Showing papers in "Cancer Immunology, Immunotherapy in 2014"
TL;DR: Interestingly, clinical responders to ipilimumab therapy showed significantly less lin− CD14+ HLA-DR− cells as compared to non-responders, suggesting that the frequency of monocytic MDSC may be used as predictive marker of response, as low frequencies identify patients more likely benefitting from ipilitationab treatment.
Abstract: Metastatic melanoma has a poor prognosis with high resistance to chemotherapy and radiation. Recently, the anti-CTLA-4 antibody ipilimumab has demonstrated clinical efficacy, being the first agent to significantly prolong the overall survival of inoperable stage III/IV melanoma patients. A major aim of patient immune monitoring is the identification of biomarkers that predict clinical outcome. We studied circulating myeloid-derived suppressor cells (MDSC) in ipilimumab-treated patients to detect alterations in the myeloid cell compartment and possible correlations with clinical outcome. Lin− CD14+ HLA-DR− monocytic MDSC were enriched in peripheral blood of melanoma patients compared to healthy donors (HD). Tumor resection did not significantly alter MDSC frequencies. During ipilimumab treatment, MDSC frequencies did not change significantly compared to baseline levels. We observed high inter-patient differences. MDSC frequencies in ipilimumab-treated patients were independent of baseline serum lactate dehydrogenase levels but tended to increase in patients with severe metastatic disease (M1c) compared to patients with metastases in skin or lymph nodes only (M1a), who had frequencies comparable to HD. Interestingly, clinical responders to ipilimumab therapy showed significantly less lin− CD14+ HLA-DR− cells as compared to non-responders. The data suggest that the frequency of monocytic MDSC may be used as predictive marker of response, as low frequencies identify patients more likely benefitting from ipilimumab treatment. Prospective clinical trials assessing MDSC frequencies as potential biomarkers are warranted to validate these observations.
459 citations
TL;DR: A personal perspective on IDO as a nodal mediator of pathogenic inflammation and immune escape in cancer is provided to provide a conceptual foundation for the clinical development of IDO inhibitors as a novel class of immunomodulators with broad application in the treatment of advanced human cancer.
Abstract: Genetic and pharmacological studies of indoleamine 2,3-dioxygenase (IDO) have established this tryptophan catabolic enzyme as a central driver of malignant development and progression. IDO acts in tumor, stromal and immune cells to support pathogenic inflammatory processes that engender immune tolerance to tumor antigens. The multifaceted effects of IDO activation in cancer include the suppression of T and NK cells, the generation and activation of T regulatory cells and myeloid-derived suppressor cells, and the promotion of tumor angiogenesis. Mechanistic investigations have defined the aryl hydrocarbon receptor, the master metabolic regulator mTORC1 and the stress kinase Gcn2 as key effector signaling elements for IDO, which also exerts a non-catalytic role in TGF-β signaling. Small-molecule inhibitors of IDO exhibit anticancer activity and cooperate with immunotherapy, radiotherapy or chemotherapy to trigger rapid regression of aggressive tumors otherwise resistant to treatment. Notably, the dramatic antitumor activity of certain targeted therapeutics such as imatinib (Gleevec) in gastrointestinal stromal tumors has been traced in part to IDO downregulation. Further, antitumor responses to immune checkpoint inhibitors can be heightened safely by a clinical lead inhibitor of the IDO pathway that relieves IDO-mediated suppression of mTORC1 in T cells. In this personal perspective on IDO as a nodal mediator of pathogenic inflammation and immune escape in cancer, we provide a conceptual foundation for the clinical development of IDO inhibitors as a novel class of immunomodulators with broad application in the treatment of advanced human cancer.
402 citations
TL;DR: Recently, several clinical studies have been initiated in which IL-12 is applied as an adjuvant in cancer vaccines, in gene therapy and in the form of tumor-targeting immunocytokines (IL-12 fused to monoclonal antibodies).
Abstract: Interleukin 12 (IL-12) seemed to represent the ideal candidate for tumor immunotherapy, due to its ability to activate both innate (NK cells) and adaptive (cytotoxic T lymphocytes) immunities. However, despite encouraging results in animal models, very modest antitumor effects of IL-12 in early clinical trials, often accompanied by unacceptable levels of adverse events, markedly dampened hopes of the successful use of this cytokine in cancer patients. Recently, several clinical studies have been initiated in which IL-12 is applied as an adjuvant in cancer vaccines, in gene therapy including locoregional injections of IL-12 plasmid and in the form of tumor-targeting immunocytokines (IL-12 fused to monoclonal antibodies). The near future will show whether this renewed interest in the use of IL-12 in oncology will result in meaningful therapeutic effects in a select group of cancer patients.
365 citations
TL;DR: In both the NL and UK cohorts, long-term benefit of ipilimumab treatment was unlikely for patients with baseline serum LDH greater than twice the upper limit of normal, and baseline serum lactate dehydrogenase was demonstrated to be the strongest predictive factor for OS.
Abstract: Ipilimumab, a cytotoxic T lymphocyte-associated antigen-4 blocking antibody, has improved overall survival (OS) in metastatic melanoma in phase III trials. However, about 80 % of patients fail to respond, and no predictive markers for benefit from therapy have been identified. We analysed a ‘real world’ population of patients treated with ipilimumab to identify markers for treatment benefit. Patients with advanced cutaneous melanoma were treated in the Netherlands (NL) and the United Kingdom (UK) with ipilimumab at 3 mg/kg. Baseline characteristics and peripheral blood parameters were assessed, and patients were monitored for the occurrence of adverse events and outcomes. A total of 166 patients were treated in the Netherlands. Best overall response and disease control rates were 17 and 35 %, respectively. Median follow-up was 17.9 months, with a median progression-free survival of 2.9 months. Median OS was 7.5 months, and OS at 1 year was 37.8 % and at 2 years was 22.9 %. In a multivariate model, baseline serum lactate dehydrogenase (LDH) was demonstrated to be the strongest predictive factor for OS. These findings were validated in an independent cohort of 64 patients from the UK. In both the NL and UK cohorts, long-term benefit of ipilimumab treatment was unlikely for patients with baseline serum LDH greater than twice the upper limit of normal. In the absence of prospective data, clinicians treating melanoma may wish to consider the data presented here to guide patient selection for ipilimumab therapy.
267 citations
TL;DR: Changes in some immunological markers between baseline and the fourth ipilimumab infusion appear to be associated with disease control and survival, but verification in prospective clinical trials is required.
Abstract: Background
Ipilimumab can induce durable disease control and long-term survival in patients with metastatic melanoma. Identification of a biomarker that correlates with clinical benefit and potentially provides an early marker of response is an active area of research.
227 citations
TL;DR: The capacity of radiation therapy to result in tumor control can be enhanced by using a unique inducible expression system to increase local levels of IFN-α exogenously, to further optimize the combination therapy strategy in terms of dosing and scheduling.
Abstract: The need for an intact immune system for cancer radiation therapy to be effective suggests that radiation not only acts directly on the tumor but also indirectly, through the activation of host immune components. Recent studies demonstrated that endogenous type I interferons (type I IFNs) play a role in radiation-mediated anti-tumor immunity by enhancing the ability of dendritic cells to cross-prime CD8+ T cells. However, it is still unclear to what extent endogenous type I IFNs contribute to the recruitment and function of CD8+ T cells. Little is also known about the effects of type I IFNs on myeloid cells. In the current study, we demonstrate that type I and type II IFNs (IFN-γ) are both required for the increased production of CXCL10 (IP-10) chemokine by myeloid cells within the tumor after radiation treatment. Radiation-induced intratumoral IP-10 levels in turn correlate with tumor-infiltrating CD8+ T cell numbers. Moreover, type I IFNs promote potent tumor-reactive CD8+ T cells by directly affecting the phenotype, effector molecule production, and enhancing cytolytic activity. Using a unique inducible expression system to increase local levels of IFN-α exogenously, we show here that the capacity of radiation therapy to result in tumor control can be enhanced. Our preclinical approach to study the effects of local increase in IFN-α levels can be used to further optimize the combination therapy strategy in terms of dosing and scheduling, which may lead to better clinical outcome.
179 citations
TL;DR: It is demonstrated that Mo-MDSC significantly increase the frequency of ALDH1Bright CSCs in a mouse model of PC and this transformation is dependent on the activation of the STAT3 pathway, and targeting STAT3 activation may be an effective therapeutic strategy in targeting C SCs in PC.
Abstract: Pancreatic cancer (PC) mobilizes myeloid cells from the bone marrow to the tumor where they promote tumor growth and proliferation. Cancer stem cells (CSCs) are a population of tumor cells that are responsible for tumor initiation. Aldehyde dehydrogenase-1 activity in PC identifies CSCs, and its activity has been correlated with poor overall prognosis in human PC. Myeloid cells have been shown to impact tumor stemness, but the impact of immunosuppressive tumor-infiltrating granulocytic and monocytic myeloid-derived suppressor cells (Mo-MDSC) on ALDH1Bright CSCs and epithelial to mesenchymal transition is not well understood. In this study, we demonstrate that Mo-MDSC (CD11b+/Gr1+/Ly6G−/Ly6Chi) significantly increase the frequency of ALDH1Bright CSCs in a mouse model of PC. Additionally, there was significant upregulation of genes associated with epithelial to mesenchymal transition. We also found that human PC converts CD14+ peripheral blood monocytes into Mo-MDSC (CD14+/HLA-DRlow/−) in vitro, and this transformation is dependent on the activation of the STAT3 pathway. In turn, these Mo-MDSC increase the frequency of ALDH1Bright CSCs and promote mesenchymal features of tumor cells. Finally, blockade of STAT3 activation reversed the increase in ALDH1Bright CSCs. These data suggest that the PC tumor microenvironment transforms monocytes to Mo-MDSC by STAT3 activation, and these cells increase the frequency of ALDH1Bright CSCs. Therefore, targeting STAT3 activation may be an effective therapeutic strategy in targeting CSCs in PC.
167 citations
TL;DR: Current knowledge on the role and function of NRP1 in Tregs and pDCs, both in physiological and cancer settings, as well as its potential as a therapeutic target in cancer are reviewed.
Abstract: Neuropilin 1 (NRP1) is a transmembrane glycoprotein that acts as a co-receptor for a number of extracellular ligands including class III/IV semaphorins, certain isoforms of vascular endothelial growth factor and transforming growth factor beta. An exact understanding of the role of NRP1 in the immune system has been obscured by the differences in NRP1 expression observed between mice and humans. In mice, NRP1 is selectively expressed on thymic-derived Tregs and greatly enhances immunosuppressive function. In humans, NRP1 is expressed on plasmacytoid dendritic cells (pDCs) where it aids in priming immune responses and on a subset of T regulatory cells (Tregs) isolated from secondary lymph nodes. Preliminary studies that show NRP1 expression on T cells confers enhanced immunosuppressive activity. However, the mechanism by which this activity is mediated remains unclear. NRP1 expression has also been identified on activated T cells and Tregs isolated from inflammatory microenvironments, suggesting NRP1 might represent a novel T cell activation marker. Of clinical interest, NRP1 may enhance Treg tumour infiltration and a decrease in NRP1+ Tregs correlates with successful chemotherapy, suggesting a specific role for NRP1 in cancer pathology. As a therapeutic target, NRP1 allows simultaneous targeting of NRP1-expressing tumour vasculature, NRP1+ Tregs and pDCs. With the development of anti-NRP1 monoclonal antibodies and cell-penetrating peptides, NRP1 represents a promising new target for cancer therapies. This paper reviews current knowledge on the role and function of NRP1 in Tregs and pDCs, both in physiological and cancer settings, as well as its potential as a therapeutic target in cancer.
166 citations
TL;DR: Monitoring for the frequency and functions of iTreg rather than nTreg is important in cancer, and elimination by various available strategies prior to immunotherapies may not be beneficial in all cases and needs to be undertaken with caution.
Abstract: Regulatory T cells (Treg) play a key role in maintaining the balance of immune responses in human health and in disease. Treg come in many flavors and can utilize a variety of mechanisms to modulate immune responses. In cancer, inducible (i) or adaptive Treg expand, accumulate in tissues and the peripheral blood of patients, and represent a functionally prominent component of CD4+ T lymphocytes. Phenotypically and functionally, iTreg are distinct from natural (n) Treg. A subset of iTreg expressing ectonucleotidases, CD39 and CD73, is able to hydrolyze ATP to 5′-AMP and adenosine (ADO) and thus mediate suppression of those immune cells which express ADO receptors. iTeg can also produce prostaglandin E2 (PGE2). These iTreg, expanding in response to tumor antigens and cytokines such as TGF-β or IL-10, are presumably responsible for the suppression of anti-tumor immune responses and for successful tumor escape. On the other hand, in cancers associated with prominent inflammatory infiltrates, e.g., colorectal carcinoma or certain types of breast cancer, iTreg down-regulate excessive inflammation by producing ADO and/or PGE2 and protect the host from tissue injury and tumor development. Thus, iTreg utilizing the same adenosine pathway play a key but dual role in cancer, and their plasticity is controlled and driven by the microenvironment. Thus, monitoring for the frequency and functions of iTreg rather than nTreg is important in cancer. In addition, elimination of iTreg by various available strategies prior to immunotherapies may not be beneficial in all cases and needs to be undertaken with caution.
150 citations
TL;DR: Investigating the frequency and function of immune suppressive cell subsets in the peripheral blood of 41 patients with prostate cancer and 36 healthy donors showed a significant increase in circulating CD14+ HLA-DRlow/neg monocytic MDSC and Tregs in patients with PC compared to HD, and increased frequencies of M-MDSC correlated positively with Treg levels.
Abstract: Myeloid-derived suppressor cells (MDSC) are believed to play a role in immune suppression and subsequent failure of T cells to mount an efficient anti-tumor response, by employing both direct T-cell inhibition as well as induction of regulatory T cells (Tregs). Investigating the frequency and function of immune suppressive cell subsets in the peripheral blood of 41 patients with prostate cancer (PC) and 36 healthy donors (HD) showed a significant increase in circulating CD14(+) HLA-DR(low/neg) monocytic MDSC (M-MDSC) and Tregs in patients with PC compared to HD. Furthermore, M-MDSC frequencies correlated positively with Treg levels. In vitro proliferation assay with autologous T cells confirmed M-MDSC-mediated T-cell suppression, and intracellular staining of immune suppressive enzyme iNOS revealed a higher expression in M-MDSC from patients with PC. Increased frequencies of M-MDSC correlated with known negative prognostic markers in patients with PC including elevated levels of lactate dehydrogenase and prostate-specific antigen. Accordingly, high levels of M-MDSC were associated with a shorter median overall survival. Our data strongly suggest that M-MDSC, possibly along with Tregs, play a role in establishing an immune suppressive environment in patients with PC. Moreover, correlation of M-MDSC frequency with known prognostic markers and the observed impact on OS could reflect a possible role in tumor progression. Further insight into the generation and function of MDSC and their interplay with Tregs and other cell types may suggest ways to tackle their induction and/or function to improve immunological tumor control.
144 citations
TL;DR: This work will focus on therapy-induced necrotic tumor cell death that is immunogenic due to the release of damage-associated molecular patterns and should be regarded as immune adjuvant for metastatic disease and as a tool for the generation of an in situ vaccine when applied at distinct fractionation doses or especially in combination with IT to generate immune memory against the tumor.
Abstract: The therapy of cancer emerged as multimodal treatment strategy. The major mode of action of locally applied radiotherapy (RT) is the induction of DNA damage that triggers a network of events that finally leads to tumor cell cycle arrest and cell death. Along with this, RT modifies the phenotype of the tumor cells and their microenvironment. Either may contribute to the induction of specific and systemic antitumor immune responses. The latter are boosted when additional immune therapy (IT) is applied at distinct time points during RT. We will focus on therapy-induced necrotic tumor cell death that is immunogenic due to the release of damage-associated molecular patterns. Immune-mediated distant bystander (abscopal) effects of RT when combined with dendritic cell-based IT and the role of fractionation of radiation in the induction of immunogenic tumor cell death will be discussed. Autologous whole-tumor-cell-based vaccines generated by high hydrostatic pressure technology will be introduced and the influence of cytokines and the immune modulator AnnexinA5 on the ex vivo generated or in situ therapy-induced vaccine efficacy will be outlined. RT should be regarded as immune adjuvant for metastatic disease and as a tool for the generation of an in situ vaccine when applied at distinct fractionation doses or especially in combination with IT to generate immune memory against the tumor. To identify the most beneficial combination and chronology of RT with IT is presumably one of the biggest challenges of innovative tumor research and therapies.
TL;DR: Targeting the PD-1 pathway may be a feasible approach to treating patients with breast cancer, and the results suggest a prognostic value of thePD-1+ immune cell population in such breast cancer patients.
Abstract: The programmed death-1 (PD-1) molecule is mainly expressed on functionally “exhausted” CD8+ T cells, dampening the host antitumor immune response. We evaluated the ratio between effective and regulatory T cells (Tregs) and PD-1 expression as a prognostic factor for operable breast cancer patients. A series of 218 newly diagnosed invasive breast cancer patients who had undergone primary surgery at Ruijin Hospital were identified. The influence of CD8+ cytotoxic T lymphocytes, FOXP3+ (Treg cell marker), and PD-1+ immune cell counts on prognosis was analyzed utilizing immunohistochemistry. Both PD-1+ immune cells and FOXP3+ Tregs counts were significantly associated with unfavorable prognostic factors. In bivariate, but not multivariate analysis, high tumor infiltrating PD-1+ cell counts correlated with significantly shorter patient survival. Our results suggest a prognostic value of the PD-1+ immune cell population in such breast cancer patients. Targeting the PD-1 pathway may be a feasible approach to treating patients with breast cancer.
TL;DR: The current understanding of how the catecholamines, epinephrine and norepinephrine, affect cancer cell survival and tumor progression is summarized and new data exploring the potential contributions of stress to immunosuppression in the tumor microenvironment is highlighted.
Abstract: Long conserved mechanisms maintain homeostasis in living creatures in response to a variety of stresses. However, continuous exposure to stress can result in unabated production of stress hormones, especially catecholamines, which can have detrimental health effects. While the long-term effects of chronic stress have well-known physiological consequences, recent discoveries have revealed that stress may affect therapeutic efficacy in cancer. Growing epidemiological evidence reveals strong correlations between progression-free and long-term survival and β-blocker usage in cancer patients. In this review, we summarize the current understanding of how the catecholamines, epinephrine and norepinephrine, affect cancer cell survival and tumor progression. We also highlight new data exploring the potential contributions of stress to immunosuppression in the tumor microenvironment and the implications of these findings for the efficacy of immunotherapies.
TL;DR: Application of the emerging discipline of synthetic biology to cancer, which combines elements of genetic engineering and molecular biology to create new biological structures with enhanced functionalities, is the subject of this focused research review.
Abstract: It is now well established that the immune system can control and eliminate cancer cells. Adoptive T cell transfer has the potential to overcome the significant limitations associated with vaccine-based strategies in patients who are often immune compromised. Application of the emerging discipline of synthetic biology to cancer, which combines elements of genetic engineering and molecular biology to create new biological structures with enhanced functionalities, is the subject of this focused research review.
TL;DR: Overall, data based on samples obtained from women with ovarian cancer is presented, suggesting the PD-1 pathway may be used as a reliable diagnostic marker in OC, as well as a viable target for use withPD-1/PD-L1-directed antibody immunotherapy.
Abstract: The programmed death-1 (PD-1) pathway is important in the maintenance of peripheral tolerance and homeostasis through suppression of T cell receptor signaling. As such, it is employed by many tumors as a means of immune escape. We have investigated the role of this pathway in human ovarian cancer (OC) to assess its potential role as a diagnostic and/or prognostic marker and therapeutic target, following recent clinical trial success of antibody therapy directed at this pathway. We show programmed death ligand-1 (PD-L1) expression on monocytes in the ascites and blood of patients with malignant OC is strikingly higher than those with benign/borderline disease, with no overlap in the values between these groups. We characterize the regulation of this molecule and show a role of IL-10 present in ascitic fluid. Flow cytometric analysis of T cells present in the ascites and blood showed a correlation of PD-1 expression with malignant tumors versus benign/borderline, in a similar manner to PD-L1 expression on monocytes. Finally, we demonstrate functional links between PD-L1 expression on monocytes and OC tumor cells with suppression of T cell responses. Overall, we present data based on samples obtained from women with ovarian cancer, suggesting the PD-1 pathway may be used as a reliable diagnostic marker in OC, as well as a viable target for use with PD-1/PD-L1-directed antibody immunotherapy.
TL;DR: Based on the functional relevance of immune networking in tumors, it is advantageous to merge monitoring immune biomarkers into the traditional patient’s categorization and treatment regiments, which will provide new prognostic and/or predictive tools to clinical practice.
Abstract: Chronic inflammation typical to various chronic diseases is associated with immunosuppression, mediated primarily by immature myeloid-derived suppressor cells (MDSCs). A variety of factors induce MDSC differentiation arrest, thus manipulating the host’s immune function and suppressing the innate and adaptive immune systems, as reflected by their impaired status associated with down-regulated expression of the CD247 molecule. Such chronic inflammation-induced immunosuppressive features are also found in many tumors, generating tumor micro- and macro-environments that act as critical barriers to effective anti-tumor responses and therapies. This knowledge offers new and novel candidate immune targets for therapeutic interventions, in combination with more conventional approaches as chemotherapy, radiotherapy, and cancer cell targeted therapy. Therapeutic manipulation of chronic inflammation during cancer development is likely to enhance efficacy of treatments such as vaccinations, and adoptive T cell transfer, thus switching the chronic pro-cancer inflammatory environments into an anti-cancer milieu. Based on the functional relevance of immune networking in tumors, it is advantageous to merge monitoring immune biomarkers into the traditional patient’s categorization and treatment regiments, which will provide new prognostic and/or predictive tools to clinical practice. A better identification of environmental and tumor-specific inflammatory mechanisms will allow directing the clinical management of cancer toward a more personalized medicine.
TL;DR: The results indicate that the PD-1/PD-L1 interaction and B7-H4 could be possible targets for immune intervention in uterine cancer patients as well as mediation of MDSC function.
Abstract: The major hurdle for cancer vaccines to be effective is posed by tumor immune evasion. Several common immune mechanisms and mediators are exploited by tumors to avoid immune destruction. In an attempt to shed more light on the immunosuppressive environment in uterine tumors, we analyzed the presence of PD-L1, PD-L2, B7-H4, indoleamine 2,3-dioxygenase (IDO), galectin-1, galectin-3, arginase-1 activity and myeloid-derived suppressor cell (MDSC) infiltration. IDO, PD-L1, PD-L2 and B7-H4 were analyzed by immunohistochemistry. PD-L2 was mostly expressed at low levels in these tumors. We found high IDO expression in 21 % of endometrial carcinoma samples and in 14 % of uterine sarcoma samples. For PD-L1 and B7-H4, we found high expression in 92 and 90 % of endometrial cancers, respectively, and in 100 and 92 % of the sarcomas. Galectin-1 and 3 were analyzed in tissue lysates by ELISA, but we did not find an increase in both molecules in tumor lysates compared with benign tissues. We detected expression of galectin-3 by fibroblasts, immune cells and tumor cells in single-cell tumor suspensions. In addition, we noted a highly significant increase in arginase-1 activity in endometrial carcinomas compared with normal endometria, which was not the case for uterine sarcomas. Finally, we could demonstrate MDSC infiltration in fresh tumor suspensions from uterine tumors. These results indicate that the PD-1/PD-L1 interaction and B7-H4 could be possible targets for immune intervention in uterine cancer patients as well as mediation of MDSC function. These observations are another step toward the implementation of inhibitors of immunosuppression in the treatment of uterine cancer patients.
TL;DR: Yeast-CEA vaccination had minimal toxicity and induced some antigen-specific T cell responses and CEA stabilization in a heterogeneous, heavily pre-treated patient population of patients with metastatic CEA-expressing carcinomas.
Abstract: Yeast-CEA (GI-6207) is a therapeutic cancer vaccine genetically modified to express recombinant carcinoembryonic antigen (CEA) protein, using heat-killed yeast (Saccharomyces cerevisiae) as a vector. In preclinical studies, yeast-CEA induced a strong immune response to CEA and antitumor responses. Patients received subcutaneous vaccines every 2 weeks for 3 months and then monthly. Patients were enrolled at 3 sequential dose levels: 4, 16, and 40 yeast units (107 yeast particles/unit). Eligible patients were required to have serum CEA > 5 ng/mL or > 20 % CEA+ tumor block, ECOG PS 0–2, and no history of autoimmunity. Restaging scans were performed at 3 months and then bimonthly. Peripheral blood was collected for the analysis of immune response (e.g., by ELISPOT assay). Twenty-five patients with metastatic CEA-expressing carcinomas were enrolled. Median patient age was 52 (range 39–81). A total of 135 vaccines were administered. The vaccine was well tolerated, and the most common adverse event was grade 1/2 injection-site reaction. Five patients had stable disease beyond 3 months (range 3.5–18 months), and each had CEA stabilization while on-study. Some patients showed evidence post-vaccination of increases in antigen-specific CD8+ T cells and CD4+ T lymphocytes and decreases in regulatory T cells. Of note, a patient with medullary thyroid cancer had substantial T cell responses and a vigorous inflammatory reaction at sites of metastatic disease. Yeast-CEA vaccination had minimal toxicity and induced some antigen-specific T cell responses and CEA stabilization in a heterogeneous, heavily pre-treated patient population. Further studies are required to determine the clinical benefit of yeast-CEA vaccination.
TL;DR: Associations between overall survival and immune cell subsets prior to treatment, and the change in a given immune cell subset 70 days post-initiation of therapy, were evaluated and found that an increase in Tim-3+ natural killer cells post- versus pre-vaccination associated with longer OS.
Abstract: We recently reported the clinical results of a Phase I trial combining ipilimumab with a vaccine containing transgenes for prostate-specific antigen (PSA) and for a triad of costimulatory molecules (PROSTVAC) in patients with metastatic castration-resistant prostate cancer. Thirty patients were treated with escalating ipilimumab and a fixed dose of vaccine. Of 24 chemotherapy-naive patients, 58 % had a PSA decline. Combination therapy did not exacerbate the immune-related adverse events associated with ipilimumab. Here, we present updated survival data and an evaluation of 36 immune cell subsets pre- and post-therapy. Peripheral blood mononuclear cells were collected before therapy, at 13 days and at 70 days post-initiation of therapy, and phenotyped by flow cytometry for the subsets of T cells, regulatory T cells, natural killer cells, and myeloid-derived suppressor cells. Associations between overall survival (OS) and immune cell subsets prior to treatment, and the change in a given immune cell subset 70 days post-initiation of therapy, were evaluated. The median OS was 2.63 years (1.77–3.45). There were trends toward associations for longer OS and certain immune cell subsets before immunotherapy: lower PD-1+Tim-3NEGCD4EM (P = 0.005, adjusted P = 0.010), higher PD-1NEGTim-3+CD8 (P = 0.002, adjusted P = 0.004), and a higher number of CTLA-4NEG Tregs (P = 0.005, adjusted P = 0.010). We also found that an increase in Tim-3+ natural killer cells post- versus pre-vaccination associated with longer OS (P = 0.0074, adjusted P = 0.015). These results should be considered as hypothesis generating and should be further evaluated in larger immunotherapy trials.
TL;DR: There was no evidence that the addition of low-dose adjuvant GM-CSF increased Lin-DR-CD11b+ MDSC in patients receiving combination chemoimmunotherapy in patients with advanced pancreatic cancer receiving the combination of gem citabine and capecitabine.
Abstract: In pre-clinical models, the only two chemotherapy drugs which have been demonstrated to directly reduce the number of myeloid-derived suppressor cells (MDSCs) are gemcitabine and 5-fluorouracil Here we analyze the dynamics of MDSCs, phenotyped as Lin-DR-CD11b+, in patients with advanced pancreatic cancer receiving the combination of gemcitabine and capecitabine, a 5-FU pro-drug We found no evidence that gemcitabine and capecitabine directly reduce MDSC% in patients Gemcitabine and capecitabine reduced MDSCs in 42 % of patients (n = 19) and MDSC% fell in only 3/9 patients with above-median baseline MDSCs In 5/8 patients with minimal tumour volume change on treatment, the MDSC% went up: increases in MDSC% in these patients appeared to correlate with sustained cancer-related inflammatory cytokine upregulation In a separate cohort of 21 patients treated with gemcitabine and capecitabine together with concurrently administered GV1001 vaccine with adjuvant GM-CSF, the MDSC% fell in 18/21 patients and there was a significant difference in the trajectory of MDSCs between those receiving GV1001 and GM-CSF in combination with chemotherapy and those receiving chemotherapy alone Thus, there was no evidence that the addition of low-dose adjuvant GM-CSF increased Lin-DR-CD11b+ MDSC in patients receiving combination chemoimmunotherapy 9/21 patients developed an immune response to GV1001 and the MDSCs fell in 8 of these 9 patients, 6 of whom had above-median pre-vaccination MDSC levels A high pre-vaccination MDSC% does not preclude the development of immunity to a tumour-associated antigen
TL;DR: The basic biology of NK cells is reviewed, highlighting characteristics which make NK cells particularly useful in cancer therapies and current treatment strategies that have been used for cancer as well as discuss potential future directions for the field.
Abstract: The past decade has witnessed a burgeoning of research and further insight into the biology and clinical applications of natural killer (NK) cells. Once thought to be simple innate cells important only as cytotoxic effector cells, our understanding of NK cells has grown to include memory-like responses, the guidance of adaptive responses, tissue repair, and a delicate paradigm for how NK cells become activated now termed "licensing" or "arming." Although these cells were initially discovered and named for their spontaneous ability to kill tumor cells, manipulating NK cells in therapeutic settings has proved difficult and complex in part due to our emerging understanding of their biology. Therapies involving NK cells may either activate endogenous NK cells or involve transfers of exogenous cells by hematopoietic stem cell transplantation or adoptive cell therapy. Here, we review the basic biology of NK cells, highlighting characteristics which make NK cells particularly useful in cancer therapies. We also explore current treatment strategies that have been used for cancer as well as discuss potential future directions for the field.
TL;DR: The findings suggest that the combination therapy of anti-CD40 mAb with celecoxib enhances anti-glioma activities via promotion of type-1 immunity both in myeloid cells and T-cells.
Abstract: Malignant gliomas are heavily infiltrated by immature myeloid cells that mediate immunosuppression. Agonistic CD40 monoclonal antibody (mAb) has been shown to activate myeloid cells and promote antitumor immunity. Our previous study has also demonstrated blockade of cyclooxygenase-2 (COX-2) reduces immunosuppressive myeloid cells, thereby suppressing glioma development in mice. We therefore hypothesized that a combinatory strategy to modulate myeloid cells via two distinct pathways, i.e., CD40/CD40L stimulation and COX-2 blockade, would enhance anti-glioma immunity. We used three different mouse glioma models to evaluate therapeutic effects and underlying mechanisms of a combination regimen with an agonist CD40 mAb and the COX-2 inhibitor celecoxib. Treatment of glioma-bearing mice with the combination therapy significantly prolonged survival compared with either anti-CD40 mAb or celecoxib alone. The combination regimen promoted maturation of CD11b(+) cells in both spleen and brain, and enhanced Cxcl10 while suppressing Arg1 in CD11b(+)Gr-1(+) cells in the brain. Anti-glioma activity of the combination regimen was T-cell dependent because depletion of CD4(+) and CD8(+) cells in vivo abrogated the anti-glioma effects. Furthermore, the combination therapy significantly increased the frequency of CD8(+) T-cells, enhanced IFN-γ-production and reduced CD4(+)CD25(+)Foxp3(+) T regulatory cells in the brain, and induced tumor-antigen-specific T-cell responses in lymph nodes. Our findings suggest that the combination therapy of anti-CD40 mAb with celecoxib enhances anti-glioma activities via promotion of type-1 immunity both in myeloid cells and T-cells.
TL;DR: Vaccination with EMD640744 elicited T-cell responses against survivin peptides in the majority of patients, demonstrating the immunologic efficacy of EMD 640744.
Abstract: Survivin is a member of the inhibitor-of-apoptosis family. Essential for tumor cell survival and overexpressed in most cancers, survivin is a promising target for anti-cancer immunotherapy. Immunogenicity has been demonstrated in multiple cancers. Nonetheless, few clinical trials have demonstrated survivin-vaccine-induced immune responses. This phase I trial was conducted to test whether vaccine EMD640744, a cocktail of five HLA class I-binding survivin peptides in Montanide® ISA 51 VG, promotes anti-survivin T-cell responses in patients with solid cancers. The primary objective was to compare immunologic efficacy of EMD640744 at doses of 30, 100, and 300 μg. Secondary objectives included safety, tolerability, and clinical efficacy. In total, 49 patients who received ≥2 EMD640744 injections with available baseline- and ≥1 post-vaccination samples [immunologic-diagnostic (ID)-intention-to-treat] were analyzed by ELISpot- and peptide/MHC-multimer staining, revealing vaccine-activated peptide-specific T-cell responses in 31 patients (63 %). This cohort included the per study protocol relevant ID population for the primary objective, i.e., T-cell responses by ELISpot in 17 weeks following first vaccination, as well as subjects who discontinued the study before week 17 but showed responses to the treatment. No dose-dependent effects were observed. In the majority of patients (61 %), anti-survivin responses were detected only after vaccination, providing evidence for de novo induction. Best overall tumor response was stable disease (28 %). EMD640744 was well tolerated; local injection-site reactions constituted the most frequent adverse event. Vaccination with EMD640744 elicited T-cell responses against survivin peptides in the majority of patients, demonstrating the immunologic efficacy of EMD640744.
TL;DR: It is demonstrated for the first time that the JAK2–STAT3 pathway regulated by miR-375 is involved in H. pylori-induced inflammation; this pathway promotes neoplastic transformation by affecting the expression of BCL-2 and TWIST1, hence offering a potential therapeutic target for inflammation-related cancers, especially those related to H.pylori.
Abstract: Gastric cancer remains the second leading cause of cancer-related deaths worldwide. Although Helicobacter pylori (H. pylori) is considered to be a critical risk factor, the molecular mechanisms underlying H. pylori-induced gastric carcinogenesis are still poorly defined. Recently, accumulating studies have revealed that microRNAs play key roles in development, differentiation, immune regulation, and even carcinogenesis. This study was performed to explore the mechanism of microRNA-375 (miR-375) in H. pylori promotion of gastric carcinogenesis. It was shown that miR-375 was down-regulated in response to H. pylori infection in gastric epithelial cell lines; this finding was quite opposite to the expression patterns of pro-inflammatory cytokines observed in a co-culture cell model. Moreover, the ectopic expression of miR-375 aggravated cell proliferation and migration. It was further observed that Janus kinase 2 (JAK2) was a bona fide target of miR-375 and further activated signal transducer and activator of transcription 3 (STAT3) and other downstream target molecules. Both gain-of-function and loss-of-function experiments showed that decreased miR-375 expression could mimic the oncogenic effects of the JAK2–STAT3 pathway. In addition, pretreatment with siRNAs targeting JAK2 prevented gastric epithelial cells from increasing proliferation and migration even in response to H. pylori infection. For the first time, our results demonstrate that the JAK2–STAT3 pathway regulated by miR-375 is involved in H. pylori-induced inflammation; this pathway promotes neoplastic transformation by affecting the expression of BCL-2 and TWIST1, hence offering a potential therapeutic target for inflammation-related cancers, especially those related to H. pylori.
TL;DR: The first combination of DC vaccination and TIL infusion in malignant melanoma is reported, safe and feasible, though it is expected that administration of lymphodepleting chemotherapy and IL-2 will likely increase treatment efficacy.
Abstract: Adoptive transfer of in vitro-expanded tumor-infiltrating lymphocytes (TIL) has shown great clinical benefit in patients with malignant melanoma. TIL therapy itself has little side effects, but conditioning chemo- or radiotherapy and postinfusion interleukin 2 (IL-2) injections are associated with severe adverse advents. We reasoned that combining TIL infusion with dendritic cell (DC) vaccination could circumvent the need for conditioning and IL-2 support and thus represent a milder treatment approach. Eight patients with stage IV melanoma were enrolled in the MAT01 study, consisting of vaccination with autologous tumor-lysate-loaded DC, followed by TIL infusion. Six of eight patients were treated according to protocol, while one patient received only TIL and one only DC. Treatments were well tolerated with a single grade 3 adverse event. The small study size precludes analysis of clinical responses, though interestingly one patient showed a complete remission and two had stable disease. Analysis of the infusion products revealed that mature DC were generated in all cases. TIL after expansion were CD3+ T cells, dominated by effector memory CD8+ cytotoxic T cells. Analysis of the T cell receptor repertoire revealed presence of highly dominant clones in most infusion products, and many of these could be detected in the circulation for weeks after T cell transfer. Here, we report the first combination of DC vaccination and TIL infusion in malignant melanoma. This combined treatment was safe and feasible, though after evaluating both clinical and immunological parameters, we expect that administration of lymphodepleting chemotherapy and IL-2 will likely increase treatment efficacy.
TL;DR: The function of NKT cells in tumor immunity and their interaction with other regulatory cells, especially CD4+CD25+Foxp3+ regulatory T cells are discussed.
Abstract: NKT cells are CD1d-restricted T cells that recognize lipid antigens. They also have been shown to play critical roles in the regulation of immune responses. In the immune responses against tumors, two subsets of NKT cells, type I and type II, play opposing roles and cross-regulate each other. As members of both the innate and adaptive immune systems, which form a network of multiple components, they also interact with other immune components. Here, we discuss the function of NKT cells in tumor immunity and their interaction with other regulatory cells, especially CD4(+)CD25(+)Foxp3(+) regulatory T cells.
TL;DR: It remains controversial about the expression of Foxp3 in cells other than Treg, but understanding the potential expression and function of this master regulator in different cell subsets could have a wide range of implications for immune tolerance and several pathologies including autoimmune disorders and immune responses to cancer.
Abstract: Forkhead box P3 (Foxp3) is an important transcription factor that belongs to the forkhead/winged-helix family of transcriptional regulators. Foxp3 has been extensively studied over the past 13 years as a master regulator of transcription in a specific T-cell type, CD4+ regulatory T cells (Treg), both in humans and in mice. Compelling data characterize Foxp3 as critically important and necessary for the development and the differentiation of Treg. It has been considered initially as the only specific marker for Treg. However, recent work has proposed that Foxp3 can be expressed by other types of lymphoid cells or myeloid cells and also by some non-hematopoietic cells such as epithelial cells. It remains controversial about the expression of Foxp3 in cells other than Treg, but understanding the potential expression and function of this master regulator in different cell subsets could have a wide range of implications for immune tolerance and several pathologies including autoimmune disorders and immune responses to cancer.
TL;DR: The path the team has followed in the development of TriMixDC-MEL, a potent DC-based cellular therapy, is reviewed, discussing its development as well as further modifications and applications.
Abstract: Since decades, the main goal of tumor immunologists has been to increase the capacity of the immune system to mediate tumor regression. In this regard, one of the major focuses of cancer immunotherapy has been the design of vaccines promoting strong tumor-specific cytotoxic T lymphocyte responses in cancer patients. Here, dendritic cells (DCs) play a pivotal role as they are regarded as nature’s adjuvant and as such have become the natural agents for antigen delivery in order to finally elicit strong T cell responses (Villadangos and Schnorrer in Nat Rev Immunol 7:543–555, 2007; Melief in Immunity 29:372–383, 2008; Palucka and Banchereau in Nat Rev Cancer 12:265–277, 2012; Vacchelli et al. in Oncoimmunology 2:e25771, 2013; Galluzzi et al. in Oncoimmunology 1:1111–1134, 2012). Therefore, many investigators are actively pursuing the use of DCs as an efficient way of inducing anticancer immune responses. Nowadays, DCs can be generated at a large scale in closed systems, yielding sufficient numbers of cells for clinical application. In addition, with the identification of tumor-associated antigens, which are either selectively or preferentially expressed by tumors, a whole range of strategies using DCs for immunotherapy have been designed and tested in clinical studies. Despite the evidence that DCs loaded with tumor-associated antigens can elicit immune responses in vivo, clinical responses remained disappointingly low. Therefore, optimization of the cellular product and route of administration was urgently needed. Here, we review the path we have followed in the development of TriMixDC-MEL, a potent DC-based cellular therapy, discussing its development as well as further modifications and applications.
TL;DR: Adoptive immunotherapy using CIK cells showed comparable PFS and OS to survival data of previous trials that assessed conventional chemotherapies while maintaining tolerability and showing encouraging results in terms of patient QoL in gemcitabine-refractory advanced pancreatic cancer (clinicalTrials.gov number NCT00965718).
Abstract: Second-line chemotherapy in patients with gemcitabine-refractory advanced pancreatic cancer has shown disappointing survival outcomes due to rapid disease progression and performance deterioration. The aim of this phase II trial was to evaluate the efficacy and safety of adoptive immunotherapy using ex vivo-expanded, cytokine-induced killer (CIK) cells in gemcitabine-refractory advanced pancreatic cancer. Patients with advanced pancreatic cancer who showed disease progression during gemcitabine-based chemotherapy were enrolled in this study. For generation of CIK cells, peripheral blood samples were collected from each patient and cultured with anti-CD3 monoclonal antibody and IL-2. Patients received CIK cells intravenously 10 times, every week for 5 weeks and then every other week for 10 weeks. Twenty patients were enrolled between November 2009 and September 2010. The disease control rate was 25 % (4/16 patients). The median progression-free survival (PFS) was 11.0 weeks (95 % CI 8.8–13.2), and the median overall survival (OS) was 26.6 weeks (95 % CI 8.6–44.6). Grade 3 toxicities included general weakness in two patients and thrombocytopenia in one patient. Grade 4 hematologic or non-hematologic toxicity was not observed. Patients showed improvement in pancreatic pain, gastrointestinal distress, jaundice, body image alterations, altered bowel habits, health satisfaction, and sexuality when assessing quality of life (QoL). Adoptive immunotherapy using CIK cells showed comparable PFS and OS to survival data of previous trials that assessed conventional chemotherapies while maintaining tolerability and showing encouraging results in terms of patient QoL in gemcitabine-refractory advanced pancreatic cancer (clinicalTrials.gov number NCT00965718).
TL;DR: In vivo antitumor effects of LTX-315 against intradermally established B16 melanomas in syngeneic mice indicate that intratumoral treatment with L TX-315 can provide local tumor control followed by protective immune responses and has potential as a new immunotherapeutic agent.
Abstract: A manuscript version of this article is part of Ketil Andre Camilio's doctoral thesis, which is available in Munin at http://hdl.handle.net/10037/5489