The serologically unique cell surface antigen of zajdela ascitic hepatoma is also its tumor‐associated transplantation antigen

Srivastava, Pramod K.; Das, M. R.

doi:10.1002/ijc.2910330321

Cited by 86 publications

(45 citation statements)

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“…Heat shock protein 90 in combination with tumour-specific antigens has been demonstrated to produce specific antitumour immunity (Srivastava and Das, 1984;Palladino et al, 1987;Blachere et al, 1993;Udono et al, 1994;Janetzki et al, 2000). The clinical trial being reported in this paper was initiated in 1999 to help address the issue of whether treating MRCC patients with the autologous HSP90 product vitespen induces an antitumour response, and whether subcutaneous outpatient IL-2 can convert vitespen nonresponders into responders.…”

Section: Vaccination Of Metastatic Rcc Patients E Jonasch Et Almentioning

confidence: 99%

Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings

et al. 2008

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The aim of this study was to evaluate the clinical efficacy as determined by time to progression and response rate (RR) of autologous vitespen (formerly HSPPC-96; Oncophage, Antigenics Inc., New York, NY, USA) with and without interleukin-2 (IL-2; Proleukin: Chiron, Emoryville, CA, USA) in stage IV metastatic renal cell carcinoma (RCC) patients undergoing nephrectomy. Eighty-four patients were enrolled on study, and then underwent nephrectomy and harvest of tumour tissue for use in autologous vaccine manufacture. Initial treatment schedule started approximately 4 weeks after surgery and consisted of six injections: once weekly for 4 weeks, then two injections biweekly (vaccines administered at weeks 1, 2, 3, 4, 6, 8), followed by restaging at or around week 10. Patients who had stable or responsive disease continued to receive vaccine, with four more vaccinations biweekly (at weeks 10, 12, 14, 16). Patients who had progressive disease at week-10 evaluation received four consecutive 5-day-per-week courses of 11 × 10 6 U of IL-2 subcutaneously (weeks 10, 11, 12, 13), with four doses of vitespen at 2-week intervals (at weeks 10, 12, 14, 16). At the next evaluation (week 18), patients with a complete response received two further cycles of vitespen (with IL-2 if also received during prior cycle) or until vaccine supply was exhausted. Patients with stable disease or partial response repeated their prior cycle of therapy. Disease progressors who had not yet received IL-2 began IL-2 treatment, and progressors who had already received IL-2 came off study. Of 60 evaluable patients, 2 demonstrated complete response (CR), 2 showed partial response (PR), 7 showed stable disease, and 33 patients progressed. Sixteen patients had unconfirmed stable disease. Two patients who progressed on vaccine alone experienced disease stabilisation when IL-2 was added. Treatment with vitespen did not result in a discernable benefit in the majority of patients with metastatic RCC treated in this study. Use in combination with immunoregulatory agents may enhance the efficacy of vitespen.

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Section: Vaccination Of Metastatic Rcc Patients E Jonasch Et Almentioning

confidence: 99%

Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings

et al. 2008

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“…H eat shock proteins (HSPs) purified from antigen-expressing cells chaperone antigenic peptides generated in that cell (1)(2)(3)(4). Immunization with such HSP-peptide complexes purified from tumors or pathogen-infected cells elicits specific immunity directed against the tumor or pathogen, respectively (5)(6)(7).…”

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confidence: 99%

Essential role of CD91 in re-presentation of gp96-chaperoned peptides

Binder

Srivastava

2004

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

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185

152

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Heat shock proteins (HSPs) such as gp96 are released from cells as a result of necrotic cell death. The ability of endogenous HSPpeptide complexes to elicit antigen-specific T cells requires representation of the chaperoned peptides by antigen-presenting cells. Re-presentation requires the uptake of HSP-peptide complexes through a receptor, suggested to be the low-density lipoprotein receptor-related protein or CD91. We have used short interfering RNA for CD91 to show that, as antigen-presenting cells lose expression of CD91, their re-presenting ability undergoes a corresponding and dramatic decline. Furthermore, as the cells recover from extinction of CD91 expression, they regain the ability to re-present peptides. The ability of cells to bind ␣2 macroglobulin, a previously known CD91 ligand, or HSP gp96, and their ability to process peptides chaperoned by ␣2 macroglobulin, undergo identical variations. These results have been obtained from studies in vitro and from an assay that measures re-presentation in vivo. In additional studies in vivo, protective tumor immunity elicited by tumor-derived gp96 -peptide complexes is shown to be abrogated by anti-CD91 antisera. These studies show that CD91 is essential for re-presentation of gp96-chaperoned peptides by MHC molecules and have an important bearing on the mechanism of immunogenicity of necrotic cells.heat shock proteins ͉ tumor immunity ͉ ␣2-macroglobulin ͉ receptor-associated protein ͉ LRP H eat shock proteins (HSPs) purified from antigen-expressing cells chaperone antigenic peptides generated in that cell (1-4). Immunization with such HSP-peptide complexes purified from tumors or pathogen-infected cells elicits specific immunity directed against the tumor or pathogen, respectively (5-7). The mechanism of immunogenicity of HSP-peptide complexes is increasingly clear. The HSP-peptide complex is targeted to the antigen-presenting cells (APCs) through interaction of HSP with a receptor identified as CD91 (8,9). In case of the HSP gp96, it appears that the HSP-peptide complex is endocytosed into a compartment positive for Fc receptor and MHC I and negative for Rab5a, CD1, and transferrin (10). The subsequent fate of the HSP molecule itself remains unclear, but the peptide is transported to the cytosol through a mechanism yet to be determined. The peptide is further transported into the endoplasmic reticulum through a transporterassociated with antigen processing-dependent (9, 11) or -independent (see refs. 11 and 12) mechanism. Following a classical pathway within the endoplasmic reticulum, the peptide is charged onto a cognate MHC I molecule, and the MHC I-peptide complex present at the cell surface now stimulates cognate CD8 ϩ T cells. Because the endocytosed HSP-peptide complex is taken up into a compartment that is MHC I ϩ (10), the possibility that the gp96-chaperoned peptide is charged onto the MHC I in that compartment, independently of the endoplasmic reticulum, merits consideration.Among the several HSPs that follow this path, the endoplasmic reticulum-r...

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“…Fractions of tumor lysates were tested in vivo and revealed the HSPs as sought-after tumor-rejection antigens. 2,37,38 They included Gp96, 2,[38][39][40] Hsp90, 39,41 Hsc70/Hsp70 39,42,43 as well as calreticulin, 44,45 Hsp110 and Grp170. [46][47][48] In the ensuing years, these chaperones were extensively studied and successfully applied in preclinical cancer vaccination approaches (Table 1).…”

Section: Discovery Of Hsps Gp96 and Their Immunological Propertiesmentioning

confidence: 99%

“…2,38 A number of animal studies documented that Gp96 purified from tumors is able to initiate efficient tumorspecific CTL responses and protective immunity. Moreover, Gp96 works in both prophylactic and therapeutic protocols.…”

Section: Discovery Of Hsps Gp96 and Their Immunological Propertiesmentioning

confidence: 99%

“…Moreover, Gp96 works in both prophylactic and therapeutic protocols. 2,38,40,[71][72][73][74][75][76] The phylogenetically conserved HSP Gp96 found in tumors and in normal tissues show identical amino acid sequences, suggesting that the cancer-derived Gp96 itself does not account for the initiation of cancer-specific immune responses. [77][78][79] Immunological specificity originates from bound peptides.…”

Section: Discovery Of Hsps Gp96 and Their Immunological Propertiesmentioning

confidence: 99%

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Active‐specific immunotherapy of human cancers with the heat shock protein Gp96—revisited

Randazzo

Terness

Opelz

et al. 2012

Intl Journal of Cancer

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The passive administration of specific antibodies that selectively target tumors is a well-known strategy in cancer treatment. Active immunotherapy using peptide vaccines, in contrast, is expected to induce specific, cytolytic T cells in the patient, which react against tumor antigens and destroy malignant cells. Although several concepts exist, the identification and low immunogenicity of tumor-specific peptides remain a serious problem. Heat shock proteins (HSPs), notably glycoprotein (Gp) 96, are of special interest, because they are able to take molecular peptide-fingerprints of the protein array characteristic for a particular cell. Association of Gp96 with peptides has been shown to be essential for crosspresentation and activation of T cells. Consequently, Gp96-peptide complexes extracted from cancer cells harbor the tumor-specific peptides and are immunogenic, thus offering a tool for active immunization against the tumor. Already, several immunotherapy studies of human cancers have been carried out, showing no severe adverse effects but unfortunately only limited improvement in the clinical outcome. Vitespen, a commercial HSP-peptide complex vaccine based on tumor-derived Gp96, seems to induce an improved overall survival for subsets of early stage melanoma and kidney cancer patients. The limited access to vaccine material derived from the autologous tumor requires the development of alternative protocols. Moreover, counteracting immunosuppressive mechanisms induced by the malignancy might further improve the efficacy of vaccinations. This review critically analyzes the current state of clinical immunotherapy with Gp96, with special attention to Vitespen.Heat shock proteins (HSPs) came to attention of immunologists, because they chaperone peptides and interact with antigen-presenting cells (APCs) in a specific manner. As molecular chaperones, HSPs are essential for maintaining cellular functions by preventing misfolding and aggregation of nascent polypeptides and by facilitating protein folding. This function has been described for every organism. 1In the 1980s, the potential importance of HSPs for tumor therapy emerged, when it was observed that preparations of certain HSPs isolated from cancer cells elicited immunity by capturing the antigenic fingerprint of a specific cancer, so that they could act as a vaccine against subsequent tumor challenge.2 Since then, the immunological properties of HSPs were studied intensively, particularly those of endoplasmic reticulum (ER)-resident HSPs glycoprotein (Gp)96 (Grp94)

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The serologically unique cell surface antigen of zajdela ascitic hepatoma is also its tumor‐associated transplantation antigen

Cited by 86 publications

References 25 publications

Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings

Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings

Essential role of CD91 in re-presentation of gp96-chaperoned peptides

Active‐specific immunotherapy of human cancers with the heat shock protein Gp96—revisited

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