Advertisement
help button home button The Oncologist
HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Baar, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Baar, J.
The Oncologist, Vol. 4, No. 2, 140-144, April 1999
© 1999 AlphaMed Press

Physician Education

Clinical Applications of Dendritic Cell Cancer Vaccines

Joseph Baar

University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania USA

Correspondence: Joseph Baar, M.D., Ph.D., University of Pittsburgh Cancer Institute, Division of Hematology/Oncology, 200 Lothrop Street, Room MUH N-755, Pittsburgh, Pennsylvania 15213-2582, USA. Telephone: 412-648-6507; Fax: 412-648-6579: e-mail: BAARJ{at}MSX.UPMC.EDU


   Introduction
Top
 Introduction
Dendritic Cells and Cellular...
 Tumor Antigens for Dendritic...
 Clinical Trials of Dendritic...
 Summary and Future Directions
 References
 
It has been more than 100 years since Dr. William B. Coley reported the regression of tumors in some patients who had been injected with bacterial extracts [1]. Since this early exercise in cancer vaccination, clinicians and scientists have attempted to harness the immune system to mediate the rejection of tumors in vivo. Because of many important recent discoveries in immunology and tumor cell biology, we now have the exciting opportunity to explore the therapeutic potentials of novel cancer vaccines.


   Dendritic Cells and Cellular Immunity to Tumors
Top
 Introduction
 Dendritic Cells and Cellular...
Tumor Antigens for Dendritic...
 Clinical Trials of Dendritic...
 Summary and Future Directions
 References
 
It can be demonstrated in some transplantation challenge models that irradiated tumor cells express tumor antigens which are presented on the cell surface by major histocompatibility (MHC) class I or class II molecules and are capable of eliciting tumor-specific immune responses in syngeneic animals. Immunized animals reject subsequent challenges of the immunizing tumor and may occasionally reject unrelated syngeneic tumors expressing common antigens. In these models, tumor cell rejection is mediated by CD8+ cytotoxic T lymphocytes (CTL) which recognize a complex made up of an MHC class I heavy chain allele, a ß2-microglobulin light chain, and an 8-12 amino acid-long, tumor-derived peptide [2-4]. CD4+ helper T lymphocytes, in contrast, recognize MHC class II molecules presenting a 10 to 25 amino acid-long peptide [5].

Antigen-presenting cells (APCs) are critical for the antigen-specific priming of T cells, and dendritic cells (DCs) are the most potent stimulatory APCs. DCs constitute a heterogeneous population of cells [6], and although the precise ontogeny of DCs remains to be elucidated, they can differentiate from both bone marrow (BM) and peripheral blood precursors [7]. DCs exhibit at least five important characteristics for the generation of T-cell-mediated anti-tumor immunity ( Table 1) [8, 9].


View this table:
[in this window]
[in a new window]
  		Table 1. The five characteristics exhibited by DCs for the generation of T-cell-mediated anti-tumor immunity
 
DCs are readily obtained in large numbers from peripheral blood or CD34+ bone marrow progenitors expanded in vitro in medium containing various combinations of cytokines, including GM-CSF, interleukin 4 (IL-4), c-kit ligand, and tumor necrosis factor {alpha} (TNF-{alpha}). Furthermore, of major importance in the design of DC-based cancer vaccines, it has been demonstrated that functional DCs can be generated in cancer patients from CD34+ BM progenitors mobilized in vivo with high-dose cyclophosphamide, IL-3, and G-CSF [10]. Also, administration by s.c. injection to mice of a newly described cytokine, flt-3 ligand, has been shown to expand both lymphoid and myeloid DCs in vivo [11]. The phenotype of DCs varies according to the cytokines added to the culture media. For example, media containing IL-4 and GM-CSF [12, 13] appear to stimulate the outgrowth of "immature" DCs, which have high phagocytic capacity for antigen but low expression of costimulatory molecules such as CD80 and CD86, or other molecules such as MHC class I and class II, CD83 and p55. The main role of "immature" DCs appears to be the uptake and processing of antigen in tissues. Addition of TNF-{alpha} or monocyte-conditioned medium to DC cultures results in the outgrowth of more "mature" DCs, characterized by high expression of MHC class I, class II, and costimulatory molecules, but with little or no phagocytic capacity. The main role of "mature" DCs appears to be the priming of T cells in lymphoid tissues. Immature and mature DCs form an evolutionary biological continuum rather than two distinct populations of DCs: the uptake of antigen by immature DCs rapidly leads to phenotypic changes in DCs associated with maturation.


   Tumor Antigens for Dendritic Cell Vaccines
Top
 Introduction
 Dendritic Cells and Cellular...
 Tumor Antigens for Dendritic...
Clinical Trials of Dendritic...
 Summary and Future Directions
 References
 
The application of autologous DCs to cancer therapy has received much interest [14-16]. Animal models have clearly documented the ability of syngeneic BM-derived DCs prepulsed with tumor-derived peptide epitopes or genetically engineered to express immunostimulatory cytokines to serve as effective immunogens of antitumor CTLs in vivo [17-22].

A number of tumor-associated antigens have been identified as potential immunogens in DC-based vaccination strategies. Such tumor rejection antigens derive, for example, from oncogenes (ras) [23], overexpressed genes (HER-2/neu) [24, 25], embryonic genes (MAGE, BAGE, GAGE) [26-28], normal differentiation genes (MART-1/ Melan-A, gp100, tyrosinase) [29-32], viral genes (HPV) [33], tumor-suppressor genes (p53) [34], B-cell idiotypes [35], and other tumor-associated proteins (PSMA, MUC1) [36, 37].

The major advantage of such peptide-based immunization resides in the fine specificity of the CTL reactivity raised against the tumor epitope of interest. However, there are two important limitations to peptide-based vaccination strategies. First, the majority of identified tumor peptides are presented in an HLA-restricted fashion, and therefore such vaccines are available only to patients with specific HLA haplotypes. Second, because of tumor heterogeneity, not all tumor cells may express the target epitope of interest. Given these limitations, other sources of tumor antigen are being sought for DC-based vaccines. These include tumor-derived RNA [38], tumor-derived apoptotic bodies [39], and tumor lysates [40, 41]. Using these strategies, there is no need to identify a priori the relevant tumor antigen(s) for immunization. Furthermore, because whole-cell products are being used, there is the possibility of immunizing against more than one tumor-derived antigen. Finally, because autologous tumor cells serve as the source of antigen, such vaccines are available to all patients, irrespective of HLA type.


   Clinical Trials of Dendritic Cell Cancer Vaccines
Top
 Introduction
 Dendritic Cells and Cellular...
 Tumor Antigens for Dendritic...
 Clinical Trials of Dendritic...
Summary and Future Directions
 References
 
The evidence that DCs can mediate the in vivo rejection of established tumors in murine models and the relative ease with which it is possible to generate large numbers of DCs in vitro has made them feasible components in human cancer vaccine protocols.

In a report from Hsu et al. [35], autologous DCs were pulsed ex vivo with tumor-specific idiotype protein to stimulate host antitumor immunity in four patients with follicular non-Hodgkin's B-cell lymphoma. Patients received a series of three or four infusions of antigen-pulsed DCs followed by s.c. injections of soluble antigen two weeks later. Antitumor cellular immune responses were detected in all four patients, and three of the four patients had either partial or total regression of detectable disease.

Nestle et al. [40] have reported on the vaccination of 16 melanoma patients with peptide- or tumor lysate-pulsed DCs. Keyhole limpet hemocyanin was added as a CD4 helper antigen and immunological tracer molecule. DC vaccination induced a positive peptide-specific delayed-type hypersensitivity (DTH) response in 11 patients. Five of 16 patients demonstrated objective responses to the DC vaccine (two complete responses, three partial responses) with regression of metastases in various organs (skin, soft tissue, lung, and pancreas).

In a report from Chakraborty et al. [41], patients with malignant melanoma were immunized with a tumor cell lysate-loaded autologous APC-based vaccine. Seventeen patients (11 with metastatic disease) were immunized intradermally with the vaccine in a phased dose escalation (105-107 cells/injection) monthly for four months. One patient had a partial regression of an s.c. nodule. Nine patients had a DTH response at the vaccine site. Five of nine vaccine-infiltrating lymphocyte (VIL) specimens were predominantly CD8+. Antigen-specific CD8+ T-cell responses were detected in three of the five CD8+ VIL specimens.

In a report by Mukherji et al. [42], patients with malignant melanoma who were HLA-A1+ and whose tumors expressed the MAGE-1 gene were immunized with a vaccine consisting of a MAGE-1 nonapeptide (EADPTGHSY) pulsed onto autologous APCs. Vaccination induced autologous melanoma-reactive and peptide-specific CTL responses. In particular, the frequency of circulating autologous melanoma-reactive CTL precursors was increased. In a follow-up study, Hu et al. [43] showed that in vitro stimulation of the post-immunization peripheral blood lymphocytes with the MAGE-1 nonapeptide loaded onto APCs resulted in a significant expansion of peptide-specific and autologous melanoma-reactive CTL responses.

Salgaller et al. [44] have reported on DC-based immunotherapy of prostate cancer. The authors performed a phase 1 clinical trial assessing the administration of autologous DCs pulsed with an HLA-A0201-specific prostate-specific membrane antigen (PSMA) for the treatment of 51 men with hormone-refractory prostate cancer. Participants were divided into five groups receiving four or five infusions of peptides alone (PSM-P1 or PSM-P2; groups 1 and 2, respectively), autologous DC (group 3), or DC pulsed with PSM-P1 or P2 (groups 4 and 5, respectively). Immune reactivity against PSM-P2 was detected in HLA–A2+ patients infused with DC pulsed with PSM-P1 or -P2 (groups 4 and 5). An average decrease in PSA was observed only in group 5. Seven men had partial responses.

Wen et al. [45] have reported on idiotypic (Id) protein-pulsed DCs in the immunotherapy of a patient with multiple myeloma (MM). DCs were pulsed with autologous Id protein and administered to a patient with advanced-stage refractory MM. Id-specific immune responses were detected, as characterized by T-cell-proliferative responses and the production of anti-Id antibodies. A T-cell line generated after vaccination lysed autologous Id-pulsed targets and recognized fresh autologous MM cells.

All of these studies have demonstrated that the administration of the various DC vaccines is safe with little or no toxicity.


   Summary and Future Directions
Top
 Introduction
 Dendritic Cells and Cellular...
 Tumor Antigens for Dendritic...
 Clinical Trials of Dendritic...
 Summary and Future Directions
References
 
DC-based cancer vaccines offer the potential for an effective, non-toxic, and outpatient-based approach to cancer therapy. As depicted in Figure 1, future-generation clinical trials will undoubtedly incorporate DCs pulsed with tumor epitopes derived from newly identified tumor-associated peptides, RNA, lysates, or apoptotic bodies. These tumor-derived compounds would be processed by DCs for presentation in the context of both MHC class I and class II molecules for the priming of T cells. DCs might also be genetically modified with cDNAs encoding, for example, immunostimulatory cytokines such as IL-12 to augment the generation of effective anti-tumor CTL responses, or with full-length cDNAs encoding TAAs. While the majority of DC-based clinical trials is being undertaken in patients with melanoma, such trials will eventually serve as a basis for future DC vaccine trials incorporating patients with more common malignancies such as breast, colon, lung, and prostate cancer. As a result of the major advances in cancer immunobiology, we now find ourselves at the threshold of a novel, exciting, and hopefully rewarding approach to the treatment of cancer. Undoubtedly, Dr. Coley would be amazed and gratified by the progress achieved in the immunotherapy of cancer.



View larger version (37K):
[in this window]
[in a new window]
  		Figure 1. Future directions for dendritic cell-based vaccines for cancer.

 


   References
Top
 Introduction
 Dendritic Cells and Cellular...
 Tumor Antigens for Dendritic...
 Clinical Trials of Dendritic...
 Summary and Future Directions
 References
 

  1. Coley WD. The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of the Streptococcus erysipelas and the Bacillus prodigius). London: John Bale & Sons Publishers 1909;1-48.
  2. Rock KL, Fleischacker C, Gamble S. Peptide-priming of cytolytic T cell immunity in vivo using microglobulin as an adjuvant. J Immunol 1993;150:1244-1252.[Abstract]
  3. Rotzschke O, Falk K, Deres K et al. Isolation and analysis of naturally processed viral peptides as recognized by cytotoxic T cells. Nature 1990;348:252-254.[Medline]
  4. Falk K, Rotzschke O, Stevanovic S et al. Allele specific motifs revealed by sequencing of self peptides eluted from MHC molecules. Nature 1991;351:290-296.[Medline]
  5. Kropshofer H, Max H, Muller CA et al. Self-peptide released from class II HLA-DR1 exhibits a hydrophobic residue contact motif. J Exp Med 1992;175:1799-1803.[Abstract/Free Full Text]
  6. Caux C, Liu YJ, Banchereau J. Recent advances in the study of dendritic cells and follicular dendritic cells. Immunol Today 1995;16:2-4.[Medline]
  7. Peters JH, Gieseler R, Thiele B et al. Dendritic cells: from ontogenic orphans to myelomonocytic descendants. Immunol Today 1996;17:273-278.[Medline]
  8. Zhou LJ, Tedder TF. A distinct pattern of cytokine gene-expression by human CD83+ blood dendritic cells. Blood 1995;86:3295-3301.[Abstract/Free Full Text]
  9. Macatonia SE, Hosken NA, Litton M et al. Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. J Immunol 1995;154:5071-5079.[Abstract]
  10. Romani N, Gruner S, Brang D et al. Proliferating dendritic cell progenitors in human blood. J Exp Med 1994;180:83-93.[Abstract/Free Full Text]
  11. Inaba K, Steinman RM, Pack MW et al. Identification of proliferating dendritic cell precursor in mouse blood. J Exp Med 1992(b);175:1157-1167.[Abstract/Free Full Text]
  12. Siena S, Di Nicola M, Bregni M et al. Massive ex vivo generation of functional dendritic cells from mobilized CD34+ blood progenitors for anticancer therapy. Exp Hematol 1995;23:1463-1471.[Medline]
  13. Maraskovsky E, Brasel K, Teepe M et al. Dramatic increase in the numbers of functionally mature dendritic cells in flt3 ligand-treated mice: multiple dendritic cell subpopulations identified. J Exp Med 1996;184:1953-1962.[Abstract/Free Full Text]
  14. Knight SC, Hunt R, Dore C et al. Influence of dendritic cells on tumor growth. Proc Natl Acad Sci USA 1985;82:4495-4497.[Abstract/Free Full Text]
  15. Young JW, Inaba K. Dendritic cells as adjuvants for class I major histocompatibility complex-restricted antitumor immunity. J Exp Med 1996;183:7-11.[Free Full Text]
  16. Paglia P, Chiodoni C, Rodolfo M et al. Murine dendritic cells loaded in vitro with soluble protein prime cytotoxic T lymphocytes against tumor antigen in vivo. J Exp Med 1996;183:317-322.[Abstract/Free Full Text]
  17. Zou JP, Shimizu J, Ikegame K et al. Tumor-immunotherapy with the use of tumor-antigen-pulsed antigen-presenting cells. Cancer Immunol Immunother 1992;35:1-6.[Medline]
  18. Mayordomo JI, Zorina T, Storkus WJ et al. Bone marrow derived dendritic cells pulsed with synthetic tumor peptides elicit protective and therapeutic anti-tumor immunity. Nat Med 1995;1:1297-1302.[Medline]
  19. Celluzzi CM, Mayordomo JI, Storkus WJ et al. Peptide-pulsed dendritic cells induce antigen-specific, CTL-mediated protective tumor immunity. J Exp Med 1996;183:283-288.[Abstract/Free Full Text]
  20. Flamand V, Sornasse T, Thielemans K et al. Murine dendritic cells pulsed in vitro with tumor antigen induce tumor resistance in vivo. Eur J Immunol 1994;23:605-610.
  21. Zitvogel L, Mayordomo JI, Tjandrawan T et al. Therapy of murine tumors with tumor peptide-pulsed dendritic cells: dependence on T cells, B7 costimulation, and T helper cell-associated cytokines. J Exp Med 1996;183:87-97.[Abstract/Free Full Text]
  22. Zitvogel L, Couderc B, Mayordomo JI et al. IL-12 engineered dendritic cells serve as effective tumor vaccine adjuvants in vivo. Ann New York Acad Sci 1996;795:284-293.[Medline]
  23. Peace DJ, Chen W, Nelson H et al. T cell recognition of transforming protein encoded by mutated ras proto-oncogenes. J Immunol 1991;146:2059-2065.[Abstract]
  24. Fisk B, Blevins TL, Wharton JT et al. Identification of an immunodominant peptide of HER2/neu protooncogene recognized by ovarian tumor-specific cytotoxic T lymphocyte lines. J Exp Med 1995;181:2109-2117.[Abstract/Free Full Text]
  25. Peoples GE, Goedegebuure PS, Smith R et al. Breast and ovarian cancer-specific cytotoxic T lymphocytes recognize the same HER2/neu-derived peptide. Proc Natl Acad Sci USA 1995;92:432-436.[Abstract/Free Full Text]
  26. Traversari C, van der Bruggen P, Luescher IF et al. A nonapeptide encoded by human gene MAGE-1 is recognized on HLA-A1 by cytolytic T lymphocytes directed against tumor antigen MZ2-E. J Exp Med 1992;176:1453-1458.[Abstract/Free Full Text]
  27. Boel P, Wildmann C, Sensi ML et al. BAGE: a new gene encoding an antigen recognized on human melanomas by cytolytic T lymphocytes. Immunity 1995;2:167-175.[Medline]
  28. van den Eynde B, Peeters O, De Backer O et al. A new family of genes coding for an antigen recognized by cytolytic T lymphocytes on a human melanoma. J Exp Med 1995;182:689-698.[Abstract/Free Full Text]
  29. Kawakami Y, Eliyahu S, Sakaguch K et al. Identification of the immunodominant peptides of MART-1 human melanoma antigen recognized by the majority of HLA-restricted tumor infiltrating lymphocytes. J Exp Med 1994;180:347-352.[Abstract/Free Full Text]
  30. Castelli C, Storkus WJ, Maeurer MJ et al. Mass spectrometric identification of a naturally-processed melanoma peptide recognized by CD8+ cytotoxic T lymphocytes. J Exp Med 1995;181:363-368.[Abstract/Free Full Text]
  31. Bakker ABH, Schreurs MWJ, de Boer AJ et al. Melanocyte lineage-specific antigen gp100 is recognized by melanoma derived tumor infiltrating lymphocytes. J Exp Med 1994;179:1005-1009.[Abstract/Free Full Text]
  32. Brichard V, Van Pel A, Wolfel T et al. The tyrosinase gene codes for an antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med 1993;178:489-495.[Abstract/Free Full Text]
  33. Lowry DR, Schiller JT. Papillomaviruses and cervical cancer: pathogenesis and vaccine development. J Natl Cancer Inst 1998;23:27-30.
  34. DeLeo AB. p53-based immunotherapy of cancer. Crit Rev Immunol 1998;18:29-35.[Medline]
  35. Hsu FJ, Benike C, Fagnoni F et al. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med 1996;2:52-55.[Medline]
  36. Tjoa B, Boynton A, Kenny G et al. Presentation of prostate tumor antigens by dendritic cells stimulates T-cell proliferation and cytotoxicity. Prostate 1996;28:65-69.[Medline]
  37. Finn O, Jerome KR, Henderson RA et al. MUC-1 epithelial tumor mucin-based immunity and cancer vaccines. Immunol Rev 1995;145:61-89.[Medline]
  38. Gilboa E, Nair SK, Lyerly HK. Immunotherapy of cancer with dendritic-cell-based vaccines. Cancer Immunol Immunother 1998;46:82-87.[Medline]
  39. Albert ML, Sauter B, Bhardwaj N. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 1998;392:86-89.[Medline]
  40. Nestle FO, Alijagic S, Gilliet M et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 1998;4:328-332.[Medline]
  41. Chakraborty NG, Sporn JR, Tortora AF et al. Immunization with a tumor-cell-lysate-loaded autologous-antigen-presenting-cell-based vaccine in melanoma. Cancer Immunol Immunother 1998;47:58-64.[Medline]
  42. Mukherji B, Chakraborty NG, Yamasaki S et al. Induction of antigen-specific cytolytic T cells in situ in human melanoma by immunization with synthetic peptide-pulsed autologous antigen presenting cells. Proc Natl Acad Sci USA 1995;92:8078-8082.[Abstract/Free Full Text]
  43. Hu X, Chakraborty NG, Sporn JR et al. Enhancement of cytolytic T lymphocyte precursor frequency in melanoma patients following immunization with the MAGE-1 peptide loaded antigen presenting cell-based vaccine. Cancer Res 1996;56:2479-2483.[Abstract/Free Full Text]
  44. Salgaller ML, Tjoa BA, Lodge PA et al. Dendritic cell-based immunotherapy of prostate cancer. Crit Rev Immunol 1998;18:109-119.[Medline]
  45. Wen YJ, Ling M, Bailey-Wood R et al. Idiotypic protein-pulsed adherent peripheral blood mononuclear cell-derived dendritic cells prime immune system in multiple myeloma. Clin Cancer Res 1998;4:957-962.[Abstract]




This Article
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Baar, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Baar, J.

HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
THE ONCOLOGIST STEM CELLS CME ALPHAMED PRESS JOURNALS