Immune System Of Cancer Patients Research Articles

Good News from Immunotherapy: Our Immune Defense Stands Up to Cancer

The immune system defends us and combats many microbes, like the viruses that cause the common cold or bacteria that enter wounds. Our defenses can also learn to protect us from more difficult situations—and they can do so with the lessons learned from vaccines. For example, the poliovirus vaccine teaches the immune system to recognize and eliminate the poliovirus, in case it ever enters the body. In recent years, scientists have found that the immune system can also be taught to attack another type of disease: cancer. Cancer is a big mistake in our body. It happens when cells lose control and start to grow without limits. The good news is that we can educate the immune system in cancer patients—this is called immunotherapy. In this article, we will explain how our defenses can learn to attack and eliminate cancer.

ASCT2 (SLC1A5)-Deficient Mice Have Normal B-Cell Development, Proliferation, and Antibody Production.

SLC1A5 (solute carrier family 1, member 5) is a small neutral amino acid exchanger that is upregulated in rapidly proliferating lymphocytes but also in many primary human cancers. Furthermore, cancer cell lines have been shown to require SLC1A5 for their survival in vitro. One of SLC1A5’s primary substrates is the immunomodulatory amino acid glutamine, which plays an important role in multiple key processes, such as energy supply, macromolecular synthesis, nucleotide biosynthesis, redox homeostasis, and resistance against oxidative stress. These processes are also essential to immune cells, including neutrophils, macrophages, B and T lymphocytes. We show here that mice with a stop codon in Slc1a5 have reduced glutamine uptake in activated lymphocytes and primary fibroblasts. B and T cell populations and maturation in resting mice were not affected by absence of SLC1A5. Antibody production in resting and immunized mice and the germinal center response to immunization were also found to be normal. SLC1A5 has been recently described as a novel target for the treatment of a variety of cancers, and our results indicate that inhibition of SLC1A5 in cancer therapy may be tolerated well by the immune system of cancer patients.

Hypoxia-inducible factor 1α in regulation of programmed death: Ligand 1 in glioma under hypoxia microenvironment.

103 Background: Glioma is a highly lethal tumor that is known for its immune inhibitory capabilities. Despite great progress in treatment modalities, the median survival time of high-grade gliomas patients is only about 11.1 months. Gliomas are aberrantly expressed programmed death–ligand 1 (PD-L1) which results in tumor-induced immune suppression. Hypoxia is well known to induce aggressiveness, promotes tumor progression and resistance to chemotherapy and radiotherapy. Recently, studies have indicated that hypoxia play a prominent role in tumor immune escape. The aim of the study was to explore the relationship between PD-L1 and hypoxia inducible factor 1α (HIF-1α) and the role in the progression of gliomas. Methods: We adopted immunohistochemistry methods to detect expressions of PD-L1 and HIF-1α in 64 surgical specimens (23 cases for low-grade and 41 cases for high-grade gliomas, respectively). Immunoreactivity was analyzed in association with patients’ clinical characteristics or survival time. Expression of the PD-L1 and HIF-1α was analyzed in three GBM cell lines, U343, U373, and U251, under in vitro hypoxia (12, 24 or 72 h at 0.1% O2). Reverse transcriptase-polymerase chain reaction (RT-PCR) was carried out to detect the mRNA expression of PD-L1 and HIF-1α. Results: PD-L1 and HIF-1α protein expression was detected in 81.25% and 84.73% of glioma specimens, respectively. The expression of PD-L1 protein is positively correlated with HIF-1α (r = 0.52; p= 0.013). Kaplan–Meier analysis revealed a significant effect of PD-L1 grade on cumulative overall survival. Patients with negative PD-L1 expression survive longer than those with positive expression ( p= 0.007). PD-L1 and HIF-1α mRNA was most consistently upregulated in relation to duration of in-vitro hypoxia (72h, p= 0.007). There was a significant and positive relationship between the PD-L1 and HIF-1α mRNA expression (r = 0.45; p= 0.01). Conclusions: The present study showed a role for hypoxia/HIF-1α in driving immune escape and provided a potential novel cancer immunotherapy targeting hypoxia to block PD-L1 expression, which may boost the immune system in cancer patients.

Promising Targets for Cancer Immunotherapy: TLRs, RLRs, and STING-Mediated Innate Immune Pathways.

Malignant cancers employ diverse and intricate immune evasion strategies, which lead to inadequately effective responses of many clinical cancer therapies. However, emerging data suggest that activation of the tolerant innate immune system in cancer patients is able, at least partially, to counteract tumor-induced immunosuppression, which indicates triggering of the innate immune response as a novel immunotherapeutic strategy may result in improved therapeutic outcomes for cancer patients. The promising innate immune targets include Toll-like Receptors (TLRs), RIG-I-like Receptors (RLRs), and Stimulator of Interferon Genes (STING). This review discusses the antitumor properties of TLRs, RLRs, and STING-mediated innate immune pathways, as well as the promising innate immune targets for potential application in cancer immunotherapy.

Abstract 4991: Immunologic analyses of uveal melanoma patients treated with radiation therapy

Abstract Early stage uveal melanoma is frequently treated by radiation therapy (RT) alone. Preclinical studies suggest the efficacy of RT in melanoma is dependent on the immune system. We studied the immune system of patients with uveal melanoma before and after RT, hypothesizing there would be associations between these parameters and clinical outcomes. With institutional review board permission, patient, tumor, peripheral blood count characteristics were extracted from medical records of 299 patients with clinically localized uveal melanoma undergoing RT. Similar data was collected for 16 patients who presented with metastatic uveal melanoma at initial diagnosis. A subset of 8 patients treated with RT for uveal melanoma underwent peripheral blood sampling before, one and three months after RT on a prospective biospecimen collection protocol. Flow cytometry was performed to characterize leukocyte populations before and after RT. Serum was analyzed for cytokines and antibody titers before and after RT. Associations between neutrophil-to-lymphocyte ratio (NLR), leukocyte subpopulations, cytokines and antibody titers with tumor response to RT and survival were investigated. NLR was significantly lower in patients presenting with clinically localized uveal melanoma (mean 2.7), compared to those presenting with metastatic uveal melanoma at initial diagnosis (mean 3.4, p<0.05). Among patients with clinically localized uveal melanoma who underwent RT, a multivariable Cox regression model found that age, tumor stage, and NLR were all significantly associated with overall survival. Changes in several leukocyte populations were observed after RT, with the overall CD8 / regulatory T cell ratio increasing by 27% one month after RT. Increases in several cytokines were observed, with C reactive protein and granulocyte-macrophage colony stimulating factor increasing 2-3 fold in the first month after RT. One of eight patients seroconverted to a positive Melan-A antibody titer three months after RT; this was associated with one of the largest reductions in tumor size observed (>60%). In conclusion, several immune system parameters of patients with uveal melanoma treated with RT appeared to change after treatment, and may be associated with tumor response and treatment outcome, including survival. Further study on the development of distant metastasis in an expanded cohort of patients is planned. Additional investigations into the capacity of RT to modulate the immune system of cancer patients are warranted. Citation Format: Christopher A. Barker, Jasmine H. Francis, Robin K. Kuriakose, Ming Lian, Brian P. Marr, David H. Abramson. Immunologic analyses of uveal melanoma patients treated with radiation therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4991.

Abstract 2229: PD-L1 is expressed on CD11bhighCD14highHLA-DR+ myeloid cells in the tumor microenvironment of non-small cell lung cancer (NSCLC)

Abstract Understanding the immune system of cancer patients is essential for the development of optimal treatment. We analyzed tumor cells and infiltrating immune cells in tumor tissues of NSCLC to determine the type of cells which expressed immune checkpoint molecules and/or their ligands, and compared them to clinicopathological characteristics. To obtain a single cell suspension from the tumor tissues of lung cancer patients, each fresh tumor sample was chopped and treated with collagenase and DNase. The dissociated tumor tissue cells (DTCs) were stained with fluorochrome-labeled mAbs and the distribution of immune cell components and expression of surface markers in DTCs were determined by FACSuite analysis. The yield of DTCs was 5.87±4.73×10⁁7/gram. PD-L1, which is a ligand for immune checkpoint molecule PD-1, is expressed on CD11bhigh myeloid cells in the blood, regardless of HLA-DR expression. On the other hand, PD-L1 is expressed on CD11highCD14highSSClow myeloid cells in the tumor site. All PD-L1 expressing cells were positive for HLA-DR, a ligand for a T cell receptor of CD4 T cells. Furthermore, these cells also expressed both CD86 and CD124. Interestingly, most tumor cells expressed very low levels of the PD-L1 molecule. And we found that CD11highCD14+HLA-DR- myeloid cells did not express PD-L1. The proportion of CD11highCD14+HLA-DR-PD-L1- myeloid cells was higher in advanced stage patients than early stage patients. In conclusion, PD-L1 is expressed on CD11bhighCD14highHLA-DR+SSClow myeloid cells, but not CD11bhighCD14+HLA-DR- myeloid cells. We propose that the PD-L1+ myeloid cells are likely to play an important role in tumor immunity. Further functional studies will be necessary to determine how the interaction between the cells will affect immunity. code noagegendersmokingstagecell typePD-L1+HLA-DR+CD14highCD11bhigh cells (%)PD-L1-HLA-DR-CD14+CD11bhi cells (%)L-03257maleyesIAmucinous adenocarcinoma39.81.2L-05281maleyesIAadenocarcinoma19.44.1L-04849maleyesIIIAsquamous cell carcinoma4.09.0L-02471maleyesIIIAadenocarcinoma11.20.4L-03665maleyesIVadenocarcinoma11.45.3L-04273maleyesIVadenocarcinoma21.65.5L-04674malenoIAadenocarcinoma6.11.6L-02167femalenoIBlarge cell, adenocarcinoma14.72.3L-01976femalenoIBadenocarcinoma15.816.7L-27145femalenoIVadenocarcinoma11.217.2L-27245femalenoIVadenocarcinoma9.924.8 Citation Format: Chung-Hee Sonn, Yunji Oh, Tae Eun Kim, Jung Sun Ha, Hong Kwan Kim, Jong Ho Cho, Sumin Shin, Jhingook Kim. PD-L1 is expressed on CD11bhighCD14highHLA-DR+ myeloid cells in the tumor microenvironment of non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2229.

Targeting Monocytes with TLR7 Ligands as a Novel Opportunity in Immuno- Oncology

Cancer immunotherapy has for the last decade been one of the fastest developing therapeutic areas in oncology with promising clinical benefits, supporting a role of immunotherapy as a cornerstone in future cancer treatment in combination with existing treatments. Treatment of early stage cancers today is very efficient due to refined surgery, chemotherapy, radiation and use of therapeutic antibodies, but a large group of patients in particular with late stage and metastatic disease have poor prognosis due to lack of efficient treatment options. Thus, there is an urgent need to develop new technologies to provide more efficient treatment of late stage cancers, focused towards cure of these patients. One approach that may lead to better treatment is utilising the immune system of these patients, in order to generate durable anti-tumor memory immune responses. One strategy to boost the immune system of cancer patients has been administration of Toll Like Receptor ligands to overcome systemic and local immune escape mechanisms. In this commentary we discuss a novel delivery technology for systemic targeting of a Toll Like Receptor 7 ligand to monocytes in relation to current knowledge in cancer immunotherapy with perspectives on challenges and opportunities for clinical use of this technology.

Engineering WT1-Encoding mRNA to Increase Translational Efficiency in Dendritic Cells.

Dendritic cells (DCs) are the orchestrators of the immune system and are frequently used in clinical trials in order to boost the immune system in cancer patients. Among several available techniques for DC modification, mRNA electroporation is an interesting technique due to the favorable characteristics of mRNA. Antigen expression level and duration can be increased by multiple optimizations of an antigen-encoding mRNA template. Here, we describe different molecular modifications to a WT1-encoding mRNA construct in order to increase antigen expression and the subsequent introduction of mRNA into DCs.

Trabectedin for the treatment of breast cancer

Introduction: Trabectedin is an anti-tumor compound registered in Europe and in several other countries, for the second-line treatment of soft tissue sarcoma (STS) and for ovarian cancer in combination with liposomal doxorubicin. Trabectedin inhibits cancer cell proliferation mainly affecting the transcription regulation. Trabectedin also acts as a modulator of tumor microenvironment by reducing the number of tumor associated macrophages (TAM). Because of its unique mechanism of action, trabectedin has the potential to act as antineoplastic agent also in several solid malignancies, including breast cancer (BC).Areas covered: This article reviews the preclinical and clinical data of trabectedin focusing on development in metastatic BC (mBC). Comments regarding the nature and the results of these trials are included.Expert opinion: Trabectedin is thought to have a crucial activity with defective DNA-repair machinery and also in modulating the tumor micro-environment and the immune-system of cancer patients. From the current available data, we recognize a potential activity of trabectedin in mBC and support the renewed efforts to better elucidate the value of trabectedin in this indication.

Abstract 464: Hypoxia-induced miR-210 potentiates MDSC function through regulation of Arg1, Il-16 and Cxcl12, and promotes tumor growth

Abstract Myeloid Derived Suppressor Cells (MDSCs) are an integral component of the hypoxic tumor microenvironment. We demonstrated that hypoxia selectively induced miR-210 via HIF-1α in splenic MDSCs from tumor-bearing mice. Overexpression of miR-210 enhanced MDSC-mediated T cell suppression under normoxia, while targeting of hypoxic miR-210 decreased MDSC function. Our data show that miR-210 modulated MDSCs function by increasing arginase activity and NO production, although it had no effect on ROS or cytokine (IL-6 and IL-10) production and PD-L1 expression. A comprehensive approach using microRNA target predictions tool, transcriptome analysis, and luciferase reporter assay strongly pointed to the regulation of Arg1, Cxcl12 and Il16 at both mRNA and protein levels by miR-210 in splenic MDSCs. In mediating the immunosuppressive effects of miR-210, targeting of Arg1, and blockade of IL-16 and CXCL12, in splenic MDSCs from tumor-bearing mice under normoxia dramatically decreased MDSC-mediated T cell proliferative response and IFN-gamma production. Interestingly, miR-210 overexpressing MDSCs enhanced in vivo their immune suppressive activity resulting in an increase in 4T1 tumor growth. Therefore, the potential therapeutic use of miR-210 inhibitor oligonucleotide alone, or along with HIF-1α inhibitors as adjuvant tool combined to immunotherapeutic approaches, may be beneficial for boosting the immune system in cancer patients. Citation Format: Muhammad Zaeem Noman, Salem Chouaib. Hypoxia-induced miR-210 potentiates MDSC function through regulation of Arg1, Il-16 and Cxcl12, and promotes tumor growth. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 464. doi:10.1158/1538-7445.AM2015-464

Low pre-operative absolute monocyte count to predict overall survival benefit for oral cavity squamous cell carcinoma.

6077 Background: With the advent of immunotherapy, the role of the immune system in cancer patients is increasingly being investigated. The role of lymphocytes as indicators of the adaptive immune ...

Pathogenesis of Cancer: Cancer Reparative Trap

Cancer is one of the leading causes of death in the world while the long-term prognosis is still unfavorable, despite the enormous efforts in the search for effective anti-cancer drugs. We think that the obstacle for creating of effective anti-cancer drugs could be existing idea that the basis of cancer is caused by the damage of the genetic apparatus of the cell. In this paper, we present the pathogenesis of cancer which is based on the formation of the special sustainable pathophysiological state of the organism what we call the state of “cancer reparative trap”. The essence of this pathophysiological state of the organism is in the reparative orientation of the immune system of cancer patients, when constant tissue repair is accompanied by systemic suppression of the anti-tumor immunity. Specifically, during the long-term exposure to carcinogens (exogenous and/or endogenous), the continuous tissue damage occurs which induces permanent stimulation of cell proliferation (imbalanced Th1 Th2 lymphocytes, M1 et al.), which creates the necessary conditions for the survival of the malignantly transformed cells, formed by the action of carcinogens. The determining role of the imbalance in the autonomous nervous system (simpathetic/hypersympathetic dominance) in the development, maintenance and generalization of the cancer process has been shown. The explanation of a number of phenomena has been presented: the cell resistance to chemotherapy, and the phenomenon of cancer cell dormancy. The promising approaches for the cancer management in clinical practice have been proposed.

Low Doses of Cisplatin can Help Dendritic Cell Vaccines to Reduce Immunosuppression in Tumor Microenvironment

ABSTRACT Introduction Lack of effectiveness of most immunotherapy methods requires new approaches. One of the most promising approaches, intensively investigated worldwide, is combined therapy based on dendritic cells (DC) and low-dose chemotherapy. The using of low-dose chemotherapy reduces the tumor's suppressor component, which in turn decreases the suppression of the immune system of cancer patients. The aim: to investigate the effect of chemo-immunotherapy on the suppression component of the immune system in murine sarcoma-37 (S37) model. Methods In experimental investigation 80 CBA mice have been involved. S37 was injected intramuscularly at lethal dose (2*106 cells per animal). Cisplatin was administered intraperitoneally five times according to the two schemes: 0.2 or 2 mg/kg on the 7th day after tumor transplantation with interval of 1 day and 3 days, respectively. DC vaccines were administered intravenously 3 times on 4 day after the chemotherapy with 3 days interval. Results We have found that both of the proposed chemoimmunotherapy schemes had a significant antitumor and immunomodulation effect. The most pronounced effect was observed when used DC-vaccine and cisplatin at dose of 2 mg/kg in combination. Combination of DC vaccine and 2 mg/kg cisplatin had a synergistic effect: significantly decreasing of primary tumor volume in animals compared to the control (p = 0.001) and DC-vaccine (p = 0.007) groups have been found. We have shown that administration of DC vaccine and 2 mg/kg cispatin decreases the TGF-b mRNA expression level in the tumor microenvironment (р = 0.0013) compared with the control group. Moreover, the administration of this combined therapy decrease VEGF mRNA expression level in tumor microenvironment in 2 times (р = 0.005) compared with the control group. Conclusions Low-dose cisplatin in combination with DC-vaccine reduces immunosuppression and neoangiogenesis in the tumor microenvironment. Disclosure All authors have declared no conflicts of interest.

Efficacy of Saam acupuncture treatment on improvement of immune cell numbers in cancer patients: a pilot study

ObjectiveTo collect preliminary data on the effects of Saam acupuncture with regard to the immunity in cancer patients. MethodsTen cancer patients were analyzed for improvements in immunity. Acupuncture was applied at the 5 acupuncture points, Jingqu (LU 8), Zutonggu (BL 66), Yanggu (SI 5), Yangchi (TE 4), and Zhongwan (CV 12) for 2 weeks with 4 sessions. We assessed the effect of Korean Saam acupuncture on the immune system in cancer patients by measuring particular blood cell subsets, including CD3+, CD4+, CD8+, CD19+, and CD56+ cells, as well as total white blood cell count, absolute neutrophil count, and fatigue score. The measurement was performed before and after acupuncture and at a 2-week follow-up. ResultsThere was a statistically significant increase in the number of CD3+ (P=0.023) and CD8+ cells (P<0.001) and T-cell subsets, as well as a decrease in the fatigue severity scale (FSS) score (P= 0.001) after Saam acupuncture using the 5 acupoints. ConclusionAcupuncture may improve the immune system by increasing the counts of a few immune cells and relieve fatigue in cancer patients by decreasing FSS scores. Although this was a non-controlled study, it constitutes preliminary research investigating the potential effects of Saam acupuncture in increasing the counts of several immune cells in cancer patients.

Abstract 2540: Immune modulation by the TLR8 agonist VTX-2337; a comparison of the pharmacodynamic response in cancer patients and healthy volunteers

Abstract Immunotherapy has proven to be a successful treatment approach for some cancer patients. One promising paradigm in immunotherapy is targeting pathogen-associated molecule pattern receptors (PAMPS) such as the toll-like receptors (TLRs) to activate the innate immune system and enhance the development of tumor-directed adaptive immune responses. However, an ongoing concern in the application of immunotherapeutics is the potential for the immune response in cancer patients to be less robust than in healthy individuals, due to the underlying advanced neoplastic disease or due to previous regimens of cytotoxic drugs. To address this concern in relation to the response to TLR8 stimulation, we compared the pharmacokinetic and pharmacodynamic (PK/PD) relationship defined in a phase 1 clinical trial of the selective small molecule TLR8 agonist VTX-2337 in oncology patients to the response in healthy volunteers. A phase 1 dose-escalation clinical trial (A101) in subjects with advanced solid tumors (n=33) demonstrated that plasma levels of multiple biomarkers of immune activation, including G-CSF, MCP-1, MIP1-β and TNFα, increased in a dose-dependent manner and correlated with increasing plasma levels of VTX-2337. The PK/PD relationship defined in the initial clinical trial was closely aligned with predictions from both in vitro assays and preclinical studies conducted in cynomolgus monkeys. A subsequent phase 1 trial (A105) was conducted as a single-center, open-label, two-period, randomized, crossover, phase 1 study in normal volunteers (n=10). The objective of this study was to compare the PK/PD profiles and local tolerance of two formulations of VTX-2337. In this study, the two preparations of VTX-2337 demonstrated comparable PK profiles and PD responses. At comparable dose levels, the PK profile and overall exposure (AUC) to VTX-2337 was similar for oncology patients and healthy volunteers. VTX-2337 induced the same repertoire of circulating cytokines and chemokines, indicative of TLR8 activation, in both populations. The magnitude of the mediator response in oncology patients was also highly comparable to the response in healthy volunteers that received a similar dose. This comparison demonstrates that the immune system of cancer patients with advanced disease remains highly responsive to TLR8 activation by VTX-2337. In summary, advanced neoplastic disease or a prior treatment history with cytotoxic agents that can negatively impact immune cell function did not appear to moderate the response to VTX-2337 based on the PK/PD relationship using predictive biomarkers. Citation Format: Greg Dietsch, Donald Northfelt, Ramesh Ramanathan, Peter Cohen, Kristi Manjarrez, Mona Newkirk, James Kyle Bryan, Robert Hershberg. Immune modulation by the TLR8 agonist VTX-2337; a comparison of the pharmacodynamic response in cancer patients and healthy volunteers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2540. doi:10.1158/1538-7445.AM2014-2540

The Combination of Antitumor Vaccine and Low Doses of Doxorubicin As an Effective Method Against Tumor Immunosuppression

ABSTRACT Aim: Combined therapy based on dendritic cells (DC) and low-dose chemotherapy is being intensively investigated worldwide. The using of low-dose chemotherapy, such as cyclophosphamide, reduces the number of T-regulatory cells, which in turn decreases the suppression of the immune system of cancer patients. The aim: to investigate the influence of combined immunotherapy on T-regulatory component of the immune system in murine sarcoma-37 model. Methods: In experimental investigation 120 CBA mice have been involved. Sarcoma-37 was injected intramuscularly at lethal dose (2*106 cells per animal). Doxorubicin was injected intraperitoneally 5 times in metronomic regimen according to the two schemes: 0.2mg/kg or 2 mg/kg on the 7th day after tumor transplantation with interval of 1 day and 3 days, respectively. DC vaccines were administered intravenously 3 times on day 4 after the chemotherapy in 3 day interval. Results: We have found that both of the proposed chemoimmunotherapy schemes had a significant antitumor and immunomodulating effect. Significant decreasing of primary tumor volume in both animal groups which received combined therapy compared with the control has been found (p Conclusions: Low-dose chemotherapeutics decrease the tumor suppression on immune system and enhance the antitumor effect of DC-based immunotherapy. These investigations form the basis to a new multimodality treatment in cancer patients. Disclosure: All authors have declared no conflicts of interest.

Phenotyping of peripheral blood mononuclear cells of patients with advanced heavily pre-treated adenocarcinoma of the stomach and gastro-esophageal junction.

Immunotherapeutic approaches are emerging as promising new treatment options for patients with solid cancers. The host immune system in cancer patients is dysfunctional due to a number of reasons. The level of immunosuppression is variable at the time of diagnosis and depends on the particular cancer entity, stage, and prior anti-cancer therapies. For many cancer entities, the immune alterations of the respective patient population have not been further characterized even though a patient's immunophenotype may be prognostic for the course of the disease or predictive for clinical/biological response to immunotherapy. In this study, we used flow cytometry to determine the phenotype of peripheral blood mononuclear cells (PBMCs) from 30 patients with heavily pre-treated, advanced adenocarcinoma of the stomach and gastro-esophageal junction. The frequencies and activation status of relevant immune effector populations were determined in PBMCs and compared to those of healthy individuals. This report provides comprehensive immune phenotyping data of a patient population with a high medical need.

The IL-2 cytokine family in cancer immunotherapy

The use of cytokines from the IL-2 family (also called the common γ chain cytokine family) such as interleukin (IL)-2, IL-7, IL-15, and IL-21 to activate the immune system of cancer patients is one of the most important areas of current cancer immunotherapy research. The infusion of IL-2 at low or high doses for multiple cycles in patients with metastatic melanoma and renal cell carcinoma was the first successful immunotherapy for cancer proving that the immune system could completely eradicate tumor cells under certain conditions. The initial clinical success observed in some IL-2-treated patients encouraged further efforts focused on developing and improving the application of other IL-2 family cytokines (IL-4, IL-7, IL-9, IL-15, and IL-21) that have unique biological effects playing important roles in the development, proliferation, and function of specific subsets of lymphocytes at different stages of differentiation with some overlapping effects with IL-2. IL-7, IL-15, and IL-21, as well as mutant forms or variants of IL-2, are now also being actively pursued in the clinic with some measured early successes. In this review, we summarize the current knowledge on the biology of the IL-2 cytokine family focusing on IL-2, IL-15 and IL-21. We discuss the similarities and differences between the signaling pathways mediated by these cytokines and their immunomodulatory effects on different subsets of immune cells. Current clinical application of IL-2, IL-15 and IL-21 either as single agents or in combination with other biological agents and the limitation and potential drawbacks of these cytokines for cancer immunotherapy are also described. Lastly, we discuss the future direction of research on these cytokines, such as the development of new cytokine mutants and variants for improving cytokine-based immunotherapy through differential binding to specific receptor subunits.

A therapeutic perspective of cytokines in tumor management

Malignant cancer is a serious threat to the health of men and women worldwide, yet no single or combine treatment strategy exists that can effectively eliminate this disease. Recent years, significant interest has been generated in targeting immune system of cancer patients for therapeutic and preventive purposes. Among the several components of immune system, chemokines and cytokines are key potential targets for immunotherapy of cancer. This review provides a brief overview of the current knowledge and recent updates on the use of cytokines or chemokines in cancer therapy and management.

Nanoparticles in the Development of Therapeutic Cancer Vaccines

Cancer vaccines have garnered great interest as a potential arsenal to treat patients with cancer. The main goal and challenge in cancer immunotherapy includes the activation of the otherwise indolent immune system of cancer patients. It has been discovered that cytotoxic T cell mediated immune response is most efficacious in killing cancer cells. However, even if the immune system of a cancer patient is activated, there is no guarantee that such activation will be translated into cancer cell death. Nanotechnology has already transformed the field of small molecule therapy and holds promise to have similar impact on the field of cancer vaccines. Nanoparticles can be tailored to target specific receptors in immune competent or cancer cells and even elicit specific type of immune response. Desirable effects of nanoparticles can be controlled through modification of factors such shape, size, surface charge, composition, and hydrophobicity. Another advantage of nanoparticles includes the ability of simultaneous delivery of multiple antigens and adjuvant-antigen combinations, thereby increasing the likelihood of triggering an immune response. Extrapolating from the progress that nanoparticles have helped to make in other areas, it can be anticipated that nanotechnology approach would accelerate the process of clinical applications of cancer vaccines.