HSP and CD91 references

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Primary Articles

*Papers authored by Antigenics scientists.

2007 | 2006 | 2005 | 2004 | 2003 | 2002 | 2001 | 2000 | 1999 | 1998 | 1997 | pre-1996 | Review articles

2008

Bolhassani A, Zahedifard F, Taghikhani M, Rafati S. Enhanced immunogenicity of HPV16E7 accompanied by Gp96 as an adjuvant in two vaccination strategies. Vaccine. Jun 19 2008;26(26):3362-3370.

*Callahan MK, Garg M, Srivastava PK. Heat-shock protein 90 associates with N-terminal extended peptides and is required for direct and indirect antigen presentation. Proc Natl Acad Sci U S A. Feb 5 2008;105(5):1662-1667.

di Pietro A, Tosti G, Ferrucci PF, Testori A. Oncophage: step to the future for vaccine therapy in melanoma. Expert Opin Biol Ther. Dec 2008;8(12):1973-1984.

*Jonasch E, Wood C, Tamboli P, et al. Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings. Br J Cancer. Apr 22 2008;98(8):1366-1341.

Koelle DM, Magaret A, McClurkan CL, et al. Phase I dose-escalation study of a monovalent heat shock protein 70-herpes simplex virus type 2 peptide-based vaccine designed to prime or boost CD8 T-cell responses in HSV-naive or HSV-2-infected subjects. Clin Vaccine Immunol. May 2008;15(5):773-782.

Liu B, Li Z. Endoplasmic reticulum HSP90b1 (gp96, grp94) optimizes B-cell function via chaperoning integrin and TLR but not immunoglobulin. Blood. Aug 15 2008;112(4):1223-1230.

Marincek BC, Kuhnle MC, Srokowski C, Schild H, Hammerling G, Momburg F. Heat shock protein-antigen fusions lose their enhanced immunostimulatory capacity after endotoxin depletion. Mol Immunol. Nov 2008;46(1):181-191.

Oizumi S, Deyev V, Yamazaki K, et al. Surmounting tumor-induced immune suppression by frequent vaccination or immunization in the absence of B cells. J Immunother. May 2008;31(4):394-401.

Robert J, Ramanayake T, Maniero GD, Morales H, Chida AS. Phylogenetic conservation of glycoprotein 96 ability to interact with CD91 and facilitate antigen cross-presentation. J Immunol. Mar 1 2008;180(5):3176-3182.

Strbo N, Podack ER. Secreted heat shock protein gp96-Ig: an innovative vaccine approach. Am J Reprod Immunol. May 2008;59(5):407-416.

*Testori A, Richards J, Whitman E, et al. Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician's choice of treatment for stage IV melanoma: the C-100-21 Study Group. J Clin Oncol. Feb 20 2008;26(6):955-962.

Tewalt EF, Maynard JC, Walters JJ, et al. Redundancy renders the glycoprotein 96 receptor scavenger receptor A dispensable for cross priming in vivo. Immunology. May 15 2008.

Wieland A, Denzel M, Schmidt E, et al. Recombinant complexes of antigen with stress proteins are potent CD8 T-cell-stimulating immunogens. J Mol Med. Sep 2008;86(9):1067-1079.

*Wood C, Srivastava P, Bukowski R, et al. An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial. Lancet. Jul 12 2008;372(9633):145-154.

Zeng R, Zhang Z, Mei X, Gong W, Wei L. Protective effect of a RSV subunit vaccine candidate G1F/M2 was enhanced by a HSP70-Like protein in mice. Biochem Biophys Res Commun. Dec 12 2008;377(2):495-499.

2007

Bae J, Mitsiades C, Tai YT, Bertheau R, Shammas M, Batchu RB, Li C, Catley L, Prabhala R, Anderson KC, Munshi NC. Phenotypic and functional effects of heat shock protein 90 inhibition on dendritic cell. J Immunol. 2007;178:7730-7.

*Binder RJ, Kelly JB 3rd, Vatner RE, Srivastava PK. Specific Immunogenicity of Heat Shock Protein gp96 Derives from Chaperoned Antigenic Peptides and Not from Contaminating Proteins. J Immunol. 2007;179:7254-61.

Chang CL, Tsai YC, He L, Wu TC, Hung CF. Cancer immunotherapy using irradiated tumor cells secreting heat shock protein 70. Cancer Res 2007;67:10047-57.

Graner MW, Cumming RI, Bigner DD. The heat shock response and chaperones/heat shock proteins in brain tumors: surface expression, release, and possible immune consequences. J Neurosci 2007;27:11214-27.

Kurotaki T, Tamura Y, Ueda G, Oura J, Kutomi G, Hirohashi Y, Sahara H, Torigoe T, Hiratsuka H, Sunakawa H, Hirata K, Sato N. Efficient cross-presentation by heat shock protein 90-peptide complex-loaded dendritic cells via an endosomal pathway. J Immunol. 2007;179:1803-13.

Maki RG, Livingston PO, Lewis JJ, et al. A phase I pilot study of autologous heat shock protein vaccine HSPPC-96 in patients with resected pancreatic adenocarcinoma. Dig Dis Sci. Aug 2007;52(8):1964.

Oizumi S, Strbo N, Pahwa S, Deyev V, Podack ER. Molecular and cellular requirements for enhanced antigen cross-presentation to CD8 cytotoxic T lymphocytes. J Immunol 2007;179:2310-7.

*Oki Y, McLaughlin P, Fayad LE et al. Experience with heat shock protein-peptide complex 96 vaccine therapy in patients with indolent non-Hodgkin lymphoma. Cancer 2007;109:77-83.

Pockley AG, Fairburn B, Mirza S, Slack LK, Hopkinson K, Muthana M. A non-receptor-mediated mechanism for internalization of molecular chaperones. Methods. Nov 2007;43(3):238-244.

Wood CG. Multimodal approaches in the management of locally advanced and metastatic renal cell carcinoma: combining surgery and systemic therapies to improve patient outcome. Clin Cancer Res 2007;13:697s-702s.

*Yang Y, Liu B, Dai J et al. Heat shock protein gp96 is a master chaperone for Toll-like receptors and is important in the innate function of macrophages. Immunity 2007 [e-publication ahead of print].

2006

*Aalamian M, Fuchs E, Gupta R, Levey DL. Autologous renal cell cancer vaccines using heat shock protein-peptide complexes. Urol Oncol 2006;24:425-433.

Biswas C, Sriram U, Ciric B, Ostrovsky O, Gallucci S, Argon Y. The N-terminal fragment of GRP94 is sufficient for peptide presentation via professional antigen-presenting cells. Int Immunol 2006;18:1147-1157.

Chu F, Maynard JC, Chiosis G, Nicchitta CV, Burlingame AL. Identification of novel quaternary domain interactions in the HSP90 chaperone, GRP94. Protein Sci 2006;15:1260-1269.

Facciponte JG, Wang XY, Macdonald IJ et al. Heat shock proteins HSP70 and gp96: structural insights. Cancer Immunol Immunother 2006;55:339-346.

*Fan H, Kashi RS, Middaugh CR. Conformational lability of two molecular chaperones HSC70 and gp96: effects of pH and temperature. Arch Biochem Biophys 2006;447:34-45.

*Flechtner JB, Cohane KP, Mehta S et al. High-affinity interactions between peptides and heat shock protein 70 augment CD8+ T lymphocyte immune responses. J Immunol 2006;177:1017-1027.

Kunisawa J, Shastri N. HSP90alpha chaperones large C-terminally extended proteolytic intermediates in the MHC class I antigen processing pathway. Immunity 2006;24:523-534.

Parmiani G, De Filippo A, Pilla L, Castelli C, Rivoltini L. Heat shock proteins gp96 as immunogens in cancer patients. Int J Hyperthermia 2006;22:223-227.

Pilla L, Patuzzo R, Rivoltini L et al. A phase II trial of vaccination with autologous, tumor-derived heat-shock protein peptide complexes gp96, in combination with GM-CSF and interferon-alpha in metastatic melanoma patients. Cancer Immunol Immunother 2006;55:958-968.

Wang XY, Arnouk H, Chen X, Kazim L, Repasky EA, Subjeck JR. Extracellular targeting of endoplasmic reticulum chaperone glucose-regulated protein 170 enhances tumor immunity to a poorly immunogenic melanoma. J Immunol 2006;177:1543-1551.

Warger T, Hilf N, Rechtsteiner G et al. Interaction of TLR2 and TLR4 ligands with the N-terminal domain of gp96 amplifies innate and adaptive immune responses. J Biol Chem 2006;281:22545-22553.

Zhang Y, Zan Y, Shan M et al. Effects of heat shock protein gp96 on human dendritic cell maturation and CTL expansion. Biochem Biophys Res Commun 2006;344:581-587.

2005

*Binder RJ, Srivastava PK. Peptides chaperoned by heat-shock proteins are a necessary and sufficient source of antigen in the cross-priming of CD8(+) T cells. Nature Immunol 2005;6:593-599.

This series of studies in two antigen systems demonstrates the essentiality of heat shock protein (HSP)-peptide complexes in generation of immune response.

Demine R, Walden P. Testing the role of gp96 as peptide chaperone in antigen processing. J Biol Chem 2005;280:17573-17578.

This study identifies more than a dozen peptides of diverse size, origin and composition that were eluted from gp96 derived from a human lymphoma cell line.

Kawai N, Ito A, Nakahara Y et al. Anticancer effect of hyperthermia on prostate cancer mediated by magnetite cationic liposomes and immune-response induction in transplanted syngeneic rats. Prostate 2005;64:373-381.

This study extends to a second tumor system the ability to use tumor-localized hyperthermia to induce tumor regression in a manner that correlates with increased expression of HSP70 and increased lymphocyte presence in the heated tissue.

Kebba A, Stebbing J, Rowland S et al. Expression of the common heat-shock protein receptor CD91 is increased on monocytes of exposed yet HIV-1-seronegative subjects. J Leukoc Biol 2005;78:37-42.

This study shows a positive correlation between expression on monocytes of the HSP receptor CD91 and the HIV seronegative status of individuals exposed to HIV through sexual contact with their seropositive partners.

*Levey DL, Brander C, Srivastava PK. The potential of heat shock protein-peptide complexes as a therapeutic HIV vaccine. J HIV Ther 2005;10:56-59.

*Li Z, Qiao Y, Liu B et al. Combination of imatinib mesylate with autologous leukocyte-derived heat shock protein and chronic myelogenous leukemia. Clin Cancer Res 2005;11:4460-4468.

This paper reports the results of the first clinical trial testing autologous tumor-derived HSPPC-70 administered to chronic myelogenous leukemia (CML) patients in combination with the tyrosine kinase inhibitor Gleevec. Clinical responses were observed in seven of eight chronic phase CML patients evaluated. Immune responses were observed in nine of 16 patients analyzed.

Li H, Zhou M, Han J et al. Generation of murine CTL by a hepatitis B virus-specific peptide and evaluation of the adjuvant effect of heat shock protein glycoprotein 96 and its terminal fragments. J Immunol 2005;174:195-204.

This study provides further support for the N-terminal localization of the peptide binding domain of gp96.

Pack CD, Kumaraguru U, Suvas S, Rouse BT. Heat-shock protein 70 acts as an effective adjuvant in neonatal mice and confers protection against challenge with herpes simplex virus. Vaccine 2005;23:3526-3534.

In a model of herpes simplex virus type I the authors desmontrate the ability to generate protective immunity in neonatal mice using HSP70 complexed to a CD8⁺ T-cell epitope mixed with a recombinant herpes protein that elicits a CD4⁺ T-cell response.

Pilla L, Squarcina P, Coppa J et al. Natural killer and NK-like T-cell activation in colorectal carcinoma patients treated with autologous tumor-derived heat shock protein 96. Cancer Res 2005;65:3942-3949.

This study confirms a previous finding that vaccination of cancer patients with gp96-peptide complexes activates NK cells (see also Janetzki et al. Int J Cancer 2000;88:232-238). The current study further defines the subtypes of NK cells that are activated and provides evidence that gp96 binds to NK cells directly in a specific and competable manner.

Qian J, Wang S, Yang J et al. Targeting heat shock proteins for immunotherapy in multiple myeloma: generation of myeloma-specific CTLs using dendritic cells pulsed with tumor-derived gp96. Clin Cancer Res 2005;11:8808-8815.

*Srivastava PK. Immunotherapy for human cancer using heat shock protein-peptide complexes. Curr Oncol Rep 2005;7:104-108.

Winau F, Sponaas AM, Weber S et al. Scant activation of CD8 T cells by antigen loaded on heat shock protein. Eur J Immunol 2005;35:1046-1055.

This paper demonstrates in a model system the requirement for helper CD4⁺ T cells for generation of an optimal CD8⁺ T-cell response elicited by vaccination with HSP70 complexed to a CD8 epitope. See also Ciupitu et al. J Exp Med 1998;187:685-691 for demonstration of a lack of this requirement in an different model system.

2004

*Binder RJ, Srivastava PK. Essential role of CD91 in re-presentation of gp96-chaperoned peptides. Proc Natl Acad Sci USA 2004;101:6128-6133.

Using genetic tools, this study demonstrates that the loss of CD91 expression by antigen-presenting cells leads to corresponding loss of the ability of those cells to bind to gp96 and to re-present gp96 chaperoned peptides.

*Chandawarkar RY, Wagh MS, Kovalchin JT, Srivastava P. Immune modulation with high-dose heat-shock protein gp96: therapy of murine autoimmune diabetes and encephalomyelitis. Int Immunol 2004:615-624.

This study is the first to demonstrate the ability of gp96 to prevent the onset of type 1 diabetes and experimentally induced encephalomyelitis (model for multiple sclerosis) in mice. The therapeutic activity of gp96 is shown to be mediated by suppressor CD4 T cells.

Doody AD, Kovalchin JT, Mihalyo MA, Hagymasi AT, Drake CG, Adler AJ. Glycoprotein 96 can chaperone both MHC class I- and class II-restricted epitopes for in vivo presentation, but selectively primes CD8(+) T cell effector function. J Immunol 2004;172:6087-6092.

This paper confirms the ability of gp96 to prime CD8 T-cell response to a viral antigen and also demonstrates priming of antigen-specific CD4 response. The qualitative nature of the two types of responses is demonstrated to differ.

Fleischer K, Schmidt B, Kastenmuller W et al. Melanoma-reactive class I-restricted cytotoxic T cell clones are stimulated by dendritic cells loaded with synthetic peptides, but fail to respond to dendritic cells pulsed with melanoma-derived heat shock proteins in vitro. J Immunol 2004;172:162-169.

This study fails to confirm the findings of several other laboratories demonstrating the ability of endogenous human melanoma-derived HSP-peptide complexes to stimulate T cells specific for defined melanoma antigens.

Gidalevitz T, Biswas C, Ding H et al. Identification of the N-terminal peptide binding site of glucose-regulated protein 94. J Biol Chem 2004;279:16543-16552.

Using mutational analysis, this study identifies a peptide-binding site in the N-terminal domain of gp96.

Kumaraguru U, Suvas S, Biswas PS, Azkur AK, Rouse BT. Concomitant helper response rescues otherwise low avidity CD8+ memory CTLs to become efficient effectors in vivo. J Immunol 2004;172:3719-3124.

This study demonstrates that memory CD8 responses induced by HSP70 complexed to a herpes virus MHC class I epitope can be enhanced by co-immunization with HSP70 complexed to a class II viral epitope.

MacAry PA, Javid B, Floto RA et al. HSP70 peptide binding mutants separate antigen delivery from dendritic cell stimulation. Immunity 2004;20:95-106.

The authors identify the minimal domain of mycobacterial HSP70 necessary for peptide binding and for antigen re-presentation by antigen-presenting cells (APCs). A mutation of a key amino acid in the peptide-binding domain abrogates re-presentation activity but not stimulation of chemokine and cytokine release by dendritic cells. The re-presentation activity of HSP70 is shown to be calcium-dependent.

Massa C, Guiducci C, Arioli I, Parenza M, Colombo MP, Melani C. Enhanced efficacy of tumor cell vaccines transfected with secretable hsp70. Cancer Res 2004;64:1502-1508.

This study demonstrates that recombinant HSP70 secreted from tumor cells is taken up by antigen-presenting cells, leading to activation of antigen-specific T cells. In addition, tumor cells engineered to secrete HSP70 induce a cytolytic T-cell response and such tumor cells are therapeutically active against experimental lung metastases.

Rapp UK, Kaufmann SH. DNA vaccination with gp96-peptide fusion proteins induces protection against an intracellular bacterial pathogen. Int Immunol 2004;16:597-605.

This is the first study to demonstrate that ability of DNA-based mammalian HSP-antigen fusion constructs to induce T-cell response and protective immunity. gp96 fused to bacterial antigens is shown to induce effector CD8 T cells, which confer resistance to challenge with lethal doses of bacteria.

*SenGupta D, Norris PJ, Suscovich TJ et al. Heat shock protein-mediated cross-presentation of exogenous HIV antigen on HLA class I and class II. J Immunol 2004;173:1987-1993.

This paper demonstrates the ability of gp96 complexed to an extended HIV peptide to stimulate T-cell clones specific for multiple epitopes contained within the peptide.

Stebbing J, Bower M, Gazzard B et al. The common heat shock protein receptor CD91 is up-regulated on monocytes of advanced melanoma slow progressors. Clin Exp Immunol 2004;138:312-316.

In this study a correlation between elevated levels of CD91 expression on monocytes and delayed disease progression in melanoma patients was observed. No differences in expression of other immunological markers examined was observed between slowly progressing and rapidly progressing melanoma patients.

Tobian AA, Canaday DH, Boom WH, Harding CV. Bacterial heat shock proteins promote CD91-dependent class I MHC cross-presentation of chaperoned peptide to CD8+ T cells by cytosolic mechanisms in dendritic cells versus vacuolar mechanisms in macrophages. J Immunol 2004;172:5277-5286.

This study demonstrates the ability of macrophages and dendritic cells to re-present antigenic peptides chaperoned by bacterial HSP70 family members in a CD91-dependent manner. The study also indicates that re-presentation activity of HSP70 by macrophages is largely independent of cytosolic antigen-processing machinery; in contrast, re-presentation activity of HSP70 by dendritic cells is largely dependent on cytosolic antigen-processing machinery.

Tobian AA, Canaday DH, Harding CV. Bacterial heat shock proteins enhance class II MHC antigen processing and presentation of chaperoned peptides to CD4+ T cells. J Immunol 2004;173:5130-5137.

This study demonstrates the ability of bacterial HSP70 family members to enhance presentation of antigenic peptides by MHC class II molecules of macrophages and dendritic cells in a CD40-independent manner.

Wang MH, Grossmann ME, Young CY. Forced expression of heat-shock protein 70 increases the secretion of Hsp70 and provides protection against tumour growth. Br J Cancer 2004;90:926-931.

This research demonstrates that cultured mouse and human prostate cancer cell lines secrete HSP70; upon transfection of the cell lines with HSP70, increased secretion is observed, which correspondingly reduces the tumorigenicity of the cells upon injection into mice.

Zeng Y, Graner MW, Feng H, Li G, Katsanis E. Imatinib mesylate effectively combines with chaperone-rich cell lysate-loaded dendritic cells to treat bcr-abl+ murine leukemia. Int J Cancer 2004;110:251-259.

The authors demonstrate synergy between imatinib mesylate (Gleevec^®) and dendritic cells pulsed with HSP-enriched tumor cell lysate in treatment of pre-existing bcr-abl+ leukemia.

2003

*Basu S, Srivastava PK. Fever-like temperature induces maturation of dendritic cells through induction of hsp90. Int Immunol 2003;15:1053-1061.

This study demonstrates a key role for HSP90 in heat-induced maturation of dendritic cells.

Berwin B, Hart JP, Rice S et al. Scavenger receptor-A mediates gp96/GRP94 and calreticulin internalization by antigen-presenting cells. EMBO J 2003;22:6127-6136.

This research suggests a role for scavenger receptors on mouse macrophage in re-presentation of peptides chaperoned by gp96 and calreticulin.

Fu Q, Meng F, Shen X, Guo R. Therapeutic efficacy of tumor-derived heat shock protein 70 immunotherapy combining interleukin-2 on tumor-bearing mice. Chin Med J 2003;116:288-291.

Demonstrates the synergistic effect of tumor-derived HSP70 preparations and interleukin 2 in a therapy of hepatocellular carcinoma in mice.

Graner MW, Zeng Y, Feng H, Katsanis E. Tumor-derived chaperone-rich cell lysates are effective therapeutic vaccines against a variety of cancers. Cancer Immunol Immunother 2003;52:226-234.

In this study tumor lysates subjected to a process that enriches for at least four heat shock proteins are demonstrated to induce tumor regression and prolong survival in a variety of mouse tumor therapy models. Adoptively transferred dendritic cells that had been pulsed in vitro with the chaperone-rich cell lysates were shown to be particularly effective in treatment of pre-existing disease.

Ito A, Shinkai M, Honda H et al. Heat shock protein 70 expression induces antitumor immunity during intracellular hyperthermia using magnetite nanoparticles. Cancer Immunol Immunother 2003;52:80-88.

This study indicates that in vivo hyperthermia localized to tumor tissue results in tumor necrosis and the release of immunogenic HSP70.

Kojima T, Yamazaki K, Tamura Y et al. Granulocyte-macrophage colony-stimulating factor gene-transduced tumor cells combined with tumor-derived gp96 inhibit tumor growth in mice. Hum Gene Ther 2003;14:715-728.

Demonstrates the synergistic effect of tumor-derived gp96 preparations and GM-CSF–secreting tumor cells in a therapy of lung cancer in mice.

Manjili MH, Wang XY, Chen X et al. HSP110-HER2/neu chaperone complex vaccine induces protective immunity against spontaneous mammary tumors in HER-2/neu transgenic mice. J Immunol 2003;171:4054-4061.

In a mouse model of spontaneous HER-2/neu+ positive breast cancer, immunization with noncovalent complexes of HSP110 and the intracellular domain of HER-2/neu elicit antigen-specific T-cell and antibody responses and delay tumor progression.

*Mazzaferro V, Coppa J, Carrabba MG et al. Vaccination with autologous tumor-derived heat-shock protein gp96 after liver resection for metastatic colorectal cancer. Clin Cancer Res 2003;9:3235-3245.

In this study more than half of the 29 patients who received HSPPC-96 demonstrated significant immunological response — which not only appeared to be correlated with clinical response but also found to be an independent factor for prognosis.

Millar DG, Garza KM, Odermatt B et al. Hsp70 promotes antigen-presenting cell function and converts T-cell tolerance to autoimmunity in vivo. Nature Med 2003;9:1469-1476.

This study shows that administration of HSP70 to mice promotes antigen-presenting function of subsequently harvested dendritic cells. A role for CD40 in mediating HSP70-induced secretion of interleukin 12 by dendritic cells is also demonstrated.

Orr AW, Pedraza CE, Pallero MA et al. Low density lipoprotein receptor-related protein is a calreticulin coreceptor that signals focal adhesion disassembly. J Cell Biol 2003;161:1179-1189.

This study provides additional evidence for direct interaction between stress proteins and the HSP receptor CD91.

Radsak MP, Hilf N, Singh-Jasuja H et al. The heat shock protein gp96 binds to human neutrophils and monocytes and stimulates effector functions. Blood 2003;101:2810–2815.

Identifies a new role for the heat shock protein gp96 in binding to and activating specialized cells that play an important role in wound healing. The study indicates that gp96 naturally released from damaged tissue can recruit cells to the damaged site to initiate the wound healing process.

*Rivoltini L, Castelli C, Carrabba M et al. Human tumor-derived heat shock protein 96 mediates in vitro activation and in vivo expansion of melanoma- and colon carcinoma-specific T cells. J Immunol 2003;171:3467-3474.

This study further demonstrates the ability of autologous, patient-derived, gp96-peptide complexes to elicit tumor-specific T-cell response in HSP-vaccinated cancer patients.

*Stebbing J, Gazzard B, Kim L et al. The heat-shock protein receptor CD91 is up-regulated in monocytes of HIV-1-infected “true” long-term nonprogressors. Blood 2003;101:4000–4004.

This study shows a positive correlation between expression of the HSP receptor CD91 and the maintenance of long-term nonprogression in HIV-infected individuals.

*Stebbing J, Gazzard B, Portsmouth S et al. Disease-associated dendritic cells respond to disease-specific antigens through the common heat shock protein receptor. Blood 2003;102:1806-1814.

Indicates that HSP-peptide complexes present in tumor lysates play an important role in stimulating T-cell immunity to cancers associated with HIV infection. The study also provides support for the role of CD91 (previously identified as an HSP receptor) on dendritic cells in antigen presentation to T lymphocytes.

Wang XY, Chen X, Manjili MH, Repasky E, Henderson R, Subjeck JR. Targeted immunotherapy using reconstituted chaperone complexes of heat shock protein 110 and melanoma-associated antigen gp100. Cancer Res 2003;63:2553-2560.

Demonstrates the ability of the heat shock protein HSP110 to form complexes with large protein antigens expressed in certain tumors; such complexes have been shown to inhibit the growth of tumors in mice in preventive and therapeutic settings.

Wang XY, Kazim L, Repasky EA, Subjeck JR. Immunization with tumor-derived ER chaperone grp170 elicits tumor-specific CD8+ T-cell responses and reduces pulmonary metastatic disease. Int J Cancer 2003;105:226-231.

This study shows the therapeutic benefit of tumor-derived preparations of the stress protein GRP170 in a mouse model of metastatic melanoma.

2002

Baker-LePain JC, Sarzotti M, Fields TA, Li CY, Nicchitta CV. GRP94 (gp96) and GRP94 N-terminal geldanamycin binding domain elicit tissue nonrestricted tumor suppression. J Exp Med 2002;196:1447-1459.

This study demonstrates that a recombinant gp96 N-terminal domain fragment containing a putative peptide binding site (see Gidalevitz et al. J Biol Chem 2004;279:16543–16552) elicits tumor immunity in mice.

*Belli F, Testori A, Rivoltini L et al. Vaccination of metastatic melanoma patients with autologous tumor-derived heat shock protein gp96-peptide complexes: clinical and immunologic findings. J Clin Oncol 2002;20:4169-4180.

This papers presents the results of Antigenics’ Phase 2 clinical trial testing Oncophage in patients with stage IV melanoma. Read a detailed summary of this paper.

*Binder RJ, Kumar SK, Srivastava PK. Naturally formed or artificially reconstituted non-covalent alpha2-macroglobulin-peptide complexes elicit CD91-dependent cellular immunity. Cancer Immunity 2002;2:16-25.

This study demonstrates in a mouse model the ability to manufacture sufficient quantities of HSP-peptide complexes from small tissue samples for use in immunotherapy of cancer.

Callahan MK, Chaillot D, Jacquin C, Clark PR, Menoret A. Differential acquisition of antigenic peptides by Hsp70 and Hsc70 under oxidative conditions. J Biol Chem 2002;277:33604-33609.

This study demonstrates that HSP70 and HSC70 bind to peptides more efficiently under oxidative conditions, indicating that formation of HSP70-peptide complexes is enhanced under stress conditions.

Ciupitu AM, Petersson M, Kono K, Charo J, Kiessling R. Immunization with heat shock protein 70 from methylcholanthrene-induced sarcomas induces tumor protection correlating with in vitro T cell responses. Cancer Immunol Immunother 2002;51:163-170.

Demonstrates that HSP70-peptide complexes isolated from tumor cells confers protection from challenge with live tumor cells. The complexes also induce tumor-specific T-cell responses. Further, the results show that autoantibodies specific for HSP70 are not detected, even after repeated vaccination with the complexes.

Hilf N, Sing-Jasuja H, Schwarzmaier P, Gouttefangeas C, Rammensee HG, Schild H. Human platelets express heat shock protein receptors and regulate dendritic cell maturation. Blood 2002;99:3676-3682.

Demonstrates that platelets bind the HSP glycoprotein 96 (gp96), a process that regulates the ability of the HSP to activate dendritic cells. Gp96 appears to bind platelets through at least two receptors, CD91 and CD36. The study has implications for regulation of wound healing.

Kumaraguru U, Gierynska M, Norman S, Bruce BD, Rouse BT. Immunization with chaperone-peptide complex induces low avidity cytotoxic T lymphocytes providing transient protection against herpes simplex virus infection. J Virol 2002;76:136-141.

Shows that a complex of HSP70 and an antigenic peptide of herpes simplex virus 1 elicits specific T-cell response and protection from lethal infection with live virus.

Manjili MH, Henderson R, Wang XY et al. Development of a recombinant HSP110-HER-2/neu vaccine using the chaperoning properties of HSP110. Cancer Res 2002;62:1737-1742.

This paper provides additional support for the ability of HSP110 to elicit cytotoxic T-lymphocyte and antibody response to noncovalently linked antigenic proteins.

Michils A, Dutry D, de Beyl VZ, Remmelink M, de Maertelaer V, Rocmans P. Peripheral blood mononuclear cell proliferation to heat shock protein-70 derived from autologous lung carcinoma. Am J Respir Crit Care Med 2002;166:749-753.

This study demonstrates that peripheral blood mononuclear cells isolated from patients with lung cancer proliferate in vitro in response to stimulation with autologous tumor-derived heat shock protein 70 (HSP70), but not in response to normal tissue-derived HSP70 or allogeneic tumor-derived HSP70. This finding supports the premise that each patient’s cancer contains a unique repertoire of antigenic peptides.

Noessner E, Gastpar R, Milani V et al. Tumor-derived heat shock protein 70 peptide complexes are cross-presented by human dendritic cells. J Immunol 2002;169:5424-5432.

This study, like that by Castelli et al. (2001), demonstrates in a human system that HSP-peptide complexes purified from tumor cells can activate cytotoxic T-cell clones specific for defined tumor antigens.

*Panjwani N, Popova L, Srivastava PK. Heat shock proteins gp96 and hsp70 activate the release of nitric oxide by APCs. J Immunol 2002;168:2997-3003.

Demonstrates the ability of gp96 and HSP70 to induce the release of nitric oxide from a variety of professional antigen-presenting cells.

Robert J, Gantress J, Rau L, Bell A, Cohen N. Minor histocompatibility antigen-specific MHC-restricted CD8 T cell response elicited by heat shock proteins. J Immunol 2002;168:1697-1703.

Shows that gp96- and HSP70-peptide complexes isolated from the adult frog Xenopus confer specific T-cell immunity against minor antigens. The ability of Xenopus tumor-derived HSPs to elicit protective immunity to tumor challenge is also demonstrated. This study confirms an earlier report on the evolutionarily conserved role of HSPs in modulating immune response.

Vabulas RM, Braedel S, Hilf N et al. The endoplasmic reticulum-resident heat shock protein Gp96 activates dendritic cells via the Toll-like receptor 2/4 pathway. J Biol Chem 2002;277:20847-20853.

This study shows for the first time the crucial role primarily of TLR4 and also TLR2 in gp96-induced cytokine secretion and dendritic cell maturation. gp96-induced signaling is also shown to be dependent on endocytosis, whereas LPS-induced signaling is shown not to depend on endocytosis.

2001

*Basu S, Binder RJ, Ramalingam T, Srivastava PK. CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70 and calreticulin. Immunity 2001;14:303-313.

Shows that the CD91 receptor expressed by dendritic cells is the only receptor involved in uptake of HSP-peptide complexes leading to re-presentation of the chaperoned peptides by MHC class I molecules.

Berwin B, Reed RC, Nicchitta CV. Virally induced lytic cell death elicits the release of immunogenic GRP94/gp96. J Biol Chem 2001;276:21083-21088.

Shows that cells that die due to infection with virus (i.e., via necrotic cell death) release HSP-peptide complexes that are capable of stimulating T cells specific for antigens encoded by the virus.

*Binder RJ, Karimeddini D, Srivastava PK. Adjuvanticity of alpha 2-macroglubulin, an independent ligand for the heat shock protein receptor CD91. J Immunol 2001;166:4968-4972.

Shows that in vitro reconstituted complexes of alpha2-macroglubulin and antigenic peptides elicit specific CTL response.

Castelli C, Ciupitu AM, Rini F et al. Human heat shock protein 70 peptide complexes specifically activate antimelanoma T cells. Cancer Res 2001;61:222-227.

This study is the first demonstration in a human system that HSP-peptide complexes purified from tumor cells can activate cytotoxic T-cell clones specific for defined tumor antigens. The peptide-dependent nature of immunogenicity of the HSP preparations was also demonstrated.

Meng S-D, Gao T, Gao GF, Tien P. HBV-specific peptide associated with heat-shock protein gp96. Lancet 2001;357:528-529.

Demonstrates that HSPs purified from human tissue infected with a pathogen are associated with peptides specific to that pathogen.

*Menoret A, Chandawarkar RY, Srivastava PK. Natural autoantibodies against heat-shock proteins hsp70 and gp96: implications for immunotherapy using heat-shock proteins. Immunology 2001;101:364-370.

This study reveals the existence of tightly regulated autoantibodies against HSPs in mice. It is demonstrated that HSP vaccination does not lead to persistent alteration in autoantibody titer or to exacerbation of symptoms of autoimmune disease.

*Menoret A, Li Z, Niswonger M, Altmeyer A, Srivastava PK. An endoplasmic reticulum protein implicated in chaperoning peptides to major histocompatibility of class I is an aminopeptidase. J Biol Chem 2001;276:33313-33318.

This study suggests that the heat shock protein gp96 plays a role in trimming peptides to the appropriate size for loading onto major histocompatibility (MHC) class I molecules in the endoplasmic reticulum for subsequent presentation to T cells.

*Robert J, Menoret A, Basu S, Cohen N, Srivastava PK. Phylogenetic conservation of the molecular and immunological properties of the chaperones gp96 and hsp70. Eur J Immunol 2001;31:186-195.

Demonstrates the ability of frog tumor-derived HSPs to vaccinate against frog cancers, emphasizing the evolutionarily conserved properties of HSPs.

Demonstrates the therapeutic efficacy of autologous HSP preparations in mice after syngeneic bone marrow transplantation.

*Somersan S, Larsson M, Fontenau JF, Basu S, Srivastava P, Bhardwaj N. Primary tumor tissue lysates are enriched in heat shock proteins and induce the maturation of human dendritic cells. J Immunol 2001;167:4844-4852.

Provides evidence that HSPs are present in greater quantities in a variety of human cancers relative to normal cells and that this increased expression correlates with the ability of lysates to cause maturation of dendritic cells.

Sponaas AM, Zuegel U, Weber S et al. Immunization with gp96 from Listeria monocytogenes-infected mice is due to N-formylated listerial peptides. J Immunol 2001;167:6480-6486.

Demonstrates that gp96 chaperones nonclassical peptides derived from intracellular bacteria and that mice immunized with such gp96-peptide complexes generate T-cell response specific for these peptides. Further, the study demonstrates for the first time in a model of infectious disease that gp96-peptide complexes can induce cytotoxic T-lymphocyte (CTL) response in the absence of CD4 T-cell help.

Wang XY, Kazim L, Repasky EA, Subjeck JR. Characterization of heat shock protein 110 and glucose-regulated protein 170 as cancer vaccines and the effect of fever-range hyperthermia on vaccine activity. J Immunol 2001;166:490-497.

Identifies two additional HSPs, HSP110 and GRP170, that elicit tumor rejection in prevention and treatment of cancer in mice.

Zheng H, Dai J, Stoilova D, Li Z. Cell surface targeting of heat shock protein gp96 induces dendritic cell maturation and antitumor immunity. J Immunol 2001;167:6731-6735.

Provides evidence that tumor cells that express gp96 on the cell surface are rejected by immunocompetent mice. Further, such tumor cells are able stimulate the maturation of – and secretion of cytokines by – dendritic cells in a contact-dependent manner.

Zugel U, Sponaas AM, Neckermann J, Schoel B, Kaufmann SH. gp96-peptide vaccination of mice against intracellular bacteria. Infec Immun 2001;69:4164-4167.

Demonstrates for the first time that HSP-peptide complexes induce protection from challenge with live intracellular bacteria, including tuberculosis and Listeria.

2000

Asea A, Kraeft SK, Kurt-Jones EA et al. HSP70 stimulates cytokine production through a CD14-dependent pathway, demonstrating its dual role as a chaperone and cytokine. Nature Med 2000;6:435-442.

Demonstrates the ability of HSP70 to stimulate nonspecific components of immune response such as cytokine secretion by macrophages.

*Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK. Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int Immunol 2000;12:1539-1546.

Demonstrates that necrotic cells, which release HSPs, cause dendritic cells to secrete cytokines and to upregulate expression of several proteins that are crucial for T-cell activation.

*Binder RJ, Anderson K, Basu S, Srivastava PK. Cutting edge: heat shock protein gp96 induces maturation and migration of CD11c+ cells in vivo. J Immunol 2000;165:6029-6035.

Shows that HSP-peptide complexes injected into the skin cause local dendritic cells to migrate to lymph nodes, where T cells are subsequently activated.

*Binder RJ, Han DK, Srivastava PK. CD91: a receptor for heat shock protein gp96. Nature Immunol 2000;2:151-155.

Identifies CD91 as a dendritic cell receptor for the heat shock protein gp96.

*Binder RJ, Harris ML, Ménoret A, Srivastava PK. Saturation, competition, and specificity in interaction of heat shock proteins (HSP) gp96, hsp90, and hsp70 with CD11b+ cells. J Immunol 2000;165:2582-2587.

Provides additional evidence for the existence of specific heat shock protein receptors on the surface of antigen-presenting cells.

Castellino F, Boucher PE, Eichelberg K et al. Receptor-mediated uptake of antigen/heat shock protein complexes results in major histocompatibility complex class I antigen presentation via two distinct processing pathways. J Exp Med 2000;191:1957-1964.

Provides additional evidence for the role of a receptor in uptake of HSP70-peptide complexes.

*Janetzki S, Palla D, Rosenhauer V, Lochs H, Lewis JJ, Srivastava PK. Immunization of cancer patients with autologous cancer-derived heat shock protein gp96 preparations: a pilot study. Int J Cancer 2000;88:232-238.

Demonstrates specificity of immune response in patients vaccinated with autologous HSP preparations.

Linderoth NA, Popowicz A, Sastry S. Identification of the peptide-binding site in the heat shock chaperone/tumor rejection antigen gp96 (Grp94). J Biol Chem 2000;275:5472-5477.

Provides evidence for the location of the peptide binding site on the heat shock protein gp96.

Singh-Jasuja H, Scherer HU, Hilf N et al. The heat shock protein gp96 induces maturation of dendritic cells and down-regulation of its receptor. Eur J Immunol 2000;30:2211-2215.

Shows that purified HSPs cause dendritic cells to secrete cytokines and to upregulate expression of several proteins that are crucial for T-cell activation.

Singh-Jasuja H, Toes RE, Spee P et al. Cross-presentation of glycoprotein 96-associated antigens on major histocompatibility complex class I molecules requires receptor-mediated endocytosis. J Exp Med 2000 191:1965-1974.

Demonstrates a requirement for receptor-mediated uptake of HSP-peptide complexes by dendritic cells for subsequent activation of CD8 T cells.

Triozzi PL, Khurram R, Aldrich WA, Walker MJ, Kim JA, Jaynes S. Intratumoral injection of dendritic cells derived in vitro in patients with metastatic cancer. Cancer 2000;89:2646-2654.

Demonstrates the specificity of autologous HSP preparations in stimulating T cells isolated from cancer patients.

1999

Arnold-Schild D, Hanau D, Spehner D et al. Cutting edge: receptor-mediated endocytosis of heat shock proteins by professional antigen-presenting cells. J Immunol 1999;162:3757-3760.

Presents evidence for specific uptake of gp96 and HSP70 by a receptor-mediated mechanism.

*Basu S, Srivastava PK. Calreticulin, a peptide-binding chaperone of the endoplasmic reticulum, elicits tumor- and peptide-specific immunity. J Exp Med 1999;189:797-802.

Describes the ability of tumor-derived calreticulin to elicit tumor-specific immunity. In addition, calreticulin complexed to defined peptides in vitro is shown to elicit peptide-specific CTL response. These properties of calreticulin are similar to those shared by the three other HSPs (gp96, HSP70, HSP90) identified in earlier studies.

*Chandawarkar RY, Wagh MS, Srivastava PK. The dual nature of specific immunological activity of tumor-derived gp96 preparations. J Exp Med 1999;189:1437-1442.

Demonstrates that immunization with tumor-derived gp96 induces a highly regulated immune response that, depending on the conditions of immunization, results in tumor immunity or downregulation.

Chen W, Syldath U, Bellmann K, Burkart V, Kolb H. Human 60-kDa heat-shock protein: a danger signal to the innate immune system. J Immunol 1999;162:3212-3219.

Reports on the proinflammatory macrophage response to contact with human HSP60, including production of nitric oxide, interleukin 12, interleukin 15 and tumor necrosis factor alpha.

*Ishii T, Udono H, Yamano T et al. Isolation of MHC class I-restricted tumor antigen peptide and its precursors associated with heat shock proteins hsp70, hsp90, and gp96. J Immunol 1999;162:130-1309.

Demonstrates that HSPs purified from tumor cells are associated not only with exact CD8 T-cell epitopes, but also with precursor peptides.

Nair S, Wearsch PA, Mitchell DA, Wassenberg JJ, Gilboa E, Nicchitta CV. Calreticulin displays in vivo peptide-binding activity and can elicit CTL responses against bound peptides. J Immunol 1999;162:6426-6432.

Demonstrates that calreticulin, a chaperone resident in the endoplasmic reticulum, binds peptides and elicits tumor- and peptide-specific cytolytic T-cell responses.

Panjwani N, Akbari O, Garcia S, Brazil M, Stockinger B. The HSC73 molecular chaperone: involvement in MHC class II antigen presentation. J Immunol 1999;163:1936-1942.

Establishes a role for HSP70 in facilitating presentation of exogenous antigens by MHC class II molecules.

Todryk S, Melcher AA, Hardwick N et al. Heat shock protein 70 induced during tumor cell killing induces Th1 cytokines and targets immature dendritic cell precursors to enhance antigen uptake. J Immunol 1999;163:1398-1408.

Provides evidence that HSP70 released from dying tumor cells plays a role in priming T cell-dependent antitumor immune responses.

Yamazaki K, Nguyen T, Podack ER. Cutting edge: tumor secreted heat shock-fusion protein elicits CD8 cells for rejection. J Immunol 1999;163:5178-5182.

Shows that a progressor tumor secreting gp96-immunoglobulin fusion protein elicits CD8 T cell-dependent tumor rejection upon transplantation into mice.

*Yedavelli SP, Guo L, Daou ME, Srivastava PK, Mittelman A, Tiwari RK. Preventive and therapeutic effect of tumor derived heat shock protein, gp96, in an experimental prostate cancer model. Int J Mol Med 1999;4:243-248.

Provides evidence of the therapeutic efficacy of tumor-derived gp96 in a rat prostate cancer model.

1998

Breloer M, Marti T, Fleischer B, von Bonin A. Isolation of processed, H-2Kb-binding ovalbumin-derived peptides associated with the stress proteins HSP70 and gp96. Eur J Immunol 1998;28:1016-1021.

Demonstrates that gp96 and HSP70 purified from cells transfected with ovalbumin are associated with an ovalbumin-derived CTL epitope.

Ciupitu A-M, Petersson M, O'Donnell CL et al. Immunization with a lymphocytic choriomeningitis virus peptide mixed with heat shock protein 70 results in protective antiviral immunity and specific cytotoxic T lymphocytes. J Exp Med 1998;187:685-691.

Shows that human HSP70 complexed exogenously to defined viral peptides protects mice from challenge with live virus and induces peptide-specific CTLs.

*Janetzki S, Blachere NE, Srivastava PK. Generation of tumor-specific cytotoxic T lymphocytes and memory T cells by immunization with tumor-derived heat shock protein gp96. J Immunother 1998;21:269-276.

Highlights novel features of HSP vaccination, including the induction of antigen-specific CTLs and generation of memory T cells.

1997

Arnold D, Wahl C, Faath S, Rammensee HG, Schild H. Influences of transporter associated with antigen processing (TAP) on the repertoire of peptides associated with the endoplasmic reticulum-resident stress protein gp96. J Exp Med 1997;186:461-466.

Provides additional evidence that purified gp96 preparations are complexed to the antigenic repertoire of peptides present in the endoplasmic reticulum.

*Blachere NE, Li Z, Chandawarkar RY et al. Heat shock protein-peptide complexes, reconstituted in vitro, elicit peptide-specific cytotoxic T lymphocyte response and tumor immunity. J Exp Med 1997;186:1315-1322.

Demonstrates in mice the ability to induce cytotoxic T-cell responses to preselected antigens that are complexed with HSP70 and gp96.

Heikema A, Agsteribbe E, Wilschut J, Huckriede A. Generation of heat shock protein-based vaccines by intracellular loading of gp96 with antigenic peptides. Immunol Lett 1997;57:69-74.

Shows that mice immunized with gp96 prepared from cells that express a defined influenza protein generate a cellular immune response against influenza-infected target cells.

*Peng P, Menoret A, Srivastava PK. Purification of immunogenic heat shock protein 70-peptide complexes by ADP-affinity chromatography. J Immunol Methods 1997;204:13-21.

Demonstrates a novel method for rapid purification of HSP70 molecules that remain associated with peptides and are immunogenic.

Spee P, Neefjes J. TAP-translocated peptides specifically bind proteins in the endoplasmic reticulum, including gp96, protein disulfide isomerase and calreticulin. Eur J Immunol 1997;27:2441-2449.

Lammert E, Arnold D, Nijenhuis M et al. The endoplasmic reticulum-resident stress protein gp96 binds peptides translocated by TAP. Eur J Immunol 1997;27:923-927.

Lammert E, Stevanovic S, Brunner J, Rammensee HG, Schild H. Protein disulfide isomerase is the dominant acceptor for peptides translocated into the endoplasmic reticulum. Eur J Immunol 1997;27:1685-1690.

Marusina K, Reid G, Gabathuler R, Jefferies W, Monaco JJ. Novel peptide-binding proteins and peptide transport in normal and TAP-deficient microsomes. Biochemistry 1997;36:856-863.

These four papers show that peptides transported by TAP (transporter associated with antigen processing) molecules into the endoplasmic reticulum are physically associated with gp96. These studies suggest a central role for gp96 in processing of peptides routed into the MHC class I presentation pathway.

*Tamura Y, Peng P, Liu K, Daou M, Srivastava PK. Immunotherapy of tumors with autologous tumor-derived heat shock protein preparations. Science 1997;278:117-120.

Shows that vaccination with gp96 and HSP70 causes regression of pre-established metastatic cancers in mice.

1996

Lammert E, Arnold D, Rammensee HG, Schild H. Expression levels of stress protein gp96 are not limiting for major histocompatibility complex class I-restricted antigen presentation. Eur J Immunol 1996;26:875-879.

Suggests that other proteins in the endoplasmic reticulum can substitute for the proposed role of gp96 in antigen presentation by MHC class I molecules.

Nieland TJ, Tan MC, Monne-van Muijen M, Koning F, Kruisbeek AM, van Bleek GM. Isolation of an immunodominant viral peptide that is endogenously bound to the stress protein GP96/GRP94. Proc Natl Acad Sci USA 1996;93:6135-6139.

Formally demonstrates that gp96 purified from virally infected cells is complexed with a defined viral epitope.

Román E, Moreno C. Synthetic peptides non-covalently bound to bacterial hsp70 elicit peptide-specific T-cell responses in vivo. Immunology 1996;88:487-492.

Demonstrates in mice the ability to induce a helper T-cell immune response specific for a defined influenza antigen that is complexed with mycobacterial HSP70.

Before 1996

*Anderson SL, Shen T, Lou J et al. The endoplasmic reticular heat shock protein gp96 is transcriptionally upregulated in interferon-treated cells. J Exp Med 1994;180:1565-1569.

Shows that gp96 genes are upregulated by gamma interferon.

Arnold D, Faath S, Rammensee H, Schild H. Cross-priming of minor histocompatibility antigen-specific cytotoxic T cells upon immunization with the heat shock protein gp96. J Exp Med 1995;182:885-889.

The first publication to independently confirm the ability of HSPs to elicit T-cell immunity to chaperoned peptides.

*Li Z, Srivastava PK. Tumor rejection antigen gp96/grp94 is an ATPase: implications for protein folding and antigen presentation. EMBO J 1993;12:3143-3151.

Shows that gp96 binds ATP and is an ATPase. Also provides the first experimental evidence that gp96 is associated with peptides.

*Maki RG, Eddy RL Jr, Byers M, Shows TB, Srivastava PK. Mapping of the genes for human endoplasmic reticular heat shock protein gp96/grp94. Somat Cell Mol Genet 1993;19:73-81.

Describes genetic mapping of the human gp96 genes.

*Maki RG, Old LJ, Srivastava PK. Human homologue of murine tumor rejection antigen gp96: 5'-regulatory and coding regions and relationship to stress-induced proteins. Proc Natl Acad Sci USA 1990;87:5658-5662.

Describes cloning of the human gp96 gene.

*Palladino MA Jr, Srivastava PK, Oettgen HF, DeLeo AB. Expression of a shared tumor-specific antigen by two chemically induced BALB/c sarcomas. Cancer Res 1987;47:5074-5079.

Demonstrates the efficacy of gp96 in prophylactic vaccination against another murine sarcoma. Also shows that gp96 prepared from one chemically induced mouse sarcoma elicits protective immunity to a second sarcoma induced by the same carcinogen.

*Srivastava PK. Studies on cell surfaces during normal and abnormal growth: purification of a tumor-associated antigen and a tumor rejection antigen from a rat hepatoma. Doctoral dissertation, Osmania University, Hyderabad, India (1982).

*Srivastava PK, Chen YT, Old LJ. 5'-structural analysis of genes encoding polymorphic antigens of chemically induced tumors. Proc Natl Acad Sci USA 1987;84:3807-3811.

Describes partial cloning and sequencing of the murine gp96 gene.

*Srivastava PK, Das MR. The serologically unique cell surface antigen of Zajdela ascitic hepatoma is also its tumor-associated transplantation antigen. Int J Cancer 1984;33:417-422.

Describes the discovery of gp96, designated here as P100. Shows the efficacy of prophylactic vaccination with autologous gp96 against a rat hepatoma. This was the first demonstration of tumor immunity being elicited by vaccination with a purified protein.

*Srivastava PK, DeLeo AB, Old LJ. Tumor rejection antigens of chemically induced sarcomas of inbred mice. Proc Natl Acad Sci USA 1986;83:3407-3411.

Demonstrates the efficacy of gp96 in prophylactic vaccination against two different mouse sarcomas.

Describes genetic mapping of the murine gp96 gene.

*Srivastava PK, Maki RG. Stress-induced proteins in immune response to cancer. Curr Top Microbiol Immunol 1991;167:109-123.

Suggests that gp96 molecules are not tumor antigens per se, but instead serve as carriers of immunogenic peptides.

*Srivastava PK, Old LJ. Identification of a human homologue of the murine tumor rejection antigen gp96. Cancer Res 1989;49:1341-1343.

Describes the identification of human gp96; also notes that gp96 is homologous to other known heat shock proteins.

*Srivastava PK, Udono H, Blachere NE, Li Z. Heat shock proteins transfer peptides during antigen processing and CTL priming. Immunogenetics 1994;39:93-98.

Proposes a general theory of the role of heat shock proteins in cell-mediated immune responses. It also predicts that matching a patient's human leukocyte antigens (HLA) with that of the tumor vaccine is unnecessary.

*Suto R, Srivastava PK. A mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. Science 1995;269:1585-1588.

Shows that gp96 is taken up by macrophages, in which gp96-associated peptides are routed for presentation by MHC class I molecules. These peptides are recognized by cytotoxic T cells.

*Udono H, Levey DL, Srivastava PK. Cellular requirements for tumor-specific immunity elicited by heat shock proteins: tumor rejection antigen gp96 primes CD8+ T cells in vivo. Proc Natl Acad Sci USA 1994;91:3077-3081.

Demonstrates that immunity elicited by gp96 follows a distinctly different pathway from that of immunity elicited by vaccination with whole cancer cells. It also demonstrates the critical role for macrophage in the efficacy of gp96.

*Udono H, Srivastava PK. Comparison of tumor-specific immunogenicities of stress-induced proteins gp96, hsp90, and hsp70. J Immunol 1994;152:5398-5403.

Analyzes each of the three major heat shock proteins derived from cancer cells and compares their relative efficacies. Shows that gp96 and HSP70 are equally immunogenic and that their immunogenicity is 10-fold greater than HSP90.

*Udono H, Srivastava PK. Heat shock protein 70-associated peptides elicit specific cancer immunity. J Exp Med 1993;178:1391-1396.

Shows for the first time that in addition to gp96, another major and well-studied heat shock protein (HSP70) isolated from cancer cells elicits immunity to cancer. Also demonstrates that HSP70 does not elicit immunity by itself, but does so because of antigenic peptides associated with it. In addition, this paper shows that HSP70 purified from normal tissues does not elicit cancer immunity.

Ullrich SJ, Robinson EA, Law LW, Willingham M, Appella E. A mouse tumor-specific transplantation antigen is a heat shock-related protein. Proc Natl Acad Sci USA 1986;83:3121-3125.

Provides the first evidence that a tumor rejection antigen is a heat shock protein.

Review Articles

*Anderson KM, Srivastava PK. Heat, heat shock, heat shock proteins and death: a central link in innate and adaptive immune responses. Immunol Lett 2000;74:35-39.

*Basu S, Srivastava PK. Heat shock proteins: the fountainhead of innate and adaptive immune responses. Cell Stress Chaperones 2000;5:443-451.

*Binder RJ, Vatner R, Srivastava P. The heat-shock protein receptors: some answers and more questions. Tissue Antigens 2004;64:442-451.

*Hoos A, Levey DL. Vaccination with heat shock protein-peptide complexes: from basic science to clinical applications. Expert Rev Vaccines 2003;2:369-379.

*Janetzki S, Srivastava PK. Heat shock protein-peptide complexes as therapeutic vaccines against human cancer. Clin Immunother 1995;3:325-329.

*Li Z, Srivastava PK. A critical contemplation on the role of heat shock proteins in transfer of antigenic peptides during antigen presentation. Behring Inst Mitt 1994;94:37-47.

Nicchitta CV. Biochemical, cell biological and immunological issues surrounding the endoplasmic reticulum chaperone GRP94/gp96. Curr Opin Immunol 1998;10:103-109.

Podack ER, Raez LE. Allogeneic tumor-cell-based vaccines secreting endoplasmic reticulum chaperone gp96. Expert Opin Biol Ther 2007;7:1679-88.

*Przepiorka D, Srivastava PK. Heat shock protein-peptide complexes as immunotherapy for human cancer. Mol Med Today 1998;4:478-484.

Schild H, Arnold-Schild D, Lammert E, Rammensee HG. Stress proteins and immunity mediated by cytotoxic T lymphocytes. Curr Opin Immunol 1999;11:109-113.

*Srivastava PK. Therapeutic cancer vaccines. Curr Opin Immunol 2006;18:201-205.

*Srivastava PK. Interaction of heat shock proteins with peptides and antigen presenting cells: chaperoning of the innate and adaptive immune responses. Ann Rev Immunol 2002;20:395-425.

*Srivastava PK. Roles of heat-shock proteins in innate and adaptive immunity. Nature Rev Immunol 2002;2:185-194.

*Srivastava PK. Heat shock proteins in immune response to cancer: the fourth paradigm. Experientia 1994;50:1054-1060.

*Srivastava PK. Immunotherapy of human cancer: lessons from mice. Nature Immunol 2000;1:363-366.

*Srivastava PK. Peptide-binding heat shock proteins in the endoplasmic reticulum: role in immune response to cancer and in antigen presentation. Adv Cancer Res 1993;62:153-177.

*Srivastava PK, Menoret A, Basu S, Binder RJ, McQuade KL. Heat shock proteins come of age: primitive functions acquire new roles in an adaptive world. Immunity 1998;8:657-665.

*Srivastava PK, Udono H. Heat shock protein-peptide complexes in cancer immunotherapy. Curr Opin Immunol 1994;6:728-732.

*Papers authored by Antigenics scientists.