Trial watch

The long-established notion that apoptosis would be immunologically silent, and hence it would go unnoticed by the immune system, if not tolerogenic, and hence it would actively suppress immune responses, has recently been revisited. In some instances, indeed, cancer cells undergo apoptosis while emitting a spatiotemporally-defined combination of signals that renders them capable of eliciting a long-term protective antitumor immune response. Importantly, only a few anticancer agents can stimulate such an immunogenic cell death. These include cyclophosphamide, doxorubicin and oxaliplatin, which are currently approved by FDA for the treatment of multiple hematologic and solid malignancies, as well as mitoxantrone, which is being used in cancer therapy and against multiple sclerosis. In this Trial Watch, we will review and discuss the progress of recent (initiated after January 2008) clinical trials evaluating the off-label use of cyclophosphamide, doxorubicin, oxaliplatin and mitoxantrone.

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[10]  Jeffrey E. Lee,et al.  Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of Smad4(Dpc4) immunostaining with pattern of disease progression. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  C. Figdor,et al.  Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice. , 2011, The Journal of clinical investigation.

[12]  M. Ross,et al.  Randomized multicenter trial of the effects of melanoma-associated helper peptides and cyclophosphamide on the immunogenicity of a multipeptide melanoma vaccine. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

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[19]  L. Zitvogel,et al.  Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress , 2011, Oncogene.

[20]  Zlatko Trajanoski,et al.  Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  L. Bracci,et al.  Cyclophosphamide synergizes with type I interferons through systemic dendritic cell reactivation and induction of immunogenic tumor apoptosis. , 2011, Cancer research.

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[24]  Ash A. Alizadeh,et al.  Calreticulin Is the Dominant Pro-Phagocytic Signal on Multiple Human Cancers and Is Counterbalanced by CD47 , 2010, Science Translational Medicine.

[25]  C. Punt,et al.  Frequency of Circulating Tregs with Demethylated FOXP3 Intron 1 in Melanoma Patients Receiving Tumor Vaccines and Potentially Treg-Depleting Agents , 2010, Clinical Cancer Research.

[26]  Great,et al.  Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial , 2010, The Lancet.

[27]  T. Gruenberger,et al.  Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study. , 2010, The Lancet. Oncology.

[28]  M. Colombo,et al.  Improved clinical outcome in indolent B-cell lymphoma patients vaccinated with autologous tumor cells experiencing immunogenic death. , 2010, Cancer research.

[29]  V. Sreenivas,et al.  Best supportive care compared with chemotherapy for unresectable gall bladder cancer: a randomized controlled study. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  J. Machiels,et al.  Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial , 2010, The Lancet.

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[32]  B. Bröker,et al.  Histone deacetylase inhibitors prevent activation of tumour-reactive NK cells and T cells but do not interfere with their cytolytic effector functions. , 2010, Cancer letters.

[33]  Andreas Schneeweiss,et al.  Intense dose-dense sequential chemotherapy with epirubicin, paclitaxel, and cyclophosphamide compared with conventionally scheduled chemotherapy in high-risk primary breast cancer: mature results of an AGO phase III study. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  J. Wolchok,et al.  Cyclophosphamide enhances immunity by modulating the balance of dendritic cell subsets in lymphoid organs. , 2010, Blood.

[35]  I. Seferyńska,et al.  Comparison of cladribine plus cyclophosphamide with fludarabine plus cyclophosphamide as first-line therapy for chronic lymphocytic leukemia: a phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 Study). , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  P. Ganly,et al.  Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  L. Zitvogel,et al.  Decoding Cell Death Signals in Inflammation and Immunity , 2010, Cell.

[38]  J. Beck,et al.  The histone deacetylase inhibitor vorinostat induces calreticulin exposure in childhood brain tumour cells in vitro , 2010, Cancer Chemotherapy and Pharmacology.

[39]  M. Manns,et al.  Low-dose Cyclophosphamide Treatment Impairs Regulatory T Cells and Unmasks AFP-specific CD4+ T-cell Responses in Patients With Advanced HCC , 2010, Journal of immunotherapy.

[40]  L. Zitvogel,et al.  Tumor cell death and ATP release prime dendritic cells and efficient anticancer immunity. , 2010, Cancer research.

[41]  J. Pignon,et al.  Immunogenic death of colon cancer cells treated with oxaliplatin , 2010, Oncogene.

[42]  L. Raez,et al.  Oxaliplatin in first-line therapy for advanced non-small-cell lung cancer. , 2010, Clinical lung cancer.

[43]  E. Perez,et al.  Cyclophosphamide, epirubicin, and Fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by Paclitaxel versus Doxorubicin and cyclophosphamide followed by Paclitaxel in node-positive or high-risk node-negative breast cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[44]  Jeffrey W. Clark,et al.  Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study. , 2010, The Lancet. Oncology.

[45]  L. Zitvogel,et al.  Chemotherapy induces ATP release from tumor cells , 2009, Cell cycle.

[46]  James R. Anderson,et al.  Vincristine, actinomycin, and cyclophosphamide compared with vincristine, actinomycin, and cyclophosphamide alternating with vincristine, topotecan, and cyclophosphamide for intermediate-risk rhabdomyosarcoma: children's oncology group study D9803. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[47]  J. Tschopp,et al.  Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunity against tumors , 2009, Nature Medicine.

[48]  Ashkan Emadi,et al.  Cyclophosphamide and cancer: golden anniversary , 2009, Nature Reviews Clinical Oncology.

[49]  Michael R. Elliott,et al.  Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance , 2009, Nature.

[50]  R. Weichselbaum,et al.  Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. , 2009, Blood.

[51]  Jeffrey S. Morris,et al.  Phase II study of capecitabine and oxaliplatin for advanced adenocarcinoma of the small bowel and ampulla of Vater. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[52]  D. Green,et al.  Immunogenic and tolerogenic cell death , 2009, Nature Reviews Immunology.

[53]  P. van Endert,et al.  Mechanisms of pre‐apoptotic calreticulin exposure in immunogenic cell death , 2009, The EMBO journal.

[54]  R A Knight,et al.  Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009 , 2005, Cell Death and Differentiation.

[55]  K. Asadullah,et al.  Induction of Foxp3+ regulatory T cells with histone deacetylase inhibitors. , 2009, Cellular immunology.

[56]  G. Georgakis,et al.  Vorinostat inhibits STAT6-mediated TH2 cytokine and TARC production and induces cell death in Hodgkin lymphoma cell lines. , 2008, Blood.

[57]  E. Morselli,et al.  Hierarchical involvement of Bak, VDAC1 and Bax in cisplatin-induced cell death , 2008, Oncogene.

[58]  E. Morselli,et al.  Targeting p53 to mitochondria for cancer therapy , 2008, Cell cycle.

[59]  L. Zitvogel,et al.  The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death , 2008, Cell Death and Differentiation.

[60]  L. Zitvogel,et al.  The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy , 2007, Immunological reviews.

[61]  Laurence Zitvogel,et al.  Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapy , 2007, Nature Medicine.

[62]  V. Khoo,et al.  Low dose metronomic oral cyclophosphamide for hormone resistant prostate cancer: a phase II study. , 2007, The Journal of urology.

[63]  N. Pavlakis,et al.  Oxaliplatin for the treatment of cisplatin-resistant cancer: a systematic review. , 2007, Cancer treatment reviews.

[64]  L. Zitvogel,et al.  Cell death modalities: classification and pathophysiological implications , 2007, Cell Death and Differentiation.

[65]  S. Linder,et al.  Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA , 2007, International journal of cancer.

[66]  L. Zitvogel,et al.  Calreticulin exposure dictates the immunogenicity of cancer cell death , 2007, Nature Medicine.

[67]  B. Chauffert,et al.  Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients , 2007, Cancer Immunology, Immunotherapy.

[68]  Z. Trajanoski,et al.  Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome , 2006, Science.

[69]  E. Fox.  Management of worsening multiple sclerosis with mitoxantrone: a review. , 2006, Clinical therapeutics.

[70]  L. Zitvogel,et al.  Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death , 2005, The Journal of experimental medicine.

[71]  E. Hayek,et al.  Acute doxorubicin cardiotoxicity. , 2005, The New England journal of medicine.

[72]  R A Knight,et al.  Classification of cell death: recommendations of the Nomenclature Committee on Cell Death , 2005, Cell Death and Differentiation.

[73]  G. Kroemer,et al.  Oxaliplatin-induced mitochondrial apoptotic response of colon carcinoma cells does not require nuclear DNA , 2004, Oncogene.

[74]  H. Weiner,et al.  Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects , 2002, Multiple sclerosis.

[75]  P. Srivastava.  Roles of heat-shock proteins in innate and adaptive immunity , 2002, Nature Reviews Immunology.

[76]  J. Rothman,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 , 2000, The Journal of experimental medicine.

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[78]  R. Weiss.  The anthracyclines: will we ever find a better doxorubicin? , 1992, Seminars in oncology.

[79]  P. Smith,et al.  Long-term inhibition of DNA synthesis and the persistence of trapped topoisomerase II complexes in determining the toxicity of the antitumor DNA intercalators mAMSA and mitoxantrone. , 1990, Cancer research.

[80]  I. Smith,et al.  CARDIOTOXICITY ASSOCIATED WITH - MITOXANTRONE , 1984, The Lancet.

[81]  S. Siegel,et al.  Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells. , 1976, Cancer research.

[82]  L. Zitvogel,et al.  The secret ally: immunostimulation by anticancer drugs , 2012, Nature Reviews Drug Discovery.

[83]  K. Asadullah,et al.  Induction of Foxp3+ regulatory T cells with histone deacetylase inhibitors. , 2009, Cellular immunology.

[84]  B. Chauffert,et al.  Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients , 2007, Cancer Immunology, Immunotherapy.