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1.  Characterization of the Microenvironment in Positive and Negative Sentinel Lymph Nodes from Melanoma Patients 
PLoS ONE  2015;10(7):e0133363.
Melanomas are aggressive skin tumors characterized by high metastatic potential. Our previous results indicate that Natural Killer (NK) cells may control growth of melanoma. The main defect of blood NK cells was a decreased expression of activating NCR1/NKp46 receptor and a positive correlation of NKp46 expression with disease outcome in stage IV melanoma patients was found. In addition, in stage III melanoma patients, we identified a new subset of mature NK cells in macro-metastatic Lymph nodes (LN). In the present studies, we evaluated the numbers of NK cells infiltrating primary cutaneous melanoma and analyzed immune cell subsets in a series of sentinel lymph nodes (SLN). First, we show that NKp46+ NK cells infiltrate primary cutaneous melanoma. Their numbers were related to age of patients and not to Breslow thickness. Then, a series of patients with tumor-negative or -positive sentinel lymph nodes matched for Breslow thickness of the cutaneous melanoma was constituted. We investigated the distribution of macrophages (CD68), endothelial cells, NK cells, granzyme B positive (GrzB+) cells and CD8+ T cells in the SLN. Negative SLN (SLN-) were characterized by frequent adipose involution and follicular hyperplasia compared to positive SLN (SLN+). High densities of macrophages and endothelial cells (CD34), prominent in SLN+, infiltrate SLN and may reflect a tumor favorable microenvironment. Few but similar numbers of NK and GrzB+ cells were found in SLN- and SLN+: NK cells and GrzB+ cells were not correlated. Numerous CD8+ T cells infiltrated SLN with a trend for higher numbers in SLN-. Moreover, CD8+ T cells and GrzB+ cells correlated in SLN- not in SLN+. We also observed that the numbers of CD8+ T cells negatively correlated with endothelial cells in SLN-. The numbers of NK, GrzB+ or CD8+ T cells had no significant impact on overall survival. However, we found that the 5 year-relapse rate was higher in SLN with higher numbers of NK cells.
doi:10.1371/journal.pone.0133363
PMCID: PMC4517810  PMID: 26218530
2.  An autophagy-dependent anticancer immune response determines the efficacy of melanoma chemotherapy 
Oncoimmunology  2014;3(7):e944047.
There is ample experimental and clinical evidence that chemotherapies are more efficient if they succeed in (re)activating immune surveillance, hence triggering a long-term immune response against residual tumor cells. Most of the preclinical evidence supporting this notion has been obtained with transplantable cancers, for which it has been shown that chemotherapy-induced autophagy in cancer cells is mandatory for the recruitment of myeloid cells into the tumor bed and the subsequent T lymphocyte-mediated reduction in tumor growth. Here, we characterized the chemotherapeutic response of melanomas caused by 4-hydroxy-tamoxifen-induced expression of the Cre recombinase in melanocytes that results in the activation of oncogenic Braf together with the inactivation of the tumor suppressor Pten, as well as the optional inactivation of the essential autophagy gene Atg7. Systemic chemotherapy with the anthracycline Mitoxantrone (MTX) reduced the growth of autophagy-competent melanomas (genotype: BrafCa/+; Ptenfl/fl; Atg7+/+), yet failed to affect the progression of autophagy-deficient melanomas (genotype: BrafCa/+; Ptenfl/fl; Atg7fl/fl). The growth-inhibitory effect of MTX on autophagy-competent melanomas was abolished by the combined depletion of CD4+ or CD8+ T lymphocytes. In conclusion, it appears that the success of chemotherapy against “spontaneous,” genetically induced cancers is governed by the same rules as those applicable to transplantable tumors.
doi:10.4161/21624011.2014.944047
PMCID: PMC4292732  PMID: 25610726
anthracycline; autophagy; cancer
3.  Immune infiltrate in cancer 
Aging (Albany NY)  2015;7(6):358-359.
PMCID: PMC4505161  PMID: 26143478
4.  Meta-analysis of organ-specific differences in the structure of the immune infiltrate in major malignancies 
Oncotarget  2015;6(14):11894-11909.
Anticancer immunosurveillance is one of the major endogenous breaks of tumor progression. Here, we analyzed gene expression pattern indicative of the presence of distinct leukocyte subtypes within four cancer types (breast cancer, colorectal carcinoma, melanoma, and non-small cell lung cancer) and 20 different microarray datasets corresponding to a total of 3471 patients. Multiple metagenes reflecting the presence of such immune cell subtypes were highly reproducible across distinct cohorts. Nonetheless, there were sizable differences in the correlation patterns among such immune-relevant metagenes across distinct malignancies. The reproducibility of the correlations among immune-relevant metagenes was highest in breast cancer (followed by colorectal cancer, non-small cell lung cancer and melanoma), reflecting the fact that mammary carcinoma has an intrinsically better prognosis than the three other malignancies. Among breast cancer patients, we found that the expression of a lysosomal enzyme-related metagene centered around ASAH1 (which codes for N-acylsphingosine amidohydrolase-1, also called acid ceramidase) exhibited a higher correlation with multiple immune-relevant metagenes in patients that responded to neoadjuvant chemotherapy than in non-responders. Altogether, this meta-analysis revealed novel organ-specific features of the immune infiltrate in distinct cancer types, as well as a strategy for defining new prognostic biomarkers.
PMCID: PMC4494912  PMID: 26059437
meta-analysis of microarrays; breast cancer; colorectal carcinoma; melanoma; non-small cell lung cancer
5.  Trial Watch 
Oncoimmunology  2014;3:e28344.
The expression “adoptive cell transfer” (ACT) is commonly employed to indicate an immunotherapeutic regimen involving the isolation of autologous blood-borne or tumor-infiltrating lymphocytes, their selection/expansion/activation ex vivo, and their reinfusion into the patient, most often in the context of lymphodepleting pre-conditioning and in combination with immunostimulatory treatments. Optionally, the cellular material for ACT is genetically manipulated before expansion to (1) target specific tumor-associated antigens; (2) endogenously express immunostimulatory molecules; and/or (3) persist for long periods upon reinfusion. Consistent efforts have been dedicated at the amelioration of this immunotherapeutic regimen throughout the past decade, resulting in the establishment of ever more efficient and safer ACT protocols. Accordingly, the number of clinical trials testing ACT in oncological indications does not cease to increase. In this Trial Watch, we summarize recent developments in this exciting area of research, covering both high-impact studies that have been published during the last 12 months and clinical trials that have been launched in the same period to evaluate the safety and therapeutic potential of ACT in cancer patients.
doi:10.4161/onci.28344
PMCID: PMC4063152  PMID: 25050207
CD19; chimeric antigen receptor; cytokine-induced killer cells; interleukin-2; peripheral blood lymphocytes
6.  Screening of novel immunogenic cell death inducers within the NCI Mechanistic Diversity Set 
Oncoimmunology  2014;3:e28473.
Immunogenic cell death (ICD) inducers can be defined as agents that exert cytotoxic effects while stimulating an immune response against dead cell-associated antigens. When initiated by anthracyclines, ICD is accompanied by stereotyped molecular changes, including the pre-apoptotic exposure of calreticulin (CRT) on the cell surface, the lysosomal secretion of ATP during the blebbing phase of apoptosis, and the release of high mobility group box 1 (HMGB1) from dead cells. By means of genetically engineered human osteosarcoma U2OS cells, we screened the 879 anticancer compounds of the National Cancer Institute (NCI) Mechanistic Diversity Set for their ability to promote all these hallmarks of ICD in vitro. In line with previous findings from our group, several cardiac glycosides exhibit a robust propensity to elicit the major manifestations of ICD in cultured neoplastic cells. This screen pointed to septacidin, an antibiotic produced by Streptomyces fibriatus, as a novel putative inducer of ICD. In low-throughput validation experiments, septacidin promoted CRT exposure, ATP secretion and HGMB1 release from both U2OS cells and murine fibrosarcoma MCA205 cells. Moreover, septacidin-killed MCA205 cells protected immunocompetent mice against a re-challenge with living cancer cells of the same type. Finally, the antineoplastic effects of septacidin on established murine tumors were entirely dependent on T lymphocytes. Altogether, these results underscore the suitability of the high-throughput screening system described here for the identification of novel ICD inducers.
doi:10.4161/onci.28473
PMCID: PMC4063139  PMID: 25050214
apoptosis; autophagy; C57BL/6 mice; dendritic cells; HTS; mitoxantrone
7.  Trial Watch 
Oncoimmunology  2014;3:e28185.
During the past 2 decades, the possibility that preparations capable of eliciting tumor-specific immune responses would mediate robust therapeutic effects in cancer patients has received renovated interest. In this context, several approaches to vaccinate cancer patients against their own malignancies have been conceived, including the administration of DNA constructs coding for one or more tumor-associated antigens (TAAs). Such DNA-based vaccines conceptually differ from other types of gene therapy in that they are not devised to directly kill cancer cells or sensitize them to the cytotoxic activity of a drug, but rather to elicit a tumor-specific immune response. In spite of an intense wave of preclinical development, the introduction of this immunotherapeutic paradigm into the clinical practice is facing difficulties. Indeed, while most DNA-based anticancer vaccines are well tolerated by cancer patients, they often fail to generate therapeutically relevant clinical responses. In this Trial Watch, we discuss the latest advances on the use of DNA-based vaccines in cancer therapy, discussing the literature that has been produced around this topic during the last 13 months as well as clinical studies that have been launched in the same time frame to assess the actual therapeutic potential of this intervention.
doi:10.4161/onci.28185
PMCID: PMC4008456  PMID: 24800178
cross-presentation; dendritic cells; electroporation; Listeria monocytogenes; mucosal immunity; Saccharomyces cerevisiae
8.  Synthetic induction of immunogenic cell death by genetic stimulation of endoplasmic reticulum stress 
Oncoimmunology  2014;3:e28276.
Cis-diamminedichloridoplatinum(II) (CDDP), commonly referred to as cisplatin, is a chemotherapeutic drug used for the treatment of a wide range of solid cancers. CDDP is a relatively poor inducer of immunogenic cell death (ICD), a cell death modality that converts dying cells into a tumor vaccine, stimulating an immune response against residual cancer cells that permits long-lasting immunity and a corresponding reduction in tumor growth. The incapacity of CDDP to trigger ICD is at least partially due to its failure to stimulate the premortem endoplasmic reticulum (ER)-stress response required for the externalization of the “eat-me” signal calreticulin (CRT) on the surface of dying cancer cells. Here, we developed a murine cancer cell line genetically modified to express the ER resident protein reticulon-1c (Rtn-1c) by virtue of tetracycline induction and showed that enforced Rtn-1c expression combined with CDDP treatment promoted CRT externalization to the surface of cancer cells. In contrast to single agent treatments, the tetracycline-mediated Rtn-1c induction combined with CDDP chemotherapy stimulated ICD as measured by the capacity of dying tumor cells, inoculated into syngenic immunocompetent mice, to mount an immune response to tumor re-challenge 1 week later. More importantly, established tumors, forced to constitutively express Rtn-1c in vivo by continuous treatment with tetracycline, became responsive to CDDP and exhibited a corresponding reduction in the rate of tumor growth. The combined therapeutic effects of Rtn-1c induction with CDDP treatment was only detected in the context of an intact immune system and not in nu/nu mice lacking thymus-dependent T lymphocytes. Altogether, these results indicate that the artificial or “synthetic” induction of immunogenic cell death by genetic manipulation of the ER-stress response can improve the efficacy of chemotherapy with CDDP by stimulating anticancer immunity.
doi:10.4161/onci.28276
PMCID: PMC4063145  PMID: 25050202
cancer; calreticulin; chemotherapy; cisplatin; endoplasmic reticulum stress; reticulon 1C
9.  Trial Watch 
Oncoimmunology  2014;3:e27878.
Accumulating evidence suggests that the clinical efficacy of selected anticancer drugs, including conventional chemotherapeutics as well as targeted anticancer agents, originates (at least in part) from their ability to elicit a novel or reinstate a pre-existing tumor-specific immune response. One of the mechanisms whereby chemotherapy can stimulate the immune system to recognize and destroy malignant cells is commonly known as immunogenic cell death (ICD). Cancer cells succumbing to ICD are de facto converted into an anticancer vaccine and as such elicit an adaptive immune response. Several common chemotherapeutics share the ability of triggering ICD, as demonstrated in vaccination experiments relying on immunocompetent mice and syngeneic cancer cells. A large number of ongoing clinical trials involve such ICD inducers, often (but not always) as they are part of the gold standard therapeutic approach against specific neoplasms. In this Trial Watch, we summarize the latest advances on the use of cyclophosphamide, doxorubicin, epirubicin, oxaliplatin, and mitoxantrone in cancer patients, discussing high-impact studies that have been published during the last 13 months as well as clinical trials that have been initiated in the same period to assess the antineoplastic profile of these immunogenic drugs as off-label therapeutic interventions.
doi:10.4161/onci.27878
PMCID: PMC4008470  PMID: 24800173
ATP; autophagy; calreticulin; dendritic cells; epothilone B; HMGB1
10.  Immune-related gene signatures predict the outcome of neoadjuvant chemotherapy 
Oncoimmunology  2014;3:e27884.
There is ample evidence that neoadjuvant chemotherapy of breast carcinoma is particularly efficient if the tumor presents signs of either a pre-existent or therapy-induced anticancer immune response. Antineoplastic chemotherapies are particularly beneficial if they succeed in inducing immunogenic cell death, hence converting the tumor into its own therapeutic vaccine. Immunogenic cell death is characterized by a pre-mortem stress response including endoplasmic reticulum stress and autophagy. Based on these premises, we attempted to identify metagenes that reflect an intratumoral immune response or local stress responses in the transcriptomes of breast cancer patients. No consistent correlations between immune- and stress-related metagenes could be identified across several cohorts of patients, representing a total of 1045 mammary carcinomas. Moreover, few if any, of the stress-relevant metagenes influenced the probability of pathological complete response to chemotherapy. In contrast, several immune-relevant metagenes had a significant positive impact on response rates. This applies in particular to a CXCL13-centered, highly reproducible metagene signature reflecting the intratumoral presence of interferon-γ-producing T cells.
doi:10.4161/onci.27884
PMCID: PMC4004621  PMID: 24790795
autophagy; breast cancer; colorectal cancer; endoplasmic stress; immunogenic cell death; tumor-infiltrating lymphocytes
11.  Why should we need the gut microbiota to respond to cancer therapies? 
Oncoimmunology  2014;3:e27574.
Cyclophosphamide, one of the most efficient tumoricidal, antiangiogenic, and immunostimulatory drugs employed to date mediates part of its effects through intestinal bacteria, against which the host becomes immunized during treatment. Our recent work suggests that anti-commensal effector pTH17 and memory TH1 CD4+ T-cell responses are indispensable for optimal anticancer effects as mediated by cyclophosphamide.
doi:10.4161/onci.27574
PMCID: PMC4006853  PMID: 24800167
antibiotics; cancer; chemotherapy; Gram-positive bacteria; immunomodulatory regimen; microbiota; pTh17
12.  Classification of current anticancer immunotherapies 
Galluzzi, Lorenzo | Vacchelli, Erika | Pedro, José-Manuel Bravo-San | Buqué, Aitziber | Senovilla, Laura | Baracco, Elisa Elena | Bloy, Norma | Castoldi, Francesca | Abastado, Jean-Pierre | Agostinis, Patrizia | Apte, Ron N. | Aranda, Fernando | Ayyoub, Maha | Beckhove, Philipp | Blay, Jean-Yves | Bracci, Laura | Caignard, Anne | Castelli, Chiara | Cavallo, Federica | Celis, Estaban | Cerundolo, Vincenzo | Clayton, Aled | Colombo, Mario P. | Coussens, Lisa | Dhodapkar, Madhav V. | Eggermont, Alexander M. | Fearon, Douglas T. | Fridman, Wolf H. | Fučíková, Jitka | Gabrilovich, Dmitry I. | Galon, Jérôme | Garg, Abhishek | Ghiringhelli, François | Giaccone, Giuseppe | Gilboa, Eli | Gnjatic, Sacha | Hoos, Axel | Hosmalin, Anne | Jäger, Dirk | Kalinski, Pawel | Kärre, Klas | Kepp, Oliver | Kiessling, Rolf | Kirkwood, John M. | Klein, Eva | Knuth, Alexander | Lewis, Claire E. | Liblau, Roland | Lotze, Michael T. | Lugli, Enrico | Mach, Jean-Pierre | Mattei, Fabrizio | Mavilio, Domenico | Melero, Ignacio | Melief, Cornelis J. | Mittendorf, Elizabeth A. | Moretta, Lorenzo | Odunsi, Adekunke | Okada, Hideho | Palucka, Anna Karolina | Peter, Marcus E. | Pienta, Kenneth J. | Porgador, Angel | Prendergast, George C. | Rabinovich, Gabriel A. | Restifo, Nicholas P. | Rizvi, Naiyer | Sautès-Fridman, Catherine | Schreiber, Hans | Seliger, Barbara | Shiku, Hiroshi | Silva-Santos, Bruno | Smyth, Mark J. | Speiser, Daniel E. | Spisek, Radek | Srivastava, Pramod K. | Talmadge, James E. | Tartour, Eric | Van Der Burg, Sjoerd H. | Van Den Eynde, Benoît J. | Vile, Richard | Wagner, Hermann | Weber, Jeffrey S. | Whiteside, Theresa L. | Wolchok, Jedd D. | Zitvogel, Laurence | Zou, Weiping | Kroemer, Guido
Oncotarget  2014;5(24):12472-12508.
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.
PMCID: PMC4350348  PMID: 25537519
adoptive cell transfer; checkpoint blockers; dendritic cell-based interventions; DNA-based vaccines; immunostimulatory cytokines; peptide-based vaccines; oncolytic viruses; Toll-like receptor agonists
13.  NCR3/NKp30 contributes to pathogenesis in primary Sjögren’s syndrome 
Science translational medicine  2013;5(195):195ra96.
Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease characterized by a lymphocytic exocrinopathy. However, patients often have evidence of systemic autoimmunity and they are at markedly increased risk for the development of non- Hodgkin’s lymphoma. Similar to other autoimmune disorders, a strong interferon (IFN) signature is present among subsets of pSS patients, though the precise etiology remains uncertain. NCR3/NKp30 is a NK-specific activating receptor regulating the cross-talk between NK and dendritic cells and type II IFN secretion. We performed a case-control study of genetic polymorphisms of the NCR3/NKp30 gene and found that rs11575837 (G>A) residing in the promoter was associated with reduced gene transcription and function as well as protection to pSS. We also demonstrated that circulating levels of NCR3/NKp30 were markedly increased among pSS patients compared with controls and correlated with higher NCR3/NKp30 but not CD16-dependent IFN-γ secretion by NK cells. Excess accumulation of NK cells in minor salivary glands correlated with the severity of the exocrinopathy. B7H6, the ligand of NKp30, was expressed by salivary epithelial cells. These findings suggest that NK cells may promote an NKp30-dependent inflammatory state in salivary glands, and that blockade of the B7H6/NKp30 axis could be clinically relevant in pSS.
doi:10.1126/scitranslmed.3005727
PMCID: PMC4237161  PMID: 23884468
Sjögren’s syndrome; autoimmunity; NK cells; innate immunity; NKp30/NCR3
14.  Trial Watch 
Oncoimmunology  2014;3:e29179.
Toll-like receptors (TLRs) are an evolutionarily conserved group of enzymatically inactive, single membrane-spanning proteins that recognize a wide panel of exogenous and endogenous danger signals. Besides constituting a crucial component of the innate immune response to bacterial and viral pathogens, TLRs appear to play a major role in anticancer immunosurveillance. In line with this notion, several natural and synthetic TLR ligands have been intensively investigated for their ability to boost tumor-targeting immune responses elicited by a variety of immunotherapeutic and chemotherapeutic interventions. Three of these agents are currently approved by the US Food and Drug Administration (FDA) or equivalent regulatory agencies for use in cancer patients: the so-called bacillus Calmette-Guérin, monophosphoryl lipid A, and imiquimod. However, the number of clinical trials testing the therapeutic potential of both FDA-approved and experimental TLR agonists in cancer patients is stably decreasing, suggesting that drug developers and oncologists are refocusing their interest on alternative immunostimulatory agents. Here, we summarize recent findings on the use of TLR agonists in cancer patients and discuss how the clinical evaluation of FDA-approved and experimental TLR ligands has evolved since the publication of our first Trial Watch dealing with this topic.
doi:10.4161/onci.29179
PMCID: PMC4091055  PMID: 25083332
BCG; CpG-7909; Hiltonol™; damage-associated molecular patterns; polyI:C; resiquimod
15.  Mucosal Imprinting of Vaccine-Induced CD8+ T Cells Is Crucial to Inhibit the Growth of Mucosal Tumors 
Science translational medicine  2013;5(172):172ra20.
Although many human cancers are located in mucosal sites, most cancer vaccines are tested against subcutaneous tumors in preclinical models. We therefore wondered whether mucosa-specific homing instructions to the immune system might influence mucosal tumor outgrowth. We showed that the growth of orthotopic head and neck or lung cancers was inhibited when a cancer vaccine was delivered by the intranasal mucosal route but not the intramuscular route. This antitumor effect was dependent on CD8+ T cells. Indeed, only intranasal vaccination elicited mucosal-specific CD8+ T cells expressing the mucosal integrin CD49a. Blockade of CD49a decreased intratumoral CD8+ T cell infiltration and the efficacy of cancer vaccine on mucosal tumor. We then showed that after intranasal vaccination, dendritic cells from lung parenchyma, but not those from spleen, induced the expression of CD49a on cocultured specific CD8+ T cells. Tumor-infiltrating lymphocytes from human mucosal lung cancer also expressed CD49a, which supports the relevance and possible extrapolation of these results in humans. We thus identified a link between the route of vaccination and the induction of a mucosal homing program on induced CD8+ T cells that controlled their trafficking. Immunization route directly affected the efficacy of the cancer vaccine to control mucosal tumors.
doi:10.1126/scitranslmed.3004888
PMCID: PMC4086646  PMID: 23408053
16.  The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide 
Science (New York, N.Y.)  2013;342(6161):971-976.
Cyclophosphamide is one of several clinically important cancer drugs whose therapeutic efficacy is due in part to their ability to stimulate anti-tumor immune responses. Studying mouse models, we demonstrate that cyclophosphamide alters the composition of microbiota in the small intestine and induces the translocation of selected species of Gram+ bacteria into secondary lymphoid organs. There, these bacteria stimulate the generation of a specific subset of “pathogenic” T helper 17 (pTh17) cells and memory Th1 immune responses. Tumor-bearing mice that were germ-free or that had been treated with antibiotics to kill Gram+ bacteria showed a reduction in pTh17 responses and their tumors were resistant to cyclophosphamide. Adoptive transfer of pTh17 cells partially restored the anti-tumor efficacy of cyclophosphamide. These results suggest that the gut microbiota help shape the anticancer immune response.
doi:10.1126/science.1240537
PMCID: PMC4048947  PMID: 24264990
17.  Trial watch 
Oncoimmunology  2014;3:e29030.
Tumor-targeting immune responses provide a significant contribution to (when they do not entirely account for) the clinical activity of diverse antineoplastic regimens, encompassing not only a large panel of immunotherapeutic strategies but also conventional cytotoxic molecules, targeted anticancer agents and irradiation. In line with this notion, several approaches have been devised to elicit novel or boost existing anticancer immune responses, including the administration of immunomodulatory cytokines. Such a relatively unspecific intervention suffices to mediate clinical effects in (at least a subset of) patients bearing particularly immunogenic tumors, like melanoma and renal cell carcinoma. More often, however, immunostimulatory cytokines are administered to boost the immunogenic potential of other agents, including (but not limited to) immune checkpoint-blocking antibodies, anticancer vaccines, oncolytic viruses and immunogenic chemotherapeutics. Here, we summarize the latest advances in the clinical development of recombinant cytokines as an immunomodulatory intervention for cancer therapy.
doi:10.4161/onci.29030
PMCID: PMC4091551  PMID: 25083328
GM-CSF; IFN; IL-2; TGFβ1; TNFα; chemokines
18.  Trial Watch: 
Oncoimmunology  2014;3:e28694.
Oncolytic viruses are natural or genetically modified viral species that selectively infect and kill neoplastic cells. Such an innate or exogenously conferred specificity has generated considerable interest around the possibility to employ oncolytic viruses as highly targeted agents that would mediate cancer cell-autonomous anticancer effects. Accumulating evidence, however, suggests that the therapeutic potential of oncolytic virotherapy is not a simple consequence of the cytopathic effect, but strongly relies on the induction of an endogenous immune response against transformed cells. In line with this notion, superior anticancer effects are being observed when oncolytic viruses are engineered to express (or co-administered with) immunostimulatory molecules. Although multiple studies have shown that oncolytic viruses are well tolerated by cancer patients, the full-blown therapeutic potential of oncolytic virotherapy, especially when implemented in the absence of immunostimulatory interventions, remains unclear. Here, we cover the latest advances in this active area of translational investigation, summarizing high-impact studies that have been published during the last 12 months and discussing clinical trials that have been initiated in the same period to assess the therapeutic potential of oncolytic virotherapy in oncological indications.
doi:10.4161/onci.28694
PMCID: PMC4091053  PMID: 25097804
adenovirus; ColoAd1; mesenchymal stem cells; MV-NIS; reolysin; talimogene laherparepvec
19.  Treatment of gastric peritoneal carcinomatosis by combining complete surgical resection of lesions and intraperitoneal immunotherapy using catumaxomab 
BMC Cancer  2014;14:148.
Background
The peritoneum is one of the most frequent sites of recurrent gastric carcinoma after curative treatment, despite the administration of pre- and/or postoperative systemic chemotherapy. Indeed, the prognosis of peritoneal carcinomatosis from gastric carcinoma continues to be poor, with a median survival of less than one year with systemic chemotherapy. Whereas the prognosis of peritoneal carcinomatosis from colorectal cancer has changed with the development of locally administered hyperthermic intraperitoneal chemotherapy (HIPEC), survival results following carcinomatosis from gastric cancer remain disappointing, yielding a 5-year survival rate of less than 20%. Innovative surgical therapies such as intraperitoneal immunotherapy therefore need to be developed for the immediate postoperative period after complete cytoreductive surgery. In a recent randomised study, a clinical effect was obtained after intraperitoneal infusion of catumaxomab in patients with malignant ascites, notably from gastric carcinoma. Catumaxomab, a nonhumanized chimeric antibody, is characterized by its unique ability to bind to three different types of cells: tumour cells expressing the epithelial cell adhesion molecule (EpCAM), T lymphocytes (CD3) and also accessory cells (Fcγ receptor). Because the peritoneum is an immunocompetent organ and up to 90% of gastric carcinomas express EpCAM, intraperitoneal infusion of catumaxomab after complete resection of all macroscopic disease (as defined in the treatment of carcinomatosis from colorectal cancer) could therefore efficiently treat microscopic residual disease.
Methods/design
The aim of this randomized phase II study is to assess 2-year overall survival after complete resection of limited carcinomatosis synchronous with gastric carcinoma, followed by an intraperitoneal infusion of catumaxomab with different total doses administered in each of the 2 arms. Close monitoring of peri-opertive mortality, morbidity and early surgical re-intervention will be done with stopping rules. Besides this analysis, translational research will be conducted to determine immunological markers of catumaxomab efficacy and to correlate these markers with clinical efficacy.
doi:10.1186/1471-2407-14-148
PMCID: PMC3973895  PMID: 24589307
Peritoneal carcinomatosis; Gastric carcinoma; Intraperitoneal chemotherapy; Immunotherapy; Catumaxomab
20.  Trial Watch 
Oncoimmunology  2014;3:e27297.
Immunostimulatory monoclonal antibodies (mAbs) exert antineoplastic effects by eliciting a novel or reinstating a pre-existing antitumor immune response. Most often, immunostimulatory mAbs activate T lymphocytes or natural killer (NK) cells by inhibiting immunosuppressive receptors, such as cytotoxic T lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1 (PDCD1, best known as PD-1), or by engaging co-stimulatory receptors, like CD40, tumor necrosis factor receptor superfamily, member 4 (TNFRSF4, best known as OX40) or TNFRSF18 (best known as GITR). The CTLA4-targeting mAb ipilimumab has been approved by the US Food and Drug Administration for use in patients with unresectable or metastatic melanoma in 2011. The therapeutic profile of ipilimumab other CTLA4-blocking mAbs, such as tremelimumab, is currently being assessed in subjects affected by a large panel of solid neoplasms. In the last few years, promising clinical results have also been obtained with nivolumab, a PD-1-targeting mAb formerly known as BMS-936558. Accordingly, the safety and efficacy of nivolumab and other PD-1-blocking molecules are being actively investigated. Finally, various clinical trials are underway to test the therapeutic potential of OX40- and GITR-activating mAbs. Here, we summarize recent findings on the therapeutic profile of immunostimulatory mAbs and discuss clinical trials that have been launched in the last 14 months to assess the therapeutic profile of these immunotherapeutic agents.
doi:10.4161/onci.27297
PMCID: PMC3961485  PMID: 24701370
CD137; checkpoint blockade; immunogenic chemotherapy; immunosuppression; lirilumab; IPH2101; PD-L1
21.  Chemokines and chemokine receptors required for optimal responses to anticancer chemotherapy 
Oncoimmunology  2014;3:e27663.
Depending on tumor type, stage and immunological contexture, the inhibition of chemokines or their receptors may yield positive or deleterious effects on disease progression. We have recently demonstrated in several murine models of anthracycline-based chemotherapy that the inhibition of chemokine (C-C motif) ligand 2 (CCL2) or chemokine (C-C motif) receptor 2 (CCR2) may impair the elicitation of anticancer immune responses that contribute to therapeutic success.
doi:10.4161/onci.27663
PMCID: PMC4008453  PMID: 24800170
ATP; autophagy; cancer stem cells; immunogenic cell death; immunosurveillance; γδ T lymphocytes
22.  Harnessing the immune system to provide long-term survival in patients with melanoma and other solid tumors 
Oncoimmunology  2014;3:e27560.
Accumulating data from patients treated with checkpoint inhibitors and other immunomodulatory agents indicate that harnessing the power of the immune system is integral to achieve improve long-term cancer containment rates and prolong patient survival. Due to their mechanism of action, immunotherapeutic approaches have the potential to be effective against almost every tumor type. Durable responses to immunotherapy and prolonged patient survival have indeed been documented in individuals with melanoma, as well as kidney and lung cancer. These advances call for the re-evaluation of how clinical benefit is measured in an era in which long-term tumor control and survival are achievable treatment goals.
doi:10.4161/onci.27560
PMCID: PMC3973659  PMID: 24719793
checkpoint inhibitors; immunotherapy; melanoma; solid tumors; survival; ulceration
23.  Trial Watch 
Oncoimmunology  2014;3:e27048.
In 1997, for the first time in history, a monoclonal antibody (mAb), i.e., the chimeric anti-CD20 molecule rituximab, was approved by the US Food and Drug Administration for use in cancer patients. Since then, the panel of mAbs that are approved by international regulatory agencies for the treatment of hematopoietic and solid malignancies has not stopped to expand, nowadays encompassing a stunning amount of 15 distinct molecules. This therapeutic armamentarium includes mAbs that target tumor-associated antigens, as well as molecules that interfere with tumor-stroma interactions or exert direct immunostimulatory effects. These three classes of mAbs exert antineoplastic activity via distinct mechanisms, which may or may not involve immune effectors other than the mAbs themselves. In previous issues of OncoImmunology, we provided a brief scientific background to the use of mAbs, all types confounded, in cancer therapy, and discussed the results of recent clinical trials investigating the safety and efficacy of this approach. Here, we focus on mAbs that primarily target malignant cells or their interactions with stromal components, as opposed to mAbs that mediate antineoplastic effects by activating the immune system. In particular, we discuss relevant clinical findings that have been published during the last 13 months as well as clinical trials that have been launched in the same period to investigate the therapeutic profile of hitherto investigational tumor-targeting mAbs.
doi:10.4161/onci.27048
PMCID: PMC3937194  PMID: 24605265
bevacizumab; brentuximab vedotin; cetuximab; nimotuzumab; trastuzumab; tumor-associated antigen
24.  Immunological effects of chemotherapy in spontaneous breast cancers 
Oncoimmunology  2013;2(12):e27158.
doi:10.4161/onci.27158
PMCID: PMC3912056  PMID: 24498568
HER2; CD8+ T lymphocytes; MMTV-NeuT mice; oncogene addiction; p53; trastuzumab
25.  Trial Watch 
Oncoimmunology  2013;2(12):e26621.
Throughout the past 3 decades, along with the recognition that the immune system not only influences oncogenesis and tumor progression, but also determines how established neoplastic lesions respond therapy, renovated enthusiasm has gathered around the possibility of using vaccines as anticancer agents. Such an enthusiasm quickly tempered when it became clear that anticancer vaccines would have to be devised as therapeutic, rather than prophylactic, measures, and that malignant cells often fail to elicit (or actively suppress) innate and adaptive immune responses. Nonetheless, accumulating evidence indicates that a variety of anticancer vaccines, including cell-based, DNA-based, and purified component-based preparations, are capable of circumventing the poorly immunogenic and highly immunosuppressive nature of most tumors and elicit (at least under some circumstances) therapeutically relevant immune responses. Great efforts are currently being devoted to the identification of strategies that may provide anticancer vaccines with the capacity of breaking immunological tolerance and eliciting tumor-associated antigen-specific immunity in a majority of patients. In this sense, promising results have been obtained by combining anticancer vaccines with a relatively varied panels of adjuvants, including multiple immunostimulatory cytokines, Toll-like receptor agonists as well as inhibitors of immune checkpoints. One year ago, in the December issue of OncoImmunology, we discussed the biological mechanisms that underlie the antineoplastic effects of peptide-based vaccines and presented an abundant literature demonstrating the prominent clinical potential of such an approach. Here, we review the latest developments in this exciting area of research, focusing on high-profile studies that have been published during the last 13 mo and clinical trials launched in the same period to evaluate purified peptides or full-length proteins as therapeutic anticancer agents.
doi:10.4161/onci.26621
PMCID: PMC3902120  PMID: 24498550
adjuvants; dendritic cells; ipilimumab; NY-ESO-1; survivin; TLR agonists

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