Prospects for the Treatment of B Cell Tumors Using Idiotypic Vaccination

George, Andrew J.T.; Stevenson, Freda K.

doi:10.3109/08830188909044783

Cited by 49 publications

(16 citation statements)

References 130 publications

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“…There is increasing evidence from clinical observations (37)(38)(39)(40)(41)(42)(43), experimental models of dormancy (44)(45)(46)(47)(48)(49), and the findings of circulating tumor cells in patients with clinically organ-confined disease as shown in the present study that suggests that many cancers are chronic systemic diseases that are not cured by present day therapy.…”

Section: Discussionmentioning

confidence: 54%

Detection and characterization of carcinoma cells in the blood

Racila

Euhus

Weiss

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

632

449

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A highly sensitive assay combining immunomagnetic enrichment with multiparameter f low cytometric and immunocytochemical analysis has been developed to detect, enumerate, and characterize carcinoma cells in the blood. The assay can detect one epithelial cell or less in 1 ml of blood. Peripheral blood (10-20 ml) from 30 patients with carcinoma of the breast, from 3 patients with prostate cancer, and from 13 controls was examined by f low cytometry for the presence of circulating epithelial cells defined as nucleic acid ؉ , CD45 ؊ , and cytokeratin ؉ . Highly significant differences in the number of circulating epithelial cells were found between normal controls and patients with cancer including 17 with organ-confined disease. To determine whether the circulating epithelial cells in the cancer patients were neoplastic cells, cytospin preparations were made after immunomagnetic enrichment and were analyzed. Epithelial cells from patients with breast cancer generally stained with mAbs against cytokeratin and 3 of 5 for mucin-1. In contrast, no cells that stained for these antigens were observed in the blood from normal controls. The morphology of the stained cells was consistent with that of neoplastic cells. Of 8 patients with breast cancer followed for 1-10 months, there was a good correlation between changes in the level of tumor cells in the blood with both treatment with chemotherapy and clinical status. The present assay may be helpful in early detection, in monitoring disease, and in prognostication.Evidence is accumulating that primary cancers begin shedding neoplastic cells into the circulation at an early stage (1-4); however, the natural history of these cells, their ability to establish metastases, and their bearing on future relapses are unclear. For instance, circulating tumor cells have been detected by PCR in a variety of patients with a good prognosis who are unlikely to develop metastatic disease (5-8). In addition, immunocytochemistry has detected cancer cells in the bone marrow in a proportion of patients with clinically localized disease (9-11). If tumor cell shedding is, in fact, an early event in tumorigenesis, it may be possible to detect cancer cells in the bloodstream before the primary tumor is large enough to be detected by standard screening examinations.To explore this possibility, we have developed a cellular assay that is more sensitive than PCR and that allows precise enumeration and characterization of circulating carcinoma cells. In model studies, the sensitivity of the technique is below 1 epithelial cell͞ml of blood regardless of the number of leukocytes present and the recovery is between 75 and 100%. The assay was used to study the blood of 30 patients with breast cancer, 3 with prostate cancer, and 13 control individuals. An excess of circulating epithelial cells was found in virtually all of the cancer patients unless they were being treated with chemotherapy. In addition, 8 patients with breast cancer undergoing chemotherapy were followed for 1-10 months to determin...

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Section: Discussionmentioning

confidence: 54%

Detection and characterization of carcinoma cells in the blood

Racila

Euhus

Weiss

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

632

449

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“…When Id antigen coupled to carrier protein is used in humans, it has been reported that anti-Id antibody plays an important role in suppressing tumor growth (30,31). As carrier-specific stimulation of Th cells declines, exposure to even low levels of free Id antigen from residual tumor could inhibit the anti-Id response of the memory B cells.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of a vaccine-induced anti-tumor B cell response by soluble protein antigen in the absence of continuing T cell help

Savelyeva¹,

King

Vitetta³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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DNA vaccination can elicit the production of anti-tumor antibodies, thus obviating the need to continuously administer passive antibody. This vaccination strategy is particularly important where antibodies have proven to be effective anti-tumor agents. To amplify antibody responses against weak tumor antigens, we previously designed DNA-fusion vaccines incorporating tumor sequences linked to microbial genes. By using a safe idiotypic (Id) antigen from a B cell tumor fused to a fragment C (FrC) sequence from tetanus toxin, we induced both anti-Id and anti-FrC antibodies. It was important to determine whether the antigen itself, either injected or released from residual tumor cells, would boost the antibody response. Id protein not only failed to boost the response, but permanently and rapidly inhibited it by ablating Id-specific memory B cells. In contrast, an Id protein-FrC conjugate boosted both Id-specific and FrC-specific responses. Strikingly, the depletion of CD4 ؉ T cells converted the Id protein-FrC conjugate vaccine into an inhibitor. These findings support the hypothesis that the activation of memory B cells by a DNA vaccine encoding a protein antigen, in the presence of the protein itself, depends completely on T cell help. Furthermore, by using knockout mice, we have shown that inhibition of the Id-specific memory B cells by the Id protein is largely independent of the Fc␥RIIB and, hence, independent of immune complexes. The principles revealed by using a DNA vaccine have implications for all cancer vaccines designed to induce and maintain antibody responses against weak autologous tumor antigens.antibody ͉ DNA vaccination ͉ idiotype A ntibody therapy of certain B cell tumors using antibodies against determinants such as CD20, CD22, and CD52 has proven to be effective, particularly when combined with chemotherapy (1, 2). The concept of vaccination to induce continuous antibody production and cellular responses in patients is attractive. However, vaccines consisting of autologous tumor antigens alone are unlikely to induce adequate T cell help to activate and maintain antibody-producing B cells. Not only is there a limited repertoire of anti-tumor CD4 ϩ T cells, but there is the potential for tolerance through deletional or regulatory mechanisms (3). To overcome this problem, the strategy of fusing foreign sequences has been used to engage a nondeleted large CD4 ϩ T cell repertoire (4).The same principle applies to the delivery of tumor antigens via DNA vaccines (5, 6). We previously described a DNA vaccine that encodes a self-tumor antigen, comprising the idiotypic (Id) determinants of neoplastic B cells (7). These determinants are encoded by the variable regions of the heavy and light chains of the tumor Ig and are unique for each B cell. The variable regions are conveniently assembled in the vaccine as a single-chain Fv molecule that folds to express the Id determinants of the clonotypic Ig (8). To induce significant anti-Id antibody, it was necessary to fuse an immunogenic sequence to the scFv, and...

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“…We have been developing DNA vaccines to treat B cell malignancies, using as the target Ag the idiotypic (Id) 3 determinants of the clonotypic Ig, encoded by the variable region genes V H and V L (6,7). For lymphoma, anti-Id Ab is effective in killing tumor cells (6,8,9); therefore, our DNA vaccine was designed to induce Ab.…”

mentioning

confidence: 99%

“…For lymphoma, anti-Id Ab is effective in killing tumor cells (6,8,9); therefore, our DNA vaccine was designed to induce Ab. Initially, a vaccine containing the V H and V L genes assembled as single-chain fragment variable region of Ig (scFv) alone (10) proved ineffective in inducing anti-Id Ab in mouse models (11).…”

mentioning

confidence: 99%

DNA Fusion Vaccine Designed to Induce Cytotoxic T Cell Responses Against Defined Peptide Motifs: Implications for Cancer Vaccines

Rice

Elliott²,

Buchan

et al. 2001

The Journal of Immunology

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DNA vaccination offers a strategy to induce immune attack on cancer cells, but tumor Ags are often weak. Inclusion of a “foreign” protein increases immunogenicity, and we found previously that fusion of the fragment C (FrC) of tetanus toxin to the tumor Ag sequence promotes Ab and CD4+ responses against B cell tumors. For CTL responses, use of the full two-domain FrC may be less helpful, because known immunogenic MHC class I-binding peptides in the second domain could compete with attached tumor-derived epitopes. Therefore, we removed the second domain, retaining the N-terminal domain, which contains a “universal” helper epitope. We investigated the ability to induce CTL responses of candidate peptides placed at the C terminus of this domain. As test peptides, we repositioned the two known CTL motifs from the second domain to this site. Strong CTL responses to each peptide were induced by the engineered construct, as compared with the native FrC construct. Induced CTLs were able to specifically kill tumor cells transfected with FrC as a surrogate tumor Ag both in vitro and in vivo. Further reduction of the domain to a short helper epitope generated only weak CTL responses against fused peptides, and synthetic peptides mixed with the plasmid containing the first domain were ineffective. The single FrC domain-peptide vaccine design also was able to induce high levels of CTLs against a known epitope from carcinoembryonic Ag. Response to peptide was suppressed if two FrC domains were present, consistent with immunodominance. These principles and designs may have relevance for cancer vaccines delivered via DNA.

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Prospects for the Treatment of B Cell Tumors Using Idiotypic Vaccination

Cited by 49 publications

References 130 publications

Detection and characterization of carcinoma cells in the blood

Detection and characterization of carcinoma cells in the blood

Inhibition of a vaccine-induced anti-tumor B cell response by soluble protein antigen in the absence of continuing T cell help

DNA Fusion Vaccine Designed to Induce Cytotoxic T Cell Responses Against Defined Peptide Motifs: Implications for Cancer Vaccines

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