Recent advances and current challenges in tumor immunology and immunotherapy.

Despite advances in animal studies, where the cure of the majority of mice with pre-established (albeit early-stage) tumors has become almost standard, human clinical trials have been much less successful. Here we describe some of the most recent advances in the specialist field of tumor immunology and immunotherapy, highlighting salient work to identify key problem areas and potential solutions. We make particular note of recent developments in adoptive therapy; whole-cell, DNA, and peptide vaccines; and antibody therapy. We also describe the revival of interest in regulatory T cells and conclude by detailing the need for clinical trial read-out autonomy and methods to predict which patients will respond to a particular treatment.

[1]  L. Ren-Heidenreich,et al.  Comparison of the TCR ζ-chain with the FcR γ-chain in chimeric TCR constructs for T cell activation and apoptosis , 2002, Cancer Immunology, Immunotherapy.

[2]  S. Sakaguchi,et al.  Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease , 1985, The Journal of experimental medicine.

[3]  F. Marincola,et al.  Adoptive Transfer of Cloned Melanoma-Reactive T Lymphocytes for the Treatment of Patients with Metastatic Melanoma , 2001, Journal of immunotherapy.

[4]  V. Schirrmacher T cell-mediated immunotherapy of metastases: state of the art in 2005 , 2005, Expert opinion on biological therapy.

[5]  H. Ikeda,et al.  Generation of tumor-specific, HLA class I-restricted human Th1 and Tc1 cells by cell engineering with tumor peptide-specific T-cell receptor genes. , 2005, Blood.

[6]  S. Quezada,et al.  Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. , 2006, Current opinion in immunology.

[7]  S. Rosenberg,et al.  Immunization of HLA-A*0201 and/or HLA-DPβ1*04 Patients with Metastatic Melanoma Using Epitopes from the NY-ESO-1 Antigen , 2004, Journal of immunotherapy.

[8]  J. Mulé,et al.  Chemokine gene modification of human dendritic cell-based tumor vaccines using a recombinant adenoviral vector , 2004, Cancer Gene Therapy.

[9]  J W Gratama,et al.  Grafting primary human T lymphocytes with cancer-specific chimeric single chain and two chain TCR , 2000, Gene Therapy.

[10]  M. Kuroki,et al.  Generation and Targeting of Human Tumor-Specific Tc1 and Th1 Cells Transduced with a Lentivirus Containing a Chimeric Immunoglobulin T-Cell Receptor , 2004, Cancer Research.

[11]  M. Huang,et al.  Interleukin-7 gene-modified dendritic cells reduce pulmonary tumor burden in spontaneous murine bronchoalveolar cell carcinoma. , 2003, Human gene therapy.

[12]  M. Pfreundschuh,et al.  Human neoplasms elicit multiple specific immune responses in the autologous host. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[13]  M. Raffeld,et al.  Cancer Regression and Autoimmunity in Patients After Clonal Repopulation with Antitumor Lymphocytes , 2002, Science.

[14]  J. Schlom,et al.  T-cell killing of heterogenous tumor or viral targets with bispecific chimeric immune receptors , 2000, Cancer Gene Therapy.

[15]  D. Jäger,et al.  Monitoring CD8 T cell responses to NY-ESO-1: correlation of humoral and cellular immune responses. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[16]  A. Dalgleish,et al.  The biological effects of syngeneic and allogeneic cytokine-expressing prophylactic whole cell vaccines and the influence of irradiation in a murine melanoma model , 2006, Cancer Immunology, Immunotherapy.

[17]  T. Nomura,et al.  Control of Regulatory T Cell Development by the Transcription Factor Foxp3 , 2002 .

[18]  S. Rosenberg,et al.  Cancer Regression in Patients After Transfer of Genetically Engineered Lymphocytes , 2006, Science.

[19]  J. Roliński,et al.  Immunotherapy for patients with acute myeloid leukemia using autologous dendritic cells generated from leukemic blasts. , 2006, International journal of oncology.

[20]  S. Rosenberg,et al.  Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. , 1994, Journal of the National Cancer Institute.

[21]  H. Schmidt,et al.  Adoptive transfer of allogeneic cytotoxic T lymphocytes equipped with a HLA-A2 restricted MART-1 T-cell receptor: a phase I trial in metastatic melanoma. , 2006, Clinical cancer research : an official journal of the American Association for Cancer Research.

[22]  P. Robbins,et al.  Immunization with Lentiviral Vector-Transduced Dendritic Cells Induces Strong and Long-Lasting T Cell Responses and Therapeutic Immunity 1 , 2005, The Journal of Immunology.

[23]  B. Kwon,et al.  Immunotherapy Targeting 4-1BB and Its Ligand , 2006, International journal of hematology.

[24]  S. Rosenberg,et al.  A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. , 1986, Science.

[25]  M. Cascio,et al.  Therapeutic potential of a tumor-specific, MHC-unrestricted T-cell receptor expressed on effector cells of the innate and the adaptive immune system through bone marrow transduction and immune reconstitution. , 2005, Blood.

[26]  L. Liau,et al.  MART-1 adenovirus-transduced dendritic cell immunization in a murine model of metastatic central nervous system tumor , 2003, Journal of Neuro-Oncology.

[27]  S. Rosenberg,et al.  Altered CD8+ T-Cell Responses When Immunizing With Multiepitope Peptide Vaccines , 2006, Journal of immunotherapy.

[28]  M. Nishimura,et al.  Simultaneous generation of CD8+ and CD4+ melanoma-reactive T cells by retroviral-mediated transfer of a single T-cell receptor. , 2005, Cancer research.

[29]  A. Ribas Genetically modified dendritic cells for cancer immunotherapy. , 2005, Current gene therapy.

[30]  N. Goldstein,et al.  Surface-epitope masking and expression cloning identifies the human prostate carcinoma tumor antigen gene PCTA-1 a member of the galectin gene family. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[31]  L. Butterfield,et al.  Antigen presentation by MART‐1 adenovirus‐transduced interleukin‐10‐polarized human monocyte‐derived dendritic cells , 2004, Immunology.

[32]  A. Polliack,et al.  Rituximab therapy for follicular lymphoma: a comprehensive review of its efficacy as primary treatment, treatment for relapsed disease, re-treatment and maintenance. , 2003, Haematologica.

[33]  J. Schölmerich,et al.  Monocyte-Derived Human Macrophages Mediate Anergy in Allogeneic T Cells and Induce Regulatory T Cells1 , 2006, The Journal of Immunology.

[34]  N. Petrovsky,et al.  Vaccine adjuvants: Current state and future trends , 2004, Immunology and cell biology.

[35]  H. Pandha,et al.  Immunotherapeutic potential of whole tumour cells , 2002, Cancer Immunology, Immunotherapy.

[36]  J. Patard,et al.  A new gene coding for an antigen recognized by autologous cytolytic T lymphocytes on a human renal carcinoma , 2007, Immunogenetics.

[37]  M. Atkins,et al.  Immunologic Monitoring of Cancer Vaccine Therapy: Results of a Workshop Sponsored by the Society for Biological Therapy , 2002, Journal of immunotherapy.

[38]  A. Deisseroth,et al.  Multistep process through which adenoviral vector vaccine overcomes anergy to tumor-associated antigens. , 2004, Blood.

[39]  E. Puré,et al.  Breaking down the barriers to cancer immunotherapy , 2005, Nature Immunology.

[40]  Eleanor Woodward,et al.  Microarray analysis of tumour antigen expression in presentation acute myeloid leukaemia. , 2005, Biochemical and biophysical research communications.

[41]  Hans J. Stauss,et al.  Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer , 2001, Nature Immunology.

[42]  S. Liebhaber,et al.  Suppressor T cells. , 1972, Journal of immunology.

[43]  T. Hamblin,et al.  DNA vaccines with single-chain Fv fused to fragment C of tetanus toxin induce protective immunity against lymphoma and myeloma , 1998, Nature Medicine.

[44]  P. Hwu,et al.  Efficient gene transfer to human peripheral blood monocyte-derived dendritic cells using human immunodeficiency virus type 1-based lentiviral vectors. , 2000, Human gene therapy.

[45]  A. Rudensky,et al.  Foxp3 programs the development and function of CD4+CD25+ regulatory T cells , 2003, Nature Immunology.

[46]  M. Rosenblum Immunotoxins and toxin constructs in the treatment of leukemia and lymphoma. , 2004, Advances in pharmacology.

[47]  S. Stevanović,et al.  A novel MHC-associated Proteinase 3 peptide isolated from primary chronic myeloid leukaemia cells further supports the significance of this antigen for the immunotherapy of myeloid leukaemias , 2006, Leukemia.

[48]  Mark Shackleton,et al.  Recombinant NY-ESO-1 protein with ISCOMATRIX adjuvant induces broad integrated antibody and CD4(+) and CD8(+) T cell responses in humans. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[49]  E. Gilboa,et al.  Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. , 2005, The Journal of clinical investigation.

[50]  H. Yamaue,et al.  Dendritic cells genetically engineered to simultaneously express endogenous tumor antigen and granulocyte macrophage colony-stimulating factor elicit potent therapeutic antitumor immunity. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[51]  D. Scheinberg,et al.  Synthetic peptide analogs derived from bcr/abl fusion proteins and the induction of heteroclitic human T-cell responses. , 2005, Haematologica.

[52]  F. Ramsdell,et al.  An essential role for Scurfin in CD4+CD25+ T regulatory cells , 2003, Nature Immunology.

[53]  M. Dullaers,et al.  Lentivirally transduced dendritic cells as a tool for cancer immunotherapy , 2003, The journal of gene medicine.

[54]  S. Tagawa,et al.  Phase I study of intranodal delivery of a plasmid DNA vaccine for patients with Stage IV melanoma , 2003, Cancer.

[55]  C. Ottensmeier,et al.  DNA fusion gene vaccines against cancer: from the laboratory to the clinic , 2004, Immunological reviews.

[56]  G. Lizée,et al.  Lentivirus vector-mediated expression of tumor-associated epitopes by human antigen presenting cells. , 2004, Human gene therapy.

[57]  G. Adams,et al.  Monoclonal antibody therapy of cancer , 1999, Nature Biotechnology.

[58]  K. Zsebo,et al.  Systemic T Cell–independent Tumor Immunity after Transplantation of Universal Receptor–modified Bone Marrow into SCID Mice , 1996, The Journal of experimental medicine.

[59]  P. Matzinger,et al.  Is cancer dangerous to the immune system? , 1996, Seminars in immunology.

[60]  T. Schirrmann,et al.  Specific targeting of CD33(+) leukemia cells by a natural killer cell line modified with a chimeric receptor. , 2005, Leukemia research.

[61]  R. Schreiber,et al.  Interferon-γ and cancer immunoediting , 2005 .

[62]  G. Gaudernack,et al.  Immuno-gene therapy of cancer with tumour-mRNA transfected dendritic cells , 2006, Cancer Immunology, Immunotherapy.

[63]  D. Galas,et al.  Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse , 2001, Nature Genetics.

[64]  Catia,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 , 1992, The Journal of experimental medicine.

[65]  K. Mills,et al.  The tumour antigens RAGE‐1 and MGEA6 are expressed more frequently in the less lineage restricted subgroups of presentation acute myeloid leukaemia , 2006, British journal of haematology.

[66]  J. Trapani,et al.  A functional role for CD28 costimulation in tumor recognition by single-chain receptor-modified T cells , 2004, Cancer Gene Therapy.

[67]  J. Weber,et al.  Characterization of Long-Term Effector-Memory T-Cell Responses in Patients with Resected High-Risk Melanoma Receiving a Melanoma Peptide Vaccine , 2004, Journal of immunotherapy.

[68]  D. Kufe,et al.  Dendritic cell fusion vaccines for cancer immunotherapy , 2005, Expert opinion on biological therapy.

[69]  J. Shimizu,et al.  Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. , 1999, Journal of immunology.

[70]  Y. Ikeda,et al.  Lentiviral vector expression of tumour antigens in dendritic cells as an immunotherapeutic strategy , 2006, Cancer Immunology and Immunotherapy.

[71]  S. Steinberg,et al.  Evaluation of Prime/Boost Regimens Using Recombinant Poxvirus/Tyrosinase Vaccines for the Treatment of Patients with Metastatic Melanoma , 2006, Clinical Cancer Research.

[72]  B. Groner,et al.  Adoptive transfer of in vitro-targeted, activated T lymphocytes results in total tumor regression. , 1997, Journal of immunology.

[73]  Lung-Ji Chang,et al.  An effective cancer vaccine modality: lentiviral modification of dendritic cells expressing multiple cancer-specific antigens. , 2006, Vaccine.

[74]  G. Ossenkoppele,et al.  Employing the immunological synapse in AML: development of leukemic dendritic cells for active specific immunization. , 2005, Immunobiology.

[75]  Manfred Dietel,et al.  Personalized medicine and development of targeted therapies: the upcoming challenge for diagnostic molecular pathology. A review , 2006, Virchows Archiv.

[76]  A. Sloan,et al.  Dendritic Cell-Based Immunotherapy of Malignant Gliomas , 2004, Cancer investigation.

[77]  G. Mufti,et al.  Humoral detection of leukaemia-associated antigens in presentation acute myeloid leukaemia. , 2005, Biochemical and Biophysical Research Communications - BBRC.

[78]  Michel Sadelain,et al.  Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ /CD28 receptor , 2002, Nature Biotechnology.

[79]  E. Beecham,et al.  Dynamics of Tumor Cell Killing by Human T Lymphocytes Armed With an Anti-Carcinoembryonic Antigen Chimeric Immunoglobulin T-Cell Receptor , 2000, Journal of immunotherapy.

[80]  D. Pardoll,et al.  Immunotherapy of established tumors using bone marrow transplantation with antigen gene–modified hematopoietic stem cells , 2003, Nature Medicine.

[81]  S. Rosenberg,et al.  Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[82]  R. Stripecke,et al.  Making dendritic cells from the inside out: lentiviral vector-mediated gene delivery of granulocyte-macrophage colony-stimulating factor and interleukin 4 into CD14+ monocytes generates dendritic cells in vitro. , 2004, Human gene therapy.

[83]  Simon C Watkins,et al.  Intratumoral delivery of dendritic cells engineered to secrete both interleukin (IL)-12 and IL-18 effectively treats local and distant disease in association with broadly reactive Tc1-type immunity. , 2003, Cancer research.

[84]  George Coukos,et al.  Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival , 2004, Nature Medicine.

[85]  Lloyd J. Old,et al.  Cancer/testis antigens, gametogenesis and cancer , 2005, Nature Reviews Cancer.

[86]  R. Rees,et al.  Identification of tumour antigens by serological analysis of cDNA expression cloning , 2004, Cancer Immunology, Immunotherapy.

[87]  Y. Li,et al.  Characterization and utilization of two novel anti-erbB-2 monoclonal antibodies in detection of soluble ErbB-2 for breast cancer prognosis. , 2003, Cancer letters.

[88]  D. Jocham,et al.  Technology evaluation: Onyvax-P, Onyvax. , 2005, Current opinion in molecular therapeutics.

[89]  R. Brasseur,et al.  BAGE: a new gene encoding an antigen recognized on human melanomas by cytolytic T lymphocytes. , 1995, Immunity.

[90]  S. Rosenberg,et al.  Adoptive immunotherapy for cancer: building on success , 2006, Nature Reviews Immunology.

[91]  J. Kirkwood,et al.  IL-12p70 and IL-18 gene-modified dendritic cells loaded with tumor antigen-derived peptides or recombinant protein effectively stimulate specific Type-1 CD4+ T-cell responses from normal donors and melanoma patients in vitro , 2006, Cancer Gene Therapy.

[92]  R. Guest,et al.  Primary Polyclonal Human T Lymphocytes Targeted to Carcino-Embryonic Antigens and Neural Cell Adhesion Molecule Tumor Antigens by CD3ζ-Based Chimeric Immune Receptors , 2002, Journal of immunotherapy.

[93]  D. Zelterman,et al.  An adenoviral vector cancer vaccine that delivers a tumor-associated antigen/CD40-ligand fusion protein to dendritic cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[94]  D. Curiel,et al.  Adenovirus-mediated gene delivery to dendritic cells. , 2004, Methods in molecular biology.

[95]  G. Linette,et al.  Immunization Using Autologous Dendritic Cells Pulsed with the Melanoma-Associated Antigen gp100-Derived G280-9V Peptide Elicits CD8+ Immunity , 2005, Clinical Cancer Research.

[96]  S. Nakagawa,et al.  Immunological properties and vaccine efficacy of murine dendritic cells simultaneously expressing melanoma-associated antigen and interleukin-12 , 2005, Cancer Gene Therapy.

[97]  V. Sondak,et al.  Results of clinical trials with an allogenic melanoma tumor cell lysate vaccine: Melacine. , 2003, Seminars in cancer biology.

[98]  G. Mufti,et al.  IL-2/B7.1 (CD80) fusagene transduction of AML blasts by a self-inactivating lentiviral vector stimulates T cell responses in vitro: a strategy to generate whole cell vaccines for AML. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[99]  H. Ueno,et al.  Immune and Clinical Outcomes in Patients with Stage IV Melanoma Vaccinated with Peptide-Pulsed Dendritic Cells Derived From CD34+ Progenitors and Activated with Type I Interferon , 2005, Journal of immunotherapy.

[100]  G. Mufti,et al.  An immune edited tumour versus a tumour edited immune system: prospects for immune therapy of acute myeloid leukaemia , 2006, Cancer Immunology, Immunotherapy.

[101]  B. Coiffier Monoclonal antibody as therapy for malignant lymphomas. , 2006, Comptes rendus biologies.

[102]  P. Chomez,et al.  A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. , 1991, Science.

[103]  G. Winter,et al.  Mapping epitopes and antigenicity by site-directed masking. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[104]  M. Baseler,et al.  Application of the Granzyme B ELISPOT Assay for Monitoring Cancer Vaccine Trials , 2006, Journal of immunotherapy.

[105]  C. Milstein,et al.  Continuous cultures of fused cells secreting antibody of predefined specificity , 1975, Nature.

[106]  S. Rosenberg,et al.  Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells , 2005, The Journal of experimental medicine.

[107]  J. Bae,et al.  Heteroclitic CD33 Peptide With Enhanced Anti-Acute Myeloid Leukemic Immunogenicity , 2004, Clinical Cancer Research.

[108]  S. Rosenberg,et al.  Cancer immunotherapy: moving beyond current vaccines , 2004, Nature Medicine.

[109]  A. Ribas,et al.  A Phase I/II Trial Testing Immunization of Hepatocellular Carcinoma Patients with Dendritic Cells Pulsed with Four α-Fetoprotein Peptides , 2006, Clinical Cancer Research.

[110]  A. Scott,et al.  Adoptive transfer of T cells modified with a humanized chimeric receptor gene inhibits growth of Lewis-Y-expressing tumors in mice. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[111]  R. Stripecke,et al.  Potent Maturation of Monocyte-Derived Dendritic Cells After CD40L Lentiviral Gene Delivery , 2003, Journal of immunotherapy.

[112]  R. Levy,et al.  Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.