Skip to main content
  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

AACR logo

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
    • Cancer Immunology Essentials
    • Collections
      • COVID-19 & Cancer Resource Center
      • Toolbox: Advanced Technologies for Antigen Identification
      • Toolbox: Coding and Computation
      • Toolbox: Signatures and Cells
      • "Best of" Collection
      • Editors' Picks
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in
  • My Cart

Search

  • Advanced search
Cancer Immunology Research
Cancer Immunology Research
  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
    • Cancer Immunology Essentials
    • Collections
      • COVID-19 & Cancer Resource Center
      • Toolbox: Advanced Technologies for Antigen Identification
      • Toolbox: Coding and Computation
      • Toolbox: Signatures and Cells
      • "Best of" Collection
      • Editors' Picks
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

Articles

Determinants of efficacy of immunotherapy with tumor-derived heat shock protein gp96

Joseph T. Kovalchin, Ananth S. Murthy, Mark C. Horattas, Daniel P. Guyton and Rajiv Y. Chandawarkar
Joseph T. Kovalchin
1Department of Biomedical Sciences, Kent State University
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ananth S. Murthy
2Department of General Surgery, Akron General Medical Center and Northeastern Ohio University College of Medicine, Akron, OH 44307
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mark C. Horattas
2Department of General Surgery, Akron General Medical Center and Northeastern Ohio University College of Medicine, Akron, OH 44307
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel P. Guyton
2Department of General Surgery, Akron General Medical Center and Northeastern Ohio University College of Medicine, Akron, OH 44307
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rajiv Y. Chandawarkar
3Division of Plastic Surgery, Akron General Medical Center and Northeastern Ohio University College of Medicine, Akron, OH 44307
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI:  Published January 2001
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

Immunotherapy with gp96 was highly effective in mice bearing methylcholanthrene-induced fibrosarcomas (Meth A tumors) when treatment began 7 days or less after tumor challenge, but significantly less effective if the treatment began 9 days after challenge. Immunotherapy of pre-existing tumors showed all the hallmarks of specificity of gp96 and dose-restriction observed previously with prophylactic studies. When mice with large primary Meth A tumors were treated with surgery alone, or with surgery followed by therapy with Meth A-derived gp96, the mice that received surgery and immunotherapy did significantly better than those receiving surgery alone. The relationship between the time of initiation of immunotherapy with gp96 and its efficacy was also tested in a metastatic model of the Lewis lung carcinoma. In this model, immunotherapy with gp96 was very effective if treatment began up to 31 days after tumor challenge, but significantly less so if therapy was initiated day 33 post-tumor challenge. These observations suggest that the regulatory phenomena that interfere with immunotherapy gather momentum with surprising speed.

This article was published in Cancer Immunity, a Cancer Research Institute journal that ceased publication in 2013 and is now provided online in association with Cancer Immunology Research.

Introduction

Heat shock proteins (HSPs) isolated from cancer cells have been shown be immunogenic specifically against the cancers from which the HSPs were isolated (see 1,2 for reviews). HSPs isolated from normal tissues or from non-autologous tumors are not immunogenic. The specificity of immunogenicity has been shown to derive from the antigenic peptides associated with cancer-derived HSPs but not with normal tissue-derived HSPs (3), as demonstrated in murine (4) and now in human cancers (5). The mechanism of immunogenicity involves interaction of the HSPs with an HSP-receptor CD91, on the antigen presenting cells (APCs), followed by re-presentation of selected chaperoned peptides by the MHC I molecules of the APCs (6,7). The MHC I-peptide complexes then stimulate the cognate CD8+ T lymphocytes. It appears that the HSP-chaperoned peptides are also routed to presentation by the MHC II molecules and the consequent stimulation of cognate CD4+ T cells (8). Most of these aspects have been demonstrated in both the murine and human systems. The principles developed from these studies have also been extended to immunotherapy of viral infections (9,10,11).

Autologous tumor-derived preparations of the HSP gp96 are now being tested in a number of clinical trials (12,13). While tumor-derived HSPs have been shown to be effective in prophylaxis against and in therapy of a number of murine (14,15) and rat tumors (16,17), the optimum parameters have not been defined systematically. These include the optimal dosage, regimen, the stage of tumor growth, primary versus metastatic tumor, and synergy of immunotherapy with surgical excision of the tumor mass, to name a few. As an example, two immunizations have been shown to be effective in immunizing rats (16), mice (14), and frogs (18) prophylactically against a subsequent cancer challenge, but smaller and larger numbers of immunization have not been tested. Therapy has been carried out with four or more treatments (15,17) but the effects of shorter or prolonged treatments have not been measured. A dose-restriction of immunogenicity of gp96 has been observed in the prophylactic setting (14,19) but its applicability has not been tested in therapy.

An examination of these and other parameters is of crucial significance for translation of this method of immunotherapy from animal experimentation to clinical reality. This study examines some of these parameters using the murine models of the methylcholanthrene-induced BALB/c mouse fibrosarcoma Meth A as a non-metastatic primary tumor, and the spontaneous Lewis lung carcinoma of C57BL/6 mice, as a metastatic tumor.

Results

Immunotherapy of early and late primary Meth A tumors

BALB/c mice were inoculated with 100,000 Meth A cells intradermally. The tumors were allowed to grow for 5, 7 or 9 days at which time the tumors were typically 2.0, 5.1 and 8.4 mm in diameter respectively. Mice bearing these tumors were then treated either with saline, Meth A-derived gp96, or as a negative control, BALB/c liver-derived gp96. Gp96 was administered intradermally and 0.5, 1 or 5 µg gp96 per injection were administered. Each mouse received four immunizations given on alternate days. As an example, mice that began treatment on day 5 were immunized on days 5, 7, 9 and 11 (Fig. 1).

Figure 1
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1

Immunotherapy of early and late primary Meth A tumors with gp96. Mice with pre-existing tumors of different sizes were treated with gp96 as shown in the left panel. Tumor rejection assays are shown in the other columns comparing tumor diameter (Y-axis) with time (X-axis). Tumor-bearing mice were treated with buffer, Meth A-derived gp96 at 0.5, 1.0 or 5.0 µg/day, or liver-derived gp96 at 0.5 or 1.0 µg/day as indicated. Each line shows the kinetics of tumor growth in a single mouse.

It was observed that mice that began treatment with Meth A gp96 5 or 7 days after tumor cell implantation responded vigorously to immunotherapy (Figs. 1 and 2). While tumors continued to grow for up to 10 days after tumor cell implantation in all groups of mice, the tumors of Meth A gp96-treated mice began to regress at about day 10-12 and the regression continued for the next several weeks. Most mice in these groups were substantially or completely cured of visible disease. Immunization with gp96 derived from normal liver had no influence on the kinetics of tumor growth (Figs. 1 and 2) as reported previously in models of prophylactic immunity to Meth A (3). Further, immunization was effective in mice that received 1 µg per immunization, but not in those that received less (0.5 µg per immunization) or more (5 µg per immunization) gp96 (Figs. 1 and 2). Thus, the activity of gp96 was dose-restricted as has also been reported previously in models of prophylactic immunity to Meth A (14,19).

Figure 2
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 2

Immunotherapy of early, intermediate and late primary Meth A tumors demonstrating antigen specificity of gp96, timing of treatment and dosage - Summary of the data in Figure 1. (A) Tumor-bearing mice were treated with tumor-derived gp96, liver-derived gp96 or buffer alone. Tumor diameters were monitored. (B) Tumor-bearing mice received gp96-adjuvant therapy starting on day 5 (early), day 7 (intermediate) or day 9 (late). Tumor diameters were monitored. (C) Tumor-bearing mice were treated with varying doses of Meth A-derived gp96. Amounts indicated in the legend represent the dose given per injection 4 times on alternate days. Tumor diameters were monitored. Each line is an average of the data from 5 animals.

In contrast to mice that were treated beginning 5-7 days after tumor cell implantation and that responded well to immunotherapy, mice that began treatment 9 days after tumor cell implantation responded significantly but relatively poorly to immunotherapy with Meth A-derived gp96. Tumors of these mice began to undergo shrinkage with kinetics initially similar to that of mice which began treatment early; however, by day 12-15, the tumors of late-treated mice began to grow again but remained significantly smaller than the tumors of saline-treated mice (Figs. 1 and 2).

Influence of immunotherapy as an adjunct to partial surgical excision of established Meth A tumors

As mice bearing 9 day old Meth A tumors were relatively refractory to immunotherapy with gp96, further experimental treatments were attempted with them. They were treated by surgery alone or by surgery followed by immunization with 5 injections of Meth A-derived gp96 on alternate days (see Fig. 3 for experimental design). Immunization was carried out with the 1 µg per injection dose determined to be optimal in the experiments shown in Figure 2, as well as in previous studies (19). It was observed that while tumors resumed growth in mice which had undergone surgery alone (Fig. 4 B), tumors of mice that had received immunotherapy with gp96 as an adjunct to surgery remained relatively stable for nearly 20 days after surgery (Fig. 4 C, D). At that point, tumors in some of the gp96-treated mice resumed growth. However, there remained a significant difference in the size of tumors in mice that were treated with surgery alone versus those that received immunotherapy as an adjunct to surgery.

Figure 3
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 3

Study design for tumor-gp96-adjuvant therapy of post-surgical residual disease. Mice bearing late tumors underwent partial resection on day 9, with 60% residual tumor volume, and were treated with tumor-derived gp96 thereafter, as indicated.

Figure 4
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 4

Results of tumor-derived gp96 adjuvant therapy. Tumor volumes from mice that underwent surgical excision followed by treatment with buffer (A) or 5 doses of tumor-gp96 (1 µg/dose starting on day 9) after surgical incision (B). Data from (A) and (B) are summarized in (C).

Immunotherapy of metastatic Lewis lung carcinoma

Highly metastatic lines of the spontaneous Lewis lung carcinoma have been used as models of aggressive and metastatic spontaneous human cancers. This model has been used in several types of immunotherapy including immunotherapy with autologous tumor-derived gp96 (15). Syngeneic C57BL/6 mice were inoculated with 100,000 cells of the D122 line of Lewis lung carcinoma and the tumor was allowed to grow until day 24 post-tumor cell implantation. At this time, the tumor was typically 3-4 mm in diameter and was surgically excised by amputation of the foot. Untreated, these mice succumb to metastatic tumor growth in the lungs. Therapy of these mice was begun on day 29, 31 or 33 after tumor cell implantation (or day 5, 7 or 9 after surgery) (see Fig. 5 for experimental design). Mice were treated with 4 immunizations of 1 µg D122-gp96 per intradermal injection given on alternate days. Survival of mice was monitored on day 33 post-tumor cell implantation. Two significant patterns were observed (Table 1). While nearly all mice treated with buffer succumbed to tumor growth (27/28), 100% of the 20 mice that began treatment with D122-gp96 on day 29 and 31 post-tumor cell implantation (day 5 or 7 post-surgery) remained tumor-free. In contrast, of the mice that began treatment only 2 days later, i.e. on day 33 after tumor cell implantation (or day 9 post-surgery), 40% (4/10) succumbed to metastatic tumor growth. Figure 6 is a set of representative photographs that demonstrate the tumor burden within the thoraces of mice treated with gp96 at various time points.

Figure 5
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 5

Study design of post-operative adjuvant therapy of metastatic disease using gp96 derived from the completely resected primary tumor. Primary tumors, inoculated in the foot, were removed from mice by amputation of the foot, and tumors were used as a source of gp96. Mice with subsequent tumor metastasis were treated early, intermediate or late depending on the day of commencement of post-operative treatment. Control animals received either buffer or gp96 derived from liver.

View this table:
  • View inline
  • View popup
Table 1

Gp96-therapy of metastatic disease.

Figure 6
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 6

Representative photographs of thoracic cavities of D122-bearing mice treated with buffer or tumor-derived gp96. Refer to the legend to Figure 5 and in Table 1. Thoracotomies were performed via a midline sternal incision, subsequently exposing the heart and the lungs.

The second notable pattern concerns the immunological activity of liver-gp96. Significant protection from tumor growth was observed in mice that began treatment with liver-gp96 on days 29 or 31 post-tumor cell implantation. Exactly 50% of such mice (9/18) remained tumor-free. While this is significantly lower than 100% of the D122-gp96-treated mice that remained tumor-free, it is also significantly higher than the absence of protection in the buffer-treated mice. However, liver-gp96 afforded no protection among mice that began to receive treatment on day 33 post-tumor transplant.

Discussion

Our observations confirm and extend the previous studies on the immunological activity of tumor-derived heat shock protein gp96. In addition, they uncover novel aspects of the activity of gp96 in immunotherapy of pre-existing cancers and these have a significant bearing on the use of gp96 for immunotherapy of human cancer. Previous observations confirmed by our results include the ability of tumor-derived gp96 to mediate anti-tumor activity in primary and metastatic tumor models (15). Two other major facets of immunogenicity of gp96 are also reproduced here: tumor-derived but not normal tissue-derived gp96 preparations elicit anti-tumor activity (3,4) and the dose-restricted immunogenicity of gp96 (14,19).

The novelty of our observations lies in two major areas. We demonstrate a dramatic correlation between the time of initiation of treatment and the consequence of immunotherapy with gp96. Immunotherapy is very effective when begun 7 days post-tumor cell implantation (Meth A) or 31 days post-tumor cell implantation (D122). A delay of two additional days in either model makes the tumors refractory to immunotherapy. In the case of Meth A, the timing of relative resistance to immunotherapy (approximately day 9 post-tumor cell implantation) correlates well with the previously reported timing of appearance of suppressor T lymphocytes (20). It is particularly noteworthy that even at 9 days post-tumor cell implantation, the mice respond to immunotherapy with gp96 until day 15 at which time tumor growth takes over sharply and uniformly in all mice. Surgical intervention on day 9, coupled with immunotherapy with gp96, stabilizes tumor growth further. These observations indicate that although down-regulatory events begin to take the lead somewhere between days 9 and 15, these events are still not irreversible. Surgical excision of the tumor tilts the balance in favor of the host such that immunotherapy coupled with surgery still enables immunological activity against the tumor, resulting in prolonged stabilization of tumor size. These observations highlight the dynamic and fragile interplay between immunogenic and down-regulatory events between days 9-15 in Meth A and between days 31-33 in D122. The sharpness with which the mice become relatively refractory to immunotherapy suggests that the down-regulatory immunological activities are active, dominant and gain-of-function events rather than passive, co-dominant and loss-of-function events.

The second novel aspect of our results lies in the observed efficacy of liver-derived gp96, in the D122 model (Table 1). In this model, liver-gp96 is clearly more active than PBS and clearly less active than D122-gp96. The immunological activity of gp96 has been repeatedly shown to be present solely in the autologous tumor-derived gp96 preparations (3,4,15). However, if one examines the data carefully, one notes that although the tumor-derived gp96 preparations are far more efficacious than control gp96 preparations, the latter have some activity above the saline controls (4). Indeed, in the D122 model, Tamura et al. (15) noticed and commented upon this fact during a statistical analysis of the anti-tumor activity in mice immunized with saline versus normal tissue-derived gp96. The immunological basis of this activity may lie in the activation of the innate components of the immune response stimulated by interaction of gp96 with APCs as demonstrated recently (21,22). Such activation may provide a more favorable microenvironment for amplification of the adaptive anti-tumor immune response elicited by the tumor itself.

Our observations highlight the need for the examination of a number of issues, including new opportunities, for the translation of the HSP approach to human cancer immunotherapy. These include the identification of a mechanistic basis for the resistance to immunotherapy that develops in hosts with tumors growing for longer periods, the detailed and systematic analysis of the effective dosage and regimen in a number of animal models of cancer, and the use of autologous (i.e. individual tumor-derived) and generic gp96 preparations and possibly their combinations in the therapy of experimental cancers.

Materials and methods

Purification of gp96

Gp96 was purified from normal liver, Meth A ascitic cells and D122 Lewis lung carcinoma as described (23).

Immunization and tumor challenge studies

Mice were challenged with Meth A or D122 cells and were immunized with gp96 as described (15,19).

Surgical techniques

BALB/c mice were inoculated with 100,000 live Meth A cells intradermally on their backs. On day 9 following inoculation, these tumors were measured in three axes, including the diameters in two planes and the thickness. After deeply anesthetizing them, surgery was performed under sterile conditions approved by the Animal Care Committee at the Akron General Medical Center. Tumors were excised tangentially in a plane parallel to the underlying skin, taking care to leave at least 60% residual tumor volume. The tangential excision was preferred to create a new tumor surface that would be equidistant from the tumor bed, ensuring an equal nutrient supply to the outer peripheral surface. Hemostasis was achieved with pressure alone, thus preventing any confounding impact of thermocoagulation on tumors. Mice were then housed in separate cages for 2-3 hours and their recovery closely monitored. Residual tumor volumes as well as those of the tumors excised were recorded.

Acknowledgments

We thank Robert J. Binder of the University of Connecticut Medical Center, Center for Immunotherapy of Cancer and Infectious Disease for reviewing our manuscript and for his insights, James Lehman Jr. and James M. Lewis of Akron General Medical Center, Division of Plastic Surgery for their helpful comments, and Nairmeen Haller and Lisa Treen of the Kenneth L. Calhoun Research Laboratory at Akron General Medical Center for experimental help.

  • Received March 4, 2001.
  • Accepted March 22, 2001.
  • Copyright © 2001 by Rajiv Chandawarkar

References

  1. 1.↵
    1. Menoret A,
    2. Chandawarkar R
    . Heat-shock protein-based anticancer immunotherapy: an idea whose time has come. Semin Oncol 1998;25:654–60.pmid:9865680
    OpenUrlPubMed
  2. 2.↵
    1. Srivastava PK,
    2. Menoret A,
    3. Basu S,
    4. Binder RJ,
    5. McQuade KL
    . Heat shock proteins come of age: primitive functions acquire new roles in an adaptive world. Immunity 1998;8:657–65.pmid:9655479
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Udono H,
    2. Srivastava PK
    . Comparison of tumor-specific immunogenicities of stress-induced proteins gp96, hsp90, and hsp70. J Immunol 1994;152:5398–403.pmid:8189059
    OpenUrlAbstract
  4. 4.↵
    1. Udono H,
    2. Srivastava PK
    . Heat shock protein 70-associated peptides elicit cancer-specific immunity. J Exp Med 1993;178:1391–6.pmid:8376942
    OpenUrlAbstract/FREE Full Text
  5. 5.↵
    1. Castelli C,
    2. Ciupitu AM,
    3. Rini F,
    4. Rivoltini L,
    5. Mazzocchi A,
    6. Kiessling R,
    7. Parmiani G
    . Human heat shock protein 70 peptide complexes specifically activate antimelanoma T cells. Cancer Res 2001;61:222–7.pmid:11196165
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Suto R,
    2. Srivastava PK
    . A mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. Science 1995;269:1585–8.pmid:7545313
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    1. Castellino F,
    2. Boucher PE,
    3. Eichelberg K,
    4. Mayhew M,
    5. Rothman JE,
    6. Houghton AN,
    7. Germain RN
    . 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;191:1957–64.pmid:10839810
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. Matsutake T,
    2. Srivastava PK
    . The immunoprotective MHC II epitope of a chemically induced tumor harbors a unique mutation in a ribosomal protein. Proc Natl Acad Sci U S A 2001;98:3992–7.pmid:11274422
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    1. Blachere NE,
    2. Udono H,
    3. Janetzki S,
    4. Li Z,
    5. Heike M,
    6. Srivastava PK
    . Heat shock protein vaccines against cancer. J Immunother 1993;14:352–6.pmid:8280719
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Blachere NE,
    2. Li Z,
    3. Chandawarkar RY,
    4. Suto R,
    5. Jaikaria NS,
    6. Basu S,
    7. Udono H,
    8. Srivastava PK
    . Heat shock protein-peptide complexes, reconstituted in vitro, elicit peptide-specific cytotoxic T lymphocyte response and tumor immunity. J Exp Med 1997;186:1315–22.pmid:9334371
    OpenUrlAbstract/FREE Full Text
  11. 11.↵
    1. Ciupitu AM,
    2. Petersson M,
    3. O'Donnell CL,
    4. Williams K,
    5. Jindal S,
    6. Kiessling R,
    7. Welsh RM
    . 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;187:685–91.pmid:9480978
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. Janetzki S,
    2. Palla D,
    3. Rosenhauer V,
    4. Lochs H,
    5. Lewis JJ,
    6. Srivastava PK
    . Immunization of cancer patients with autologous cancer-derived heat shock protein gp96 preparations: a pilot study. Int J Cancer 2000;88:232–8.pmid:11004674
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Srivastava PK
    . Immunotherapy of human cancer: lessons from mice. Nat Immunol 2000;1:363–66.pmid:11062489
    OpenUrlCrossRefPubMed
  14. 14.↵
    1. Srivastava PK,
    2. Old LJ
    . Tumor rejection antigens of chemically induced sarcomas of inbred mice. Proc Natl Acad Sci U S A 1986;83:3407–11.pmid:3458189
    OpenUrlAbstract/FREE Full Text
  15. 15.↵
    1. Tamura Y,
    2. Peng P,
    3. Liu K,
    4. Daou M,
    5. Srivastava PK
    . Immunotherapy of tumors with autologous tumor-derived heat shock protein preparations. Science 1997;278:117–20.pmid:9311915
    OpenUrlAbstract/FREE Full Text
  16. 16.↵
    1. Srivastava PK,
    2. Das MR
    . The serologically unique cell surface antigen of Zajdela ascitic hepatoma is also its tumor-associated transplantation antigen. Int J Cancer 1984;33:417–22.pmid:6698641
    OpenUrlCrossRefPubMed
  17. 17.↵
    1. Yedavelli SP,
    2. Guo L,
    3. Daou ME,
    4. Srivastava PK,
    5. Mittelman A,
    6. Tiwari RK
    . Preventive and therapeutic effect of tumor derived heat shock protein, gp96, in an experimental prostate cancer model. Int J Mol Med 1999;4:243–8.pmid:10425272
    OpenUrlPubMed
  18. 18.↵
    1. Robert J,
    2. Menoret A,
    3. Basu S,
    4. Cohen N,
    5. Srivastava PK
    . Phylogenetic conservation of the molecular and immunological properties of the chaperones gp96 and hsp70. Eur J Immunol 2001;31:186–95.pmid:11265634
    OpenUrlCrossRefPubMed
  19. 19.↵
    1. Chandawarkar RY,
    2. Wagh MS,
    3. Srivastava PK
    . The dual nature of specific immunological activity of tumor-derived gp96 preparations. J Exp Med 1999;189:1437–42.pmid:10224283
    OpenUrlAbstract/FREE Full Text
  20. 20.↵
    1. North RJ,
    2. Bursuker I
    . Generation and decay of the immune response to a progressive fibrosarcoma. I. Ly-1+2- suppressor T cells down-regulate the generation of Ly-1-2+ effector T cells. J Exp Med 1984;159:1295–311.pmid:6232335
    OpenUrlAbstract/FREE Full Text
  21. 21.↵
    1. Basu S,
    2. Binder RJ,
    3. Suto R,
    4. Anderson KM,
    5. 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;12:1539–46.pmid:11058573
    OpenUrlAbstract/FREE Full Text
  22. 22.↵
    1. Binder RJ,
    2. Anderson KM,
    3. Basu S,
    4. Srivastava PK
    . Cutting edge: heat shock protein gp96 induces maturation and migration of CD11c+ cells in vivo. J Immunol 2000;165:6029–35.pmid:11086034
    OpenUrlAbstract/FREE Full Text
  23. 23.↵
    1. Srivastava PK
    . Purification of heat shock protein-peptide complexes for use in vaccination against cancers and intracellular pathogens. Methods 1997;12:165–71.pmid:9184380
    OpenUrlCrossRefPubMed
PreviousNext
Back to top
Cancer Immunity Archive: 1 (1)
January 2001
Volume 1, Issue 1
  • Table of Contents

Sign up for alerts

View this article with LENS

Open full page PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Cancer Immunology Research article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Determinants of efficacy of immunotherapy with tumor-derived heat shock protein gp96
(Your Name) has forwarded a page to you from Cancer Immunology Research
(Your Name) thought you would be interested in this article in Cancer Immunology Research.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Determinants of efficacy of immunotherapy with tumor-derived heat shock protein gp96
Joseph T. Kovalchin, Ananth S. Murthy, Mark C. Horattas, Daniel P. Guyton and Rajiv Y. Chandawarkar
Cancer Immun January 1 2001 (1) (1) 7;

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Determinants of efficacy of immunotherapy with tumor-derived heat shock protein gp96
Joseph T. Kovalchin, Ananth S. Murthy, Mark C. Horattas, Daniel P. Guyton and Rajiv Y. Chandawarkar
Cancer Immun January 1 2001 (1) (1) 7;
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Results
    • Discussion
    • Materials and methods
    • Acknowledgments
    • References
  • Figures & Data
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • NY-ESO-1–specific immunological pressure and escape in a patient with metastatic melanoma
  • Hsp72 mediates stronger antigen-dependent non-classical MHC class Ib anti-tumor responses than hsc73 in Xenopus laevis
  • Human ovarian tumor ascites fluids rapidly and reversibly inhibit T cell receptor-induced NF-κB and NFAT signaling in tumor-associated T cells
Show more Articles
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook   Twitter   LinkedIn   YouTube   RSS

Articles

  • Online First
  • Current Issue
  • Past Issues
  • Cancer Immunology Essentials

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians

About Cancer Immunology Research

  • About the Journal
  • Editorial Board
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2021 by the American Association for Cancer Research.

Cancer Immunology Research
eISSN: 2326-6074
ISSN: 2326-6066

Advertisement