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Journal ArticleDOI

Cancer immunotherapy – revisited

TL;DR: The recent positive results of clinical trials with novel immunoactive drugs as well as the unexpected finding of a positive interaction between immunotherapy and chemotherapy may herald a new era for the immunotherapy of cancer.
Abstract: Our insight into antitumour immune responses has increased considerably during the past decades, yet the development of immunotherapy as a treatment modality for cancer has been hampered by several factors. These include difficulties in the selection of the optimal dose and schedule, the methods of evaluation, and financial support. Although durable clinical remissions have been observed with various immunotherapeutic strategies, the percentage of patients who benefited from these interventions has remained too small to justify the general use of such strategies. However, the recent positive results of clinical trials with novel immunoactive drugs as well as the unexpected finding of a positive interaction between immunotherapy and chemotherapy may herald a new era for the immunotherapy of cancer.
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Journal ArticleDOI
TL;DR: The molecular and cellular circuitries whereby cytotoxic agents can activate the immune system against cancer, and their therapeutic implications, are discussed.
Abstract: A crucial role of the immune system in cancer progression and response to therapy has recently emerged. Here, Galluzzi and colleagues discuss the immune parameters that may predict the therapeutic response of patients to chemotherapeutics, and review the mechanisms by which current antineoplastic agents activate the immune system against cancer.

591 citations

Journal ArticleDOI
08 Feb 2019
TL;DR: Key steps are highlighted that are bringing the promise of therapeutic cancer vaccines within reach, including learning which vaccine approaches elicit the potent, balanced, and durable CD4 plus CD8 T cell expansion necessary for clinical efficacy.
Abstract: Recent advances in several areas are rekindling interest and enabling progress in the development of therapeutic cancer vaccines. These advances have been made in target selection, vaccine technology, and methods for reversing the immunosuppressive mechanisms exploited by cancers. Studies testing different tumor antigens have revealed target properties that yield high tumor versus normal cell specificity and adequate immunogenicity to affect clinical efficacy. A few tumor-associated antigens, normal host proteins that are abnormally expressed in cancer cells, have been demonstrated to serve as good targets for immunotherapies, although many do not possess the needed specificity or immunogenicity. Neoantigens, which arise from mutated proteins in cancer cells, are truly cancer-specific and can be highly immunogenic, though the vast majority are unique to each patient’s cancer and thus require development of personalized therapies. Lessons from previous cancer vaccine expeditions are teaching us the type and magnitude of immune responses needed, as well as vaccine technologies that can achieve these responses. For example, we are learning which vaccine approaches elicit the potent, balanced, and durable CD4 plus CD8 T cell expansion necessary for clinical efficacy. Exploration of interactions between the immune system and cancer has elucidated the adaptations that enable cancer cells to suppress and evade immune attack. This has led to breakthroughs in the development of new drugs, and, subsequently, to opportunities to combine these with cancer vaccines and dramatically increase patient responses. Here we review this recent progress, highlighting key steps that are bringing the promise of therapeutic cancer vaccines within reach.

429 citations

Journal ArticleDOI
Lorenzo Galluzzi, Erika Vacchelli1, José Manuel Bravo-San Pedro1, Aitziber Buqué1, Laura Senovilla1, Elisa E. Baracco, Norma Bloy, Francesca Castoldi, Jean Pierre Abastado, Patrizia Agostinis2, Ron N. Apte3, Fernando Aranda, Maha Ayyoub1, Philipp Beckhove4, Jean-Yves Blay, Laura Bracci5, Anne Caignard1, Chiara Castelli, Federica Cavallo6, Estaban Celis7, Vincenzo Cerundolo8, Aled Clayton9, Mario P. Colombo, Lisa M. Coussens10, Madhav V. Dhodapkar11, Alexander M.M. Eggermont, Douglas T. Fearon12, Wolf H. Fridman, Jitka Fucikova, Dmitry I. Gabrilovich13, Jérôme Galon, Abhishek D. Garg2, François Ghiringhelli1, François Ghiringhelli14, Giuseppe Giaccone15, Giuseppe Giaccone16, Eli Gilboa17, Sacha Gnjatic18, Axel Hoos19, Anne Hosmalin20, Anne Hosmalin1, Anne Hosmalin21, Dirk Jäger22, Pawel Kalinski23, Klas Kärre24, Oliver Kepp1, Rolf Kiessling24, John M. Kirkwood23, Eva Klein24, Alexander Knuth25, Claire E. Lewis26, Roland S. Liblau27, Roland S. Liblau1, Roland S. Liblau20, Michael T. Lotze23, Enrico Lugli, Jean-Pierre Mach28, Fabrizio Mattei5, Domenico Mavilio29, Ignacio Melero30, Cornelis J. M. Melief31, E. A. Mittendorf32, Lorenzo Moretta33, Adekunke Odunsi34, Hideho Okada35, Anna Karolina Palucka, Marcus E. Peter36, Kenneth J. Pienta37, Angel Porgador3, George C. Prendergast38, George C. Prendergast39, Gabriel A. Rabinovich40, Nicholas P. Restifo15, Naiyer A. Rizvi41, Catherine Sautès-Fridman, Hans Schreiber42, Barbara Seliger43, Hiroshi Shiku44, Bruno Silva-Santos45, Mark J. Smyth46, Mark J. Smyth47, Daniel E. Speiser48, Daniel E. Speiser28, Radek Spisek, Pramod K. Srivastava49, James E. Talmadge50, Eric Tartour, Sjoerd H. van der Burg31, Benoît Van den Eynde48, Benoît Van den Eynde51, Richard G. Vile52, Hermann Wagner53, Jeffrey S. Weber54, Theresa L. Whiteside23, Jedd D. Wolchok41, Jedd D. Wolchok55, Laurence Zitvogel, Weiping Zou56, Guido Kroemer 
French Institute of Health and Medical Research1, Katholieke Universiteit Leuven2, Ben-Gurion University of the Negev3, German Cancer Research Center4, Istituto Superiore di Sanità5, University of Turin6, Georgia Regents University7, University of Oxford8, Cardiff University9, Oregon Health & Science University10, Yale University11, Cold Spring Harbor Laboratory12, University of Pennsylvania13, University of Burgundy14, National Institutes of Health15, Georgetown University16, University of Miami17, Icahn School of Medicine at Mount Sinai18, GlaxoSmithKline19, Centre national de la recherche scientifique20, University of Paris21, Heidelberg University22, University of Pittsburgh23, Karolinska Institutet24, Hamad Medical Corporation25, University of Sheffield26, Centre Hospitalier Universitaire de Toulouse27, University of Lausanne28, University of Milan29, University of Navarra30, Leiden University31, University of Texas Health Science Center at Houston32, Istituto Giannina Gaslini33, Roswell Park Cancer Institute34, University of California, San Francisco35, Northwestern University36, Johns Hopkins University37, Thomas Jefferson University38, Main Line Health39, University of Buenos Aires40, Memorial Sloan Kettering Cancer Center41, University of Chicago42, Martin Luther University of Halle-Wittenberg43, Mie University44, University of Lisbon45, QIMR Berghofer Medical Research Institute46, University of Queensland47, Ludwig Institute for Cancer Research48, University of Connecticut49, University of Nebraska Medical Center50, Université catholique de Louvain51, Mayo Clinic52, Technische Universität München53, University of South Florida54, Cornell University55, University of Michigan56
TL;DR: A critical, integrated classification of anticancer immunotherapies is proposed and the clinical relevance of these approaches is discussed.
Abstract: During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.

375 citations

Journal ArticleDOI
TL;DR: Rec retrospective clinical analyses revealed that the administration of the CG digoxin during chemotherapy had a positive impact on overall survival in cohorts of breast, colorectal, head and neck, and hepatocellular carcinoma patients, especially when they were treated with agents other than anthracyclines and oxaliplatin.
Abstract: Some successful chemotherapeutics, notably anthracyclines and oxaliplatin, induce a type of cell stress and death that is immunogenic, hence converting the patient's dying cancer cells into a vaccine that stimulates antitumor immune responses. By means of a fluorescence microscopy platform that allows for the automated detection of the biochemical hallmarks of such a peculiar cell death modality, we identified cardiac glycosides (CGs) as exceptionally efficient inducers of immunogenic cell death, an effect that was associated with the in- hibition of the plasma membrane Na + - and K + -dependent adenosine triphosphatase (Na + /K + -ATPase). CGs ex- acerbated the antineoplastic effects of DNA-damaging agents in immunocompetent but not immunodeficient mice. Moreover, cancer cells succumbing to a combination of chemotherapy plus CGs could vaccinate synge- neic mice against a subsequent challenge with living cells of the same type. Finally, retrospective clinical analy- ses revealed that the administration of the CG digoxin during chemotherapy had a positive impact on overall survival in cohorts of breast, colorectal, head and neck, and hepatocellular carcinoma patients, especially when they were treated with agents other than anthracyclines and oxaliplatin.

345 citations

Journal ArticleDOI
TL;DR: The literature on the immunogenic effects of platinum is reviewed, the clinical advances using platinum as a cytotoxic compound with immune adjuvant properties are summarized, the limitations to these studies are discussed, and the gaps in the understanding of the immunologic effects of these drugs are discussed.
Abstract: The platinum-based drugs cisplatin, carboplatin, and oxaliplatin belong to the most widely used chemotherapeutics in oncology, showing clinical efficacy against many solid tumors. Their main mechanism of action is believed to be the induction of cancer cell apoptosis as a response to their covalent binding to DNA. In recent years, this picture has increased in complexity, based on studies indicating that cellular molecules other than DNA may potentially act as targets, and that part of the antitumor effects of platinum drugs occurs through modulation of the immune system. These immunogenic effects include modulation of STAT signaling; induction of an immunogenic type of cancer cell death through exposure of calreticulin and release of ATP and high-mobility group protein box-1 (HMGB-1); and enhancement of the effector immune response through modulation of programmed death receptor 1-ligand and mannose-6-phosphate receptor expression. Both basic and clinical studies indicate that at least part of the antitumor efficacy of platinum chemotherapeutics may be due to immune potentiating mechanisms. Clinical studies exploiting this novel mechanism of action of these old cancer drugs have been initiated. Here, we review the literature on the immunogenic effects of platinum, summarize the clinical advances using platinum as a cytotoxic compound with immune adjuvant properties, and discuss the limitations to these studies and the gaps in our understanding of the immunologic effects of these drugs. Clin Cancer Res; 20(11); 2831-7. ©2014 AACR.

341 citations


Cites background from "Cancer immunotherapy – revisited"

  • ...motherapeutics could have beneficial effects on the immune system (25), we investigated their effects on dendritic cells (DC) in vitro....

    [...]

References
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Journal ArticleDOI
TL;DR: The revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions, and a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included.

20,760 citations

Journal ArticleDOI
TL;DR: A model by which a combined assessment of all existing lesions, characterized by target lesions and nontarget lesions, is used to extrapolate an overall response to treatment is proposed, which is largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines.
Abstract: Anticancer cytotoxic agents go through a process by which their antitumor activity-on the basis of the amount of tumor shrinkage they could generate-has been investigated. In the late 1970s, the International Union Against Cancer and the World Health Organization introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical research combined forces to tackle the review of these criteria on the basis of the experience and knowledge acquired since then. After several years of intensive discussions, a new set of guidelines is ready that will supersede the former criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines. This special article also provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified, briefly within the guidelines and in more detail in Appendix I. All other aspects of response evaluation have been discussed, reviewed, and amended whenever appropriate.

14,926 citations

Journal ArticleDOI
TL;DR: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma.
Abstract: Background An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab — which blocks cytotoxic T-lymphocyte–associated antigen 4 to potentiate an antitumor T-cell response — administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. Methods A total of 676 HLA-A*0201–positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. Results The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P = 0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P = 0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. Conclusions Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)

13,081 citations


"Cancer immunotherapy – revisited" refers background in this paper

  • ...Ipilimumab was studied in a large placebo-controlled randomized trial in pretreated patients with metastatic melanoma, and it was the first treatment in 30 years to show a survival benefit in this diseas...

    [...]

Journal ArticleDOI
TL;DR: Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation in a phase 3 randomized clinical trial.
Abstract: At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. Conclusions Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann–La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.)

6,773 citations

Journal ArticleDOI
07 Dec 2000-Nature
TL;DR: It is shown that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9, and vertebrate immune systems appear to have evolved a specific Toll- like receptor that distinguishes bacterial DNA from self-DNA.
Abstract: DNA from bacteria has stimulatory effects on mammalian immune cells, which depend on the presence of unmethylated CpG dinucleotides in the bacterial DNA. In contrast, mammalian DNA has a low frequency of CpG dinucleotides, and these are mostly methylated; therefore, mammalian DNA does not have immuno-stimulatory activity. CpG DNA induces a strong T-helper-1-like inflammatory response. Accumulating evidence has revealed the therapeutic potential of CpG DNA as adjuvants for vaccination strategies for cancer, allergy and infectious diseases. Despite its promising clinical use, the molecular mechanism by which CpG DNA activates immune cells remains unclear. Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. TLR9-deficient (TLR9-/-) mice did not show any response to CpG DNA, including proliferation of splenocytes, inflammatory cytokine production from macrophages and maturation of dendritic cells. TLR9-/- mice showed resistance to the lethal effect of CpG DNA without any elevation of serum pro-inflammatory cytokine levels. The in vivo CpG-DNA-mediated T-helper type-1 response was also abolished in TLR9-/- mice. Thus, vertebrate immune systems appear to have evolved a specific Toll-like receptor that distinguishes bacterial DNA from self-DNA.

6,188 citations

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