFv. A clear synergistic effect on T-cell activation was observed that was comparable with that obtained in previous studies using SkMel63 cells transfected with the gene for the anti-CD28 scFv. As the cell surface-displayed anti-c-myc scFv can bind any c-myc-tagged protein of interest, this technique facilitates the genetic engineering of cellular vaccines for the therapy of virtually all human neoplasias.

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Section: Discussionmentioning

confidence: 96%

“…Cells were then mixed with 5 ϫ 10 4 PBLs obtained from an allogeneic healthy donor (human leukocyte antigen-A*0201) as described previously. 10 All steps were performed at 4°C. After incubation overnight at 4°C, cells were grown at 37°C for 5 days and then pulsed with 1 Ci …”

Section: Cell Proliferation Assaymentioning

confidence: 99%

A cell surface-displayed anti-c-myc single-chain antibody: new perspectives for the genetic improvement of cellular tumor vaccines

et al. 2000

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“…18,19 All immunofluorescence reagents were pretitrated. The following unconjugated mAbs were used in combination with goat F(abЈ) 2 anti-mouse immunoglobulin (G plus L)-fluorescein isothiocyanate (Tago, Camarillo, Calif) as a second-stage reagent: anti-HLA-A2 (BB7.2, ATCC), anti-CD56 (T199, Dianova, Hamburg, Germany), and anti-CD80 (MAB104, Dianova).…”

Section: Quantitative Flow Cytometrymentioning

confidence: 99%

“…The coexpression of CD80 and MHC class II resulted in the effective induction of MHC class I-restricted tumor immunity, which was mediated in part by CD4 ϩ T helper (Th) lymphocytes. 18,19,24 Alternatively, the requirement for helper cells and APCs could be bypassed by the addition of appropriate cytokines. [25][26][27][28][29][30][31] One consequence of the poor immunogenicity of tumors is that specifically reacting T lymphocytes often fail to secrete cytokines, which are important for their differentiation and propagation.…”

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confidence: 99%

Interleukin-12 requires initial CD80-mediated T-cell activation to support immune responses toward human breast and ovarian carcinoma

Gückel

Meyer

Rudy³

et al. 1999

Cancer Gene Ther

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One possible reason for the poor immunogenicity of tumors is the induction of peripheral tolerance by tumor cells that fail to deliver costimulatory signals. Furthermore, T cells stimulated with wild-type tumor cells often fail to secrete cytokines. The present study has been undertaken to identify cytokines that cooperate with CD80 in T-cell activation in vitro toward human breast and ovarian carcinoma cell lines. Tumor cell-mediated T-lymphocyte activation was analyzed directly in allogeneic mixed lymphocyte/tumor cell cultures as proliferation and effector functions were assessed in cytotoxic T-cell assays. Interleukin-7 (IL-7) amplified the proliferative response toward CD80-transfected breast and ovarian carcinomas and stimulated predominantly CD4 ϩ T lymphocytes. IL-12 represses the proliferative response of naive T cells but cooperates with CD80-mediated activation during secondary stimulations. In long-term T-cell cultures, IL-12 synergizes with CD80 expression to stimulate cytolytic CD8 ϩ T-cell lines, which recognize a breast carcinoma line in a human histocompatibility leukocyte antigen-restricted manner. These studies illustrate that costimulation is necessary for tumor cells to function as alloantigen-presenting cells. Furthermore, when added after the priming of T cells with CD80-transfected tumor cells, IL-12 could be helpful in propagating sufficient T-cell numbers to be used in adoptive transfers during cellular immunotherapy.

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“…[2][3][4][5][6] B7 transfection, however, often does not suffice to transfer immunogenicity to tumor cells such as human carcinoma cells, even when these cells are antigenic and susceptible to cytotoxic T lymphocytes (CTLs). 7 This may be due in part to the fact that B7 also interacts with a negative regulator of T-cell activation, CTLA-4. 8,9 An ideal tumor vaccine should selectively channel costimulatory signals via the CD28 pathway.…”

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confidence: 99%

An effective strategy of human tumor vaccine modification by coupling bispecific costimulatory molecules

Haas

Herold‐Mende

Gerhards³

et al. 1999

Cancer Gene Ther

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A new, generally applicable procedure is described for the introduction of defined costimulatory molecules into human cancer cells to increase their T-cell stimulatory capacity. The procedure involves infection with Newcastle disease virus to mediate the cell surface binding of costimulatory molecules (e.g., specially designed bispecific antibodies (bsAb)). The modification is independent of tumor cell proliferation and laborious recombinant gene technology and can be applied directly to freshly isolated and ␥-irradiated patient-derived tumor cells as an autologous cancer vaccine. Following the infection of tumor cells with a nonvirulent strain of Newcastle disease virus, the cells are washed and then further modified by coincubation with bsAbs, which attach with one arm to the viral hemagglutinin-neuraminidase (HN) molecule on the infected tumor cells. The second specificity of one bsAb (bs HN ϫ CD28) is directed against CD28 to augment antitumor T-cell responses by selectively channeling positive costimulatory signals via the CD28 pathway. A second bsAb (bs HN ϫ CD3) was produced to deliver T-cell receptor-mediated signals either alone (bsCD3 vaccine) or in combination with anti-CD28 (bsCD3 vaccine plus bsCD28 vaccine). In human T-cell stimulation studies in vitro, the bsCD28 vaccine caused an up-regulation of early (CD69) and late (CD25) T-cell activation markers on CD4 and CD8 T lymphocytes from either normal healthy donors or cancer patients (autologous system) and induced tumor cytostasis in nonmodified bystander tumor cells. In addition, in combination with the bsCD3 vaccine, augmented antitumor cytotoxicity and T-cell proliferative responses were observed. This tumor vaccine modification procedure is highly specific, quick, economic, and has a broad range of clinical applications. T here is now much evidence that an antigen (Ag)-specific, T-cell-mediated immune response requires, apart from the Ag, additional costimulatory signals. 1,2 These signals are normally provided by professional Ag-presenting cells (APCs) such as dendritic cells, macrophages, and activated B lymphocytes but not, for instance, by carcinoma cells, which represent the majority of human tumors and are derived from the non-APCtype cells that form the epithelial layers. In the absence of costimulation, encounters with a tumor-associated Ag (TAA) can lead to T-cell inactivation or death rather than to proliferation and differentiation into effector cells. Modern gene therapy strategies, therefore, aim at transforming carcinoma cells into professional APCs by transfecting genes that code for T-cell costimulatory molecules, such as CD80 (B7-1), 2,3 CD86 (B7-2), and/or cytokines. 4,5 In support of this concept, some nonimmunogenic transplantable tumor cells were shown to become immunogenic after CD80, CD86, and/or cytokine gene transfection, and mice that rejected such transfectants developed systemic protective immunity against the nontransfected tumor. [2][3][4][5][6] B7 transfection, however, often does not suffice to transfer immunogen...

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Development of immunogenic colorectal cancer cell lines for vaccination: Expression of CD80 (B7.1) is not sufficient to restore impaired primary T cell activation in vitro

Cited by 23 publications

References 28 publications

A cell surface-displayed anti-c-myc single-chain antibody: new perspectives for the genetic improvement of cellular tumor vaccines

A cell surface-displayed anti-c-myc single-chain antibody: new perspectives for the genetic improvement of cellular tumor vaccines

Interleukin-12 requires initial CD80-mediated T-cell activation to support immune responses toward human breast and ovarian carcinoma

An effective strategy of human tumor vaccine modification by coupling bispecific costimulatory molecules

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