Cancer Immunotherapy Research Papers - Academia.edu (original) (raw)

There is an urgent need to develop new combination therapies beyond existing surgery, radio-and chemo-therapy, perhaps initially combining chemotherapy with the targeting specificities of immunotherapy. For this, strategies to limit inflammation and immuno-suppression and evasion in the tumour microenvironment are also needed. To devise effective new immunotherapies we must first understand tumour immunology, including the roles of T cells, macrophages, myeloid suppressor cells and of exosomes and micro-vesicles (EMVs) in promoting angiogenesis, tumour growth, drug resistance and metastasis. One promising cancer immunotherapy discussed uses cationic liposomes carrying tumour RNA (RNA-lipoplexes) to provoke a strong anti-viral-like (cytotoxic CD8 1) anti-tumour immune response. Mesenchymal stem cell-derived EMVs, with their capacity to migrate towards inflammatory areas including solid tumours, have also been used. As tumour EMVs clearly exacerbate the tumour microenvironment, another therapy option could involve EMV removal. Affinity-based methods to deplete EMVs, including an immunodepletion, antibody-based affinity substrate, are therefore considered. Finally EMV and exosome-mimetic nanovesicles (NVs) delivery of siRNA or chemotherapeutic drugs that target tumours using peptide ligands for cognate receptors on the tumour cells are discussed. We also touch upon the reversal of drug efflux in EMVs from cancer cells which can sensitize cells to chemotherapy. The use of immunotherapy in combination with the advent of EMVs provides potent therapies to various cancers.

- by
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- Cancer Immunotherapy, Cancer Research, Exosomes and Microvesicles

Tumor microenvironment (TME) is a host for a complex network of heterogeneous stromal cells with overlapping or opposing functions depending on the dominant signals within this milieu. Reciprocal paracrine interactions between cancer cells with cells within the tumor stroma often reshape the TME in favor of the promotion of tumor. These complex interactions require more sophisticated approaches for cancer therapy, and, therefore, advancing knowledge about dominant drivers of cancer within the TME is critical for designing therapeutic schemes. This review will provide knowledge about TME architecture, multiple signaling, and cross communications between cells within this milieu, and its targeting for immunotherapy of cancer.

- by Masoud Najafi
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- Cancer, Breast Cancer, Chemotherapy, Cancer stem cells

PDL1 blockade produces remarkable clinical responses, thought to occur by T cell reactivation through prevention of PDL1-PD1 T cell inhibitory interactions. Here, we find that PDL1 cell-intrinsic signaling protects cancer cells from interferon (IFN) cytotoxicity and accelerates tumor progression. PDL1 inhibited IFN signal transduction through a conserved class of sequence motifs that mediate crosstalk with IFN signaling. Abrogation of PDL1 expression or antibody-mediated PDL1 blockade strongly sensitized cancer cells to IFN cytotoxicity through a STAT3/caspase-7-dependent pathway. Moreover, somatic mutations found in human carcinomas within these PDL1 sequence motifs disrupted motif regulation, resulting in PDL1 molecules with enhanced protective activities from type I and type II IFN cytotoxicity. Overall, our results reveal a mode of action of PDL1 in cancer cells as a first line of defense against IFN cytotoxicity.

- by David Escors
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- Cancer, Cancer Immunotherapy, Cancer Immunology, Signal Transduction

Immune checkpoint inhibitors and Chimeric Antigen Receptor (CAR) T-cell therapies have emerged as concomitant approaches to treat B-cell malignancies. Immune checkpoint blockade are monoclonal antibodies that override the evasion by tumors of self-destruction through inhibitory signaling. CAR T-cells are genetically modified to express CAR and, like monoclonal antibodies, are targeted therapies directed toward antigens on tumor cells. Initial studies of immune checkpoint inhibitors and CAR T-cell therapies report clinical data demonstrating safety and efficacy for both approaches and have constituted a paradigm shift in the treatment of cancer. Subsequent clinical data reveal safety and efficacy, and also associated toxicities for both approaches. Immune related adverse events can affect patients' quality of lives adversely. Further studies may focus on mitigating adverse events and benefitting patients.

- by Priya Hays
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- Cancer Immunotherapy, Hematological malignancy

Immunotherapy is becoming the standard of care for melanoma. However, resistance to therapy is a major problem. Previously, we showed that tumor-specific, cytotoxic CD4+ T cells from tyrosinase-related protein 1 transgenic mice could overcome second- ary resistance to recurring melanoma when anti–programmed cell death 1 ligand (PD-L1) checkpoint blockade was combined with either anti–lymphocyte-activated gene 3 (LAG-3) Abs or depletion of tumor-specific regulatory T (Treg) cells. In this study, we show that PD-L1 expressed by the host, not B16 melanoma, plays a major role in the early stages of exhaustion or primary resistance. We observed durable regression of melanoma in tumor-bearing PD-L12/2RAG2/2 mice with transfer of naive tumor- specific CD4+ T cells. However, exhausted tumor-specific CD4+ T cells, which included tumor-specific Treg cells, failed to maintain durable regression of tumors in PD-L12/2RAG2/2 mice unless tumor-specific Treg cells were eliminated, showing nonredundant pathways of resistance to immunotherapy were present. Translating these findings to a clinically relevant model of cancer immunotherapy, we unexpectedly showed that anti–PD-L1 checkpoint blockade mildly improved immunotherapy with tumor- specific CD4+ T cells and irradiation in wild-type mice. Instead, anti–LAG-3 checkpoint blockade, in combination with tumor- specific CD4+ T cells and irradiation, overcame primary resistance and treated established tumors resulting in fewer recurrences. Because LAG-3 negatively regulates effector T cell function and activates Treg cells, LAG-3 blockade may be more beneficial in overcoming primary resistance in combination immunotherapies using adoptive cellular therapy and irradiation than blockade of PD-L1. The Journal of Immunology, 2018, 200: 3304–3311.

- by Paul Andrew Antony, MD
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- Cancer Immunotherapy, Melanoma, Immunotherapy, CD4 cells

Immunotherapy using checkpoint-blocking antibodies against targets such as CTLA-4 and PD-1 can cure melanoma and non-small cell lung cancer in a subset of patients. The presence of CD8 T cells in the tumor correlates with improved survival. We show that immuno-positron emission tomography (immuno-PET) can visualize tumors by detecting infiltrating lymphocytes and, through longitudinal observation of individual animals, distinguish responding tumors from those that do not respond to therapy. We used 89Zr-labeled PEGylated single-domain antibody fragments (VHHs) specific for CD8 to track the presence of intratumoral CD8+ T cells in the immunotherapy-susceptible B16 melanoma model in response to checkpoint blockade. A 89Zr-labeled PEGylated anti-CD8 VHH detected thymus and secondary lymphoid structures as well as intratumoral CD8 T cells. Animals that responded to CTLA-4 therapy showed a homogeneous distribution of the anti-CD8 PET signal throughout the tumor, whereas more heterogeneous infiltration of CD8 T cells correlated with faster tumor growth and worse responses. To support the validity of these observations, we used two different transplantable breast cancer models, yielding results that conformed with predictions based on the antimelanoma response. It may thus be possible to use immuno-PET and monitor antitumor immune responses as a prognostic tool to predict patient responses to checkpoint therapies.

BCG immunotherapy has been a standard in superficial (muscle non-invasive) form of bladder cancer for more than fourty years. Schemes for application of BCG are determined for each patient individualy after transurethral resection (TUR), accordingly to guidelines proposed by European Association of Urology. Immunotherapy reduces the number of disease recurrence and progression from superficial to muscle-invasice form of disease, although some patients may not have satisfactory response to therapy. These patients are further classified into BCG-refractory, BCG-relapsing and BCG-intolerant groups. Adverse effects are numerous and common and usually include disuria, haematuria, fever and rare secondary affliction of other organs and systemic inflammatory response which require antibiotics and supportive treatment. There is a tendency to develop new medications such as nano-BCG, monoclonal antibodies or vaccines which could lessen adverse effects during and after treatment and improve patient's outcome.

- by Tena Piljušić
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- Health Sciences, Oncology, Urology, Immunology

The dismal prognosis of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) prompted recent advances in the field of therapeutic approaches beyond cytotoxic cancer therapy. In recent years, the deeper and increasing knowledge on the genomic landscape and the upcoming new data on immunotherapy enacted by HNSCCs have led to successful therapeutic targeting of the immune system. Immune checkpoint inhibitors (ICIs) have changed state of the art in R/M patients and could have a potential role even in early disease. The purpose of this work is to summarize the role of immunotherapy for R/M HNSCC in clinical practice, with insights about future perspectives. Updated immunotherapy results in other R/M head and neck cancers such as thyroid, salivary glands, nasopharynx, sinonasal cancers, and nuclear protein in testis (NUT) are presented.

" Global CAR T Cell Therapy Market & Clinical Trials Insight 2024" Report Highlights: • CAR T-Cell Therapies Delivery Pipeline & Mechanism of Action • Sales Analysis of CAR - T Cell Therapy • CAR - T Cell Therapy Market Opportunity: US$... more

- by KuicK Research
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- Oncology, Immunology, Cancer, Cell Biology

What was an innovation at one time, like the first personal computer, is nowadays ‘commercial of the shelf’ and we take this for granted. The use of computers for business and private life has had a big impact on society during the last four decades in the way we work and communicate as well as the interaction between people and machines. No longer is it just man who controls a process by using a machine as the machine has become more or less independent and controls the process where man is supervising. Computers and machines are more and more integrated i.e. printing this book ‘on demand’ starts at a website where you order the book, payment is taken care of, the command to print is given to the printer anywhere in the world and delivery at home will follow. Man is ‘only’ involved in the final step of driving the delivery truck to your home and even this last step could be done by a drone. This is just an example of how information technology has greatly influenced our lives these last forty years and what this book is all about. Information technology is regarded in this book as the way data is electronically processed in interaction with humans. A variety of international authors show their involvement on developments of information technology and innovations during the last four decades. Many authors have come together for this book to write about their experience and knowledge in this timespan focusing on their expertise. They come from The Netherlands, Israel, The Philippines and Pakistan. The authors are experts in their field and or attached to universities in Europe, the USA and Asia. These are academics as well as professionals in their own field who want to share the developments they have witnessed with any laymen. Most of the chapters can be read individually and in any order. You can find out more on subjects like soft & hardware, machine language, search engines, medical, DNA, et cetera

- by Shazia Tahira and +1
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- Programming Languages, Artificial Intelligence, Information Technology, History Of Computing

Kanserli doku çevresindeki immun sistemi adeta "uyutan" sitokinler salgılayarak kendi üzerinde selektif immunsupresyon sağlar. Peki bu immun tolerans kırılabilir mi? Lenfositlere yapay olarak belli antijenler eklenerek kanserli dokuya karşı bir alerji türetilebilir mi?...
İmmunoterapi Yabancı antijen uygulama işlemi olduğu için verilen monoklonal antikorlar ciddi advers yan etkilere yol açabilir. Kanser tedavisinde immunoterapiyi riskli bulsam da sadece mekanizmaları derlemeye çalıştım. Immunoterapi bence ancak büyük tümor kitlelerinin hızlı bir biçimde yok edilmesinde yardımcı olabilir. Monoklonal antikorlar,uygun durumlarda kullanılmadığında; bir protein grefti olarak,yabancı alerjene karşı immun tepkiler oluşturacaktır, bu da trombozdan ciddi organ iskemik yetmezliklerine kadar korkunç tablolara yol açabilir. Kanser tedavisinde temel rolü immunoterapiye vermek, fizyopatolojik mantığa yani tıbbın felsefesine aykırıdır.

- by Taylan Bektaş
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- Tumor Immunology, Cancer Immunotherapy

Cancer is one of the leading causes of death worldwide according to data from the U.S. National Cancer Institute, with approximately 14 million new cases and 8.2 million of cancer-related deaths in 2018. More than 60% of the new annual cases in the world occur in Africa, Asia, Central America, and South America, with 70% of cancer deaths in these regions. Recently they have been used for breast cancer, novel approaches among which several molecules that block signaling pathways and also reactivate the immune system by inhibiting the activities of two lymphocytes T receptor inhibitors; CTLA-4 and PD-1 in triple negative breast cancer. Although there is evidence, which supports the blocking of these inhibitory molecules, reactive the response of T cells does not always result, surely because in addition to need to reactivate the response Th1 is necessary co-activation of killer cells Natural (NK), the latter are the main actors of the anticancer response. Therefore, combining therapies with the coordinated activation of each cell of the immune response involved will probably produce better results. Through a better understanding of the interactions of the Th1 response and the action of the inhibitors of PD-1 and CTLA-4 and the intratumoral microenvironment, we believe that it would improve breast cancer therapy. In this article, recent advances in the treatment of cancer aimed at blocking signaling pathways and the use of monoclonal antibodies directed to receptors were reviewed. Likewise, it is proposed to combine therapies with antibodies that block PD-1 and CTLA-4 with the activation of the Th1 and NK response, in situ or with extracorporeal activation of autologous cells.

- by Raul Barrera
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- Breast Cancer, Cancer Immunotherapy, Immune Checkpoint Inhibitors

In this review on current therapy in non-small cell lung cancer (NSCLC), the current status of immune therapy is presented. This therapeutic area is dominated by the biological therapeutics, or “biologics”. Firstly, the immune checkpoint inhibitors include antibodies to PD-1, e.g., nivolumab (BMS-936558) and pembrolizumab (MK-3475), and anti- bodies to PD-L1, i.e., BMS-936559, MPDL-3280A and MEDI-4736. Secondly, the vaccines include the EGF vaccine (CIMAvax-EGF®), astuprotimut-R (Zumagev, MAGE-A3), belagenpumatucel-L (Lucanix®), tecemotide (L-BLP-25, Stimuvax®), tergenpumatucel-L, TG-4010, tertomotide (GV-1001), INGN-225, MVA-5T4 (TroVax®) and CV-9202. Thirdly, there are now some developments in adoptive cell transfer in NSCLC, with ongoing clinical trials involving carcinoembry- onic antigen and NY-ESO-1 as targets for “designer” T cells. Finally, new areas of immune therapy are discussed, including chimeric anti- gen receptors and peptides as immune vaccines. A number of new clin- ical trials are ongoing in immune therapy in NSCLC and these are summarized.

- by Dinah Parums
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- Pathology, Oncology, Personalized Medicine, Cancer Immunotherapy

Cancer stem cells (CSCs) are a population of self-renewal cells with high tumorigenic potency. CSCs can adopt easily with changes in the nearby milieu, and are more resistant to conventional therapies than other cells within a tumor. CSC resistance can be induced secondary to radio-and chemotherapy, or even after chemotherapy secession. A combination of both intrinsic and extrinsic factors is contributed to CSC-mediated therapy resistance. CSCs represent protective autophagy and efficient cell cycling, along with highly qualified epithelial-mesenchymal transition (EMT) regulators, reactive oxygen species (ROS) scavengers, drug transporters, and anti-apoptotic and DNA repairing systems. In addition, CSCs develop cross-talking and share some characteristics with other cells within the tumor microenvironment (TME) being more intense in higher stage tumors, and thereby sophisticating tumor-targeted therapies. TME, in fact, is a nest for aggravating resistance mechanisms in CSCs. TME is exposed constantly to the nutritional, metabolic and oxygen deprivation; these conditions promote CSC adaptation. This review is aimed to discuss main (intrinsic and extrinsic) mechanisms of CSC resistance and suggest some strategies to revoke this important promoter of therapy failure.

- by Masoud Najafi
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- Cancer, Cancer stem cells, Cancer Immunotherapy

The knowledge that the body possesses natural defenses to combat cancer existed long before the modern period, with multiple anecdotal reports of tumors miraculously disappearing, sometimes spontaneously or after a febrile or infectious episode. Spontaneous tumor regression of untreated malignant tumors is currently a well-accepted albeit rare phenomenon, and it is recognized that immunosuppression is associated with a higher cancer risk. The treatment of bladder carcinoma by intravesical administration of live attenuated Bacillus Calmette-Guérin bacteria was shown to be very effective in 1976 and is now standard treatment. Effective immunity against cancer involves complex interactions between the tumor, the host, and the environment. Cancer immunotherapy uses various strategies to augment tumor immunity and represents a paradigm shift in treating cancer, since attention has become more focused on the "biologic passport" of the individual tumor rather than the site of origin of the tumor. The different types of cancer immunotherapies discussed here include biologic modifiers, such as cytokines and vaccines, adoptive cell therapies, oncolytic viruses, and antibodies against immune checkpoint inhibitors, such as the co-inhibitory T-cell receptor PD-1 and one of its ligands, programmed death-ligand 1. ABSTRACT Article history:

Background: Tumor metabolism is a crucial factor for the carcinogenesis of oral squamous cell carcinoma (OSCC). Methods: Expression of IGF-R1, glycolysis-related proteins (GLUT-1, HK 2, PFK-1, LDHA, TKTL1), mitochondrial enzymes (SDHA, SDHB, ATP synthase) were analyzed in normal oral mucosa (n = 5), oral precursor lesions (simple hyperplasia, n = 11; squamous intraepithelial neoplasia, SIN I-III, n = 35), and OSCC specimen (n = 42) by immunohistochemistry and real-time polymerase chain reaction (qPCR) analysis in OSCC cell lines. Metabolism-related proteins were correlated with proliferation activity (Ki-67) and apoptotic properties (TUNEL assay) in OSCC. Specificity of antibodies was confirmed by western blotting in cancer cell lines. Results: Expression of IGF-R1, glycolysis-related proteins (GLUT-1, HK 2, LDHA, TKTL1), and mitochondrial enzymes (SDHA, SDHB, ATP synthase) were significantly increased in the carcinogenesis of OSCC. Metabolic active regions of OSCC were strongly correlated with proliferating cancer (Ki-67+) cells without detection of apoptosis (TUNEL assay). Conclusions: This study provides the first evidence of the expression of IGF-R1, glycolysis-related proteins GLUT-1, HK 2, PFK-1, LDHA, and TKTL1, as well as mitochondrial enzymes SDHA, SDHB, and ATP synthase in the multi-step carcinogenesis of OSCC. Both, hypoxia-related glucose metabolism and mitochondrial oxidative phosphorylation characteristics are associated with the carcinogenesis of OSCC. Acidosis and OXPHOS may drive a metabolic shift towards the pentose phosphate pathway (PPP). Therefore, inhibition of the PPP, glycolysis, and targeted anti-mitochondrial therapies (ROS generation) by natural compounds or synthetic vitamin derivatives may act as sensitizer for apoptosis in cancer cells mediated by adjuvant therapies in OSCC.

- by Mate Hidvegi
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- Oncology, Integrative Medicine, Complementary and Alternative Medicine, Cancer

A wide-range of myeloid-derived suppressor cell (MDSC)-mediated immune suppressive functions has previously been described. Nevertheless, potential novel mechanisms by which MDSCs aid tumor progression are, in all likelihood, still unrecognized. Next to its well-known expression in natural killer cells and cytotoxic T lymphocytes (CTLs), granzyme B (GzmB) expression has been found in different cell types. In an MDSC culture model, we demonstrated perforin and GzmB expression. Furthermore, similar observations were made in MDSCs isolated from tumor-bearing mice. Even in MDSCs from humans, GzmB expression was demonstrated. Of note, B16F10 melanoma cells co-cultured with perforin/GzmB knock out mice (KO) MDSCs displayed a remarkable decrease in invasive potential. B16F10 melanoma cells co-injected with KO MDSCs, displayed a significant slower growth curve compared to tumor cells co-injected with wild type (WT) MDSCs. In vivo absence of perforin/GzmB in MDSCs resulted in a higher number of CD8 + T-cells. Despite this change in favor of CD8 + T-cell infiltration, we observed low interferon-γ (IFN-γ) and high programmed death-ligand 1 (PD-L1) expression, suggesting that other immunosuppressive mechanisms render these CD8 + T-cells dysfunctional. Taken together, our results suggest that GzmB expression in MDSCs is another means to promote tumor growth and warrants further investigation to unravel the exact underlying mechanism.

- by David Escors and +3
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- Oncology, Immunology, Cancer, Tumor Immunology
- by Kaushik Banerjee
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- Immune response, Clinical Trial, Cancer Immunotherapy, Humanized mouse models

TR
Akciğer kanserinin patogenezinde rol oynayan immün hücrelerden biri, doğal öldürücü (NK) hücrelerdir ve bu hücreler, akciğer kanserinde terapötik uygulamalar için yeni hedeflerdir.
NK hücre temelli immünoterapinin akciğer kanseri sağ kalımını nasıl etkilediğine odaklanarak, akciğer kanseri üzerine uygulamaları hakkındaki güncel literatürü özetlenmektir.
NK hücrelerinin sitolitik potansiyeli, akciğer kanserinde azalır, NK hücre fonksiyonunun iyileştirilmesinin, tümör regresyonuna neden olabileceğini düşündürmektedir.
IL-2, IL-12 ve IL-15, NK-92 hücre çizgileri ve allojenik NK hücre immünoterapisini içeren sitokinler gibi NK hücre bazlı yeni tedaviler üzerinde yapılan son klinik çalışmalar, akciğer kanseri sağ kalımı üzerinde daha az yan etkiye sebep olan umut verici sonuçlar göstermiştir.
NK hücre hedefleme stratejisi henüz akciğer kanseri tedavisi için onaylanmamıştır.
Akciğer kanseri patogenezinde NK hücrelerinin rolüne odaklanan daha fazla klinik çalışma, akciğer kanserinin tedavisi için yeni NK hücre bazlı terapötik yaklaşımlar geliştirmeye hedeflenmiştir.
ENG
One of the immune cells involved in the pathogenesis of lung cancer is natural killer (NK) cells, which are new targets for therapeutic applications in lung cancer.
To summarize the current literature on lung cancer applications, focusing on how NK cell-based immunotherapy affects lung cancer survival.
The cytolytic potential of NK cells decreases in lung cancer, suggesting that improvement of NK cell function may lead to tumor regression.
Recent clinical studies on NK cell-based new therapies such as IL-2, IL-12, and IL-15, NK-92 cell lines, and cytokines including allogeneic NK cell immunotherapy have shown promising results that have a less adverse effect on lung cancer survival.
The NK cell targeting strategy has not yet been approved for the treatment of lung cancer.
More clinical trials focusing on the role of NK cells in the pathogenesis of lung cancer are aimed to develop new NK cell-based therapeutic approaches for the treatment of lung cancer.

- by Burak Can Güney
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- Immunology, Cancer, Cytokines, Cancer Immunotherapy

Cancer development often implies failure of the immune system to recognize tumor antigens and kill malignant cells. While the whole immune cell repertoire is broad, that of immune cells with the ability to react to individual tumor antigens is usually very limited. The purpose of cancer immunotherapy is to augment the power, quantitative and qualitative, of the immune system such that it readily recognizes and eliminates cancer cells. As immune therapy is shifting toward more personalized medicine, different types of tumor antigens can be used as target antigens to allow T cells to destroy tumor cells. These antigens are mostly defined as tumor associated antigens (TAA), neoantigens or minor histocompatibility antigens. Their clinical usage involve either direct injection of TAA and neoantigens, administration of peptide-loaded dendritic cells in vaccination approaches, or infusion of ex vivo expanded tumor-specific T cells. However, such cellular therapies are facing several challenges including immune suppressive tumor microenvironment, lack of persistence of ex vivo expanded antigen specific T cells and potential off-target toxicity of these therapies. In this review, we will discuss recent advances allowing for better expansion of tumor reactive T cells and novel strategies used to overcome the challenges facing cellular therapy for cancer.

- by Denis-Claude Roy
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- Immunology, Cancer Immunotherapy, Immunotherapy, adoptive T cell transfer

Recent years have seen significant efforts in understanding and modulating the immune response in cancer. In this context, immunosuppressive cells, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), have come under intense investigation for their proposed roles in suppressing tumor-specific immune responses and establishing an immunosuppressive tumor microenvironment, thus enabling tumor immune evasion. Additionally, recent evidence indicates that Tregs comprise diverse and heterogeneous subsets; phenotypically and functionally distinct subsets of tumor-infiltrating Tregs could contribute differently to cancer prognosis and clinical outcomes. Understanding Treg biology in the setting of cancer, and specifically the tumor microenvironment, is important for designing effective cancer therapies. In this review, we critically examine the role of Tregs in the tumor microenvironment and in cancer progression focusing on human studies. We also discuss the impact of current therapeutic modalities on Treg biology and the therapeutic opportunities for targeting Tregs to enhance anti-tumor immune responses and clinical benefits.

The approval of cancer drugs by the United States Food and Drug Administration have increased progressively over the past
two decades with a trend towards the adoption of targeted drugs which are more precise in their mechanisms of action.
Advances in genetic profiling, immunohistochemical analysis of tumors, biomarker development, and a renewed appreciation
of the tumor microenvironment have produced a new generation of targeted chemical and biological therapies. These
innovations are the fruits of basic research in molecular and cellular biology, biochemistry, and immunology.
Purpose: To elucidate the paradigm shift in cancer drug development that has impacted the lives of patients in terms of
quality of life, tumor responses, over-all survival, and potential cures.
Methods: This review is based on an examination of published literature using the National Center for Biotechnology Information
(NCBI), the USFDA/National Institutes of Health (NIH) websites, USFDA approved product literature, Center Watch,
industry-sponsored websites, and clinicaltrials.gov websites. Cancer drugs are classified and described based on their proposed
mechanisms of action.
Results: The last two decades witnessed a paradigm shift in cancer drug development toward molecular targeted therapies
and targeted drug delivery. Molecular targets include tyrosine kinase receptors, serinethreonine kinase signaling pathways,
and growth factors. An increasing number of antibody-based therapies have emerged. Improvements in drug delivery include
the use of albumin-bound nanoparticles for targeting the enhanced permeability and retention effects seen in tumors.
Recent developments in the fields of cancer immunotherapy and gene therapy are exceedingly encouraging.
Conclusions: A review of USFDA-approved drugs and cancer drugs in clinical development, based on their mechanisms of
action, is presented. The progressive shift in cancer drug development towards targeted therapies and cancer immunotherapy
raises hope for improved outcomes for many types of cancer in the future.

- by Jacobs Publishers
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- Targeted Drug Delivery, Cancer Immunotherapy, Sarcoma, Monoclonal Antibodies

Immunotherapies are achieving clinical success for the treatment of many cancers. However, it has taken a long time to exploit the potential of the immune system for the treatment of human cancers. We cannot forget that this has been the consequence of very extensive work in basic research in pre-clinical models and in human patients. Thus, it is rather hard to compile all of it while giving a comprehensive view on this subject. Here we have attempted to give an overall perspective in immunotherapy of melanoma. A brief overview on current therapies is provided, followed by adoptive cell therapies. Gene engineering strategies to improve these therapies are also explained, finishing with therapies based on interference with immune checkpoint pathways.

- by maria gato cañas and +3
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- Oncology, Cancer, Gene Therapy, Cancer Biology

KEY POINTS
Hematopoietic cell transplantation continues to be the only established immune therapy
for childhood cancer.
Cellular therapy shows great promise to either replace HCT and act as an adjuvant to standard
chemotherapy for childhood cancer.
Survival after HCT has improved primarily due to new approaches to decrease it’s toxicity.
Better understanding of the immune mechanisms of the graft-versus-leukemia/tumor effect
are needed to improve the efficacy of HCT.

- by Maxim Yankelevich
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- Cancer Immunotherapy

What in the World is Immunotherapy for Cancer? explores the ever-lasting problem of cancer and how it can be defeated utilizing one's own immune system. Gone are the days of chemotherapy and radiation, which can still provide a chance of one re-developing the disease. What in the World is Immunotherapy for Cancer? explores the history of cancer, the history of immunotherapy, insights into how it all works, and what might be the future of immunotherapy.

- by Austin A Mardon and +3
- •
- Cancer, Cancer Immunotherapy, Tumour immunology, Cancer Immunotherapy, Immunotherapy

Modern cancer immunotherapies represent a major shift in paradigm with respect to how we understand innate and adaptive responses to malignancy. Successful tumors co-opt normal immunosurveillance mechanisms by potent interactions between the tumor and local draining lymph nodes. Tumor cells mediate a complex and dynamic immunoediting procedure that results in increased vascular efflux into the draining lymphatics, an immunosuppressive microenvironment rich in regulatory T-lymphocytes, dysfunctional antigen presentation, and downregulation of normal effector lymphocyte responses. Our current approach to reversing this process for antitumor effect involves mainly systemic administration of immunotherapeutic agents, many of which have become standard of care in the management of a variety of cancers. Despite this, we are still learning how best to administer these drugs alone and in combination to maximize efficacy while minimizing adverse events. Increasing evidence suggests that comparable efficacy may be achieved by local administration of immunotherapies in the tumor or tumor-draining lymph nodes with substantially lower doses and better tolerability, even with combination therapy. Herein, we review the literature on intratumoral and intranodal immunotherapies in pre-clinical models and early-phase studies, with particular emphasis on approaches potentially suitable for translation to larger-scale clinical trials. Modern cancer immunology traces its roots to the 1950s, when Burnet and Thomas proposed the theory of immune surveillance (1); however, immunotherapy did not gain traction until the 1990s, when tumor-associated antigens (TAAs) (2–5) and peripheral immune tolerance due to lack of costimulation were demonstrated (6– 9). Immunotherapies have since become mainstream treatments of several cancers; however, we are still learning how to balance their efficacy against their unique adverse effects. Clinically significant morbidity and mortality have resulted from the systemic immune activation induced by current immunotherapies (10–17). In light of increasing evidence of potential systemic immunogenicity of peritumoral immunomodulation, local therapies are being explored that target the tumor microenvironment and the center of immune education, the tumor-draining lymph node (TDLN). Successful tumors undergo immune editing, whereby immunogenic cells are destroyed and only those able to evade recognition remain (18,19). In addition to TAA downregulation, immune escape entails modification of the tumor microenvironment and the immune milieu through a wide range of mechanisms, including adaptations of tumors themselves. Central to this process is the TDLN, where antigen-presenting cells (APCs) and effector cells integrate complex signaling networks to generate the net immune response (20). We will briefly review the role of the tumor environment and the TDLN in mediating antitumor immune responses, as well as provide a comprehensive overview of preclinical and clinical experience with local (tumor-and lymph node–directed) cancer immunotherapies.

- by Vivek Murthy
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- Cancer Immunotherapy
- by Cleo Goyvaerts and +1
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- Cancer Immunotherapy, Dendritic Cells, Oncoimmunology, Myeloid Derived Suppressor Cells

Radiotherapy is one of the most common treatment modalities for controlling a wide range of tumors. However, it has been shown that radiotherapy alone is unable to completely eradicate some tumors and could be associated with a high possibility of tumor recurrence. To date, various experimental and clinical studies have been conducted to explore some efficient targets within tumor microenvironment (TME) to enhance tumor response to radiotherapy; thus help eliminate or eradicate tumors. Although targeting DNA damage responses (DDRs) is associated with severe toxicities, studies in recent decade suggest that inhibition of some apoptosis/survival targets within TME is promising. This is also associated with changes in the numbers of T regulatory cells (Tregs) and cytotoxic T lymphocytes (CTLs). The inhibition of cyclooxygenase-2 (COX-2), phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), mitogen-activated protein kinases (MAPKs) and vascular en-dothelial growth factor (VEGF) have also shown promising results. The combination of receptor tyrosine kinase (RTK) inhibitors with radiotherapy is interesting as well as the clinical use of some drugs and antibodies. Epidermal growth factor receptor (EGFR) inhibitors are the most common RTK inhibitors. Some clinical trials in recent years have shown very interesting results for immune checkpoint inhibitors (ICIs), especially programmed death-ligand 1 (PD-L1) and CTLs-associated antigen 4 (CTLA-4) inhibitors. It has been suggested that administration of ICIs during or after hypofractionated radiotherapy could lead to best results. In this review, we explain TME response to radiotherapy and potential targets for sensitization of cancer cells to radiotherapy.

- by Masoud Najafi
- •
- Cancer, Cancer Immunotherapy, Hypoxia targeted cancer therapy, Cancer radiotherapy

Introduction Cancer cervix is the second most common cancer
among women worldwide and is the cause of largest number of
cancer-related deaths among women in the developing countries.
In India cervical cancer is the commonest cancer among women
(126 000 new cases, 71 000 deaths around the year 2000). Due to
the lack of any population based screening in India nearly 80% of
the patients are detected at stage III or higher. There are trials
that do not conclusively prove that currently recommended
chemo-radiation will be equally effective in treating these large
number of advanced cases. With the objectives to evaluate
response and survival rates in patients with stage-III cervical
cancer treated with immunotherapy concomitant with
radiotherapy and compare the same with concomitant
chemo-radiation and to evaluate the safety of concomitant
immunotherapy and radiation this phase II trial was conducted by
Chittaranjan National Cancer Institute from 2008 to 2010 and
patients were followed up at 3 monthly intervals for 3 years.
Methods Stage III cervical cancer patients were randomized to study
arm (N = 104) or control arm (N = 105). In both arms the patients
received standard external beam radiation followed by brachytherapy.
In the study arm the patients received interferon-alpha 2b (3 mIU
subcutaneously thrice a week for 4 weeks) and retinoic acid (40 mg/
day orally for 30 days) starting from first day of radiation. Patients in
the control arm received cisplatin (40 mg/m2 once a week for
5 weeks) starting from first day of radiation. Patients were evaluated
for response 1 month after completion of treatment. They were
followed up every 3 months for 3 years or till death.
Results The study arms were comparable for demographic and
disease variables. Complete response was seen in 84.6% in study
arm and 80.0% in control arm (P = 0.47). The 3 years overall
survival was superior in the control arm (Log Rank analysis:
X2 = 7.93; P = 0.005). The study and the control arms were
comparable for disease-free survival (Log Rank analysis:
X2 = 2.69; P = 0.10). The most frequently observed grade 3/4
toxicities were anemia, neutropenia and gastro-intestinal toxicities,
which were significantly more frequent in chemo-radiation arm
compared to immuno-radiation arm.
Conclusions Immuno-radiation therapy had the same response
rate and disease-free survival as chemo-radiation but better
toxicity profile. The overall survival was inferior.

- by Sujoy Dasgupta and +2
- •
- Chemotherapy, Cancer Immunotherapy, Immunotherapy, Cervical Cancer

Cancer immunotherapy has been proposed as a powerful treatment modality. Active immunotherapy aspires to stimulate the patient's immune system, particularly T cells. These cells can recognize and kill cancer cells and can form an immunological memory. Dendritic cells (DCs) are the professional antigen-presenting cells of our immune system. They take up and process antigens to present them to T cells. Consequently, DCs have been investigated as a means to stimulate cancer-specific T-cell responses. An efficient strategy to program DCs is the use of mRNA, a well-defined and safe molecule that can be easily generated at high purity. Importantly, vaccines consisting of mRNA-modified DCs showed promising results in clinical trials. Therefore, we will introduce cancer immunotherapy and DCs and give a detailed overview on the application of mRNA to generate cancer-fighting DC vaccines.

- by Aude Bonehill
- •
- Cancer Immunotherapy, Dendritic Cells, Cancer Vaccines, Antigen Presentation

Treatment of lung cancer remains a challenge, and lung cancer is still the leading cause of cancer-related mortality. Immunotherapy has previously failed in lung cancer but has recently emerged as a very effective new therapy, and there is now growing worldwide enthusiasm in cancer immunotherapy. We summarize why immune checkpoint blockade therapies have generated efficacious and durable responses in clinical trials and why this has reignited interest in this field. Cancer vaccines have also been explored in the past with marginal success. Identification of optimal candidate neoantigens may improve cancer vaccine efficacy and may pave the way to personalized immunotherapy, alone or in combination with other immunotherapy such as immune checkpoint blockade. Understanding the steps in immune recognition and eradication of cancer cells is vital to understanding why previous immunotherapies failed and how current therapies can be used optimally. We hold an optimistic view for the future prospect in lung cancer immunotherapy.

- by Scott Fisher and +1
- •
- Cancer Immunotherapy, Lung Cancer, Mesothelioma

Hepatocellular carcinoma (HCC) is the most lethal and common type of liver cancer with limited treatment options at the advanced stage. The use of immune checkpoint inhibitor (ICI) based immunotherapy is exponentially increasing in the treatment of patients with advanced solid tumors. The expression of immune checkpoints on tumor cells leading to lower activity of T-cells is one of the major mechanisms of immune escape. Checkpoint blockade immunotherapies with antibodies against PD-1, PD-L1 or CTLA-4 are being investigated in clinical trials in HCC patients. ICIs have improved survival in patients with inoperable advanced stage HCC where other curative treatments are not applicable. However, the response rates remain low with only a small subset of patients responding to this therapy. There is an unmet need to identify predictive markers to select those HCC patients who would benefit from ICI therapies. Importantly, epithelial-to-mesenchymal transition (EMT), a major process driving HCC invasion and metastasis by regulating the phenotypic cellular switching from epithelial to mesenchymal state, has been implicated as a resistance mechanism associated with ICI therapies. The role of EMT as a regulator of immune checkpoint molecule in HCC is just emerging. However, the consequence of EMT as a resistance mechanism in HCC patients undergoing ICI treatments remains unexplored. In this review, we summarize the recent clinical studies with ICIs in HCC and highlight the trials underway featuring novel monotherapies and combinatorial approaches based on immune and non-immune therapies. We will discuss the ongoing efforts to discover new immune checkpoint molecules in HCC as potential drug targets. We also highlight the role of EMT in facilitating therapy resistance in HCC treated with ICIs and discuss potential strategies to circumvent resistance in ICI treated HCC patients.

- by Hepatoma Research
- •
- Cancer Immunotherapy, Hepatology, Liver diseases, Gastroentrology & Hepatology

Alteration in the density and composition of extracellular matrix (ECM) occurs in tumors. The alterations toward both stiffness and degradation are contributed to tumor growth and progression. Cancer‐associated fibroblasts (CAFs) are the main contributors to ECM stiffness and degradation. The cells interact with almost all cells within the tumor microenvironment (TME) that could enable them to modulate ECM components for tumorigenic purposes. Cross‐talks between CAFs with cancer cells and macrophage type 2 (M2) cells are pivotal for ECM stiffness and degradation. CAFs induce hypoxia within the TME, which is one of the key inducers of both stiffness and degradation. Cancer cell modulatory roles in integrin receptors are key for adjusting ECM constituents to either fates. Cancer cell proliferation, migration, and invasion as well as angiogenesis are consequences of ECM stiffness and degradation. ECM stiffness in a transforming growth factor‐β (TGF‐β) related pathway could make a bridge in the basement membrane, and ECM degradation in a matrix metalloproteinase (MMP)‐related pathway could make a path in the TME, both of which contribute to cancer cell invasion. ECM stiffness is also obstructive for drug penetration to the tumor site. Therefore, it would be a promising strategy to make a homeostasis in ECM for easy penetration of chemotherapeutic drugs and increasing the efficacy of antitumor approaches. MMP and TGF‐β inhibitors, CAF and M2 reprogramming toward their normal counterparts, reduction of TME hypoxia and hampering integrin signaling are among the promising approaches for the modulation of ECM in favor of tumor regression.

- by Masoud Najafi
- •
- Cancer, Chemotherapy, Cancer stem cells, Hypoxia

Most patients diagnosed with hepatocellular carcinoma (HCC) present with advanced or metastatic disease. The lack of therapeutic options in the treatment of advanced HCC accounts for its high mortality and recurrence rate. HCC is known as an immunogenic tumor, which develops in chronically inflamed livers. Anti-PD-1/PD-L1 antibodies (immune checkpoint inhibitors, ICB) were approved by the FDA to treat advanced HCC in patients previously treated with sorafenib as a second line. This has opened up a new era of anticancer treatment, although the response rate of HCC to anti-PD-1/PD-L1 antibodies is only around 20%. Other than ICB treatment, adoptive cell transfer, dendritic cell-based vaccines and oncolytic therapy are currently under clinical trials. In this review, different immunotherapy approaches for HCC is presented. Current knowledge on the mechanisms of action for each approach is discussed and relevant, ongoing clinical trials are presented. We also discuss the future of immunotherapy and combination treatment for HCC patients.

- by Hepatoma Research
- •
- Immune response, Cytokines, Cancer Immunotherapy, Dendritic Cells

While advances have been made in different cancer therapeutic modalities, immunotherapy is a stand out and has changed how we prevent and treat cancer. Intense research has deepened our understanding of the complex structure, organization, and effector mechanisms of the immune system, and potential ways to unmask tumor cells to immune surveillance. Although more funding is needed for researchers to find answers to the many elusive cellular, molecular and tumor immunology questions and its clinical translation, developments made so far have led to the successful harnessing of the immune system to increase anti-tumor responses. Immunotherapy has chalked many successes in recent times. In particular, discoveries of immune checkpoint pathways have led to the development and FDA approval of multiple immune checkpoint agents for treatment of different cancers. This review addresses advancements in cancer immunotherapy with emphasis on three immune checkpoint agents, the future it holds for breast cancer patients and BCRF's impact in the field.

- by Abdul Rashid Abdulai
- •
- Immunology, Breast Cancer, Cancer Biology, Cancer Immunotherapy

Carcinosarcomas (CS) in gynecology are very infrequent and represent only 2–5% of uterine cancers. Despite surgical cytoreduction and subsequent chemotherapy being the primary treatment for uterine CS, the overall five-year survival rate is 30 ± 9% and recurrence is extremely common (50–80%). Due to the poor prognosis of CS, new strategies have been developed in the last few decades, targeting known dysfunctional molecular pathways for immunotherapy. In this paper, we aimed to gather the available evidence on the latest therapies for the treatment of CS. We performed a systematic review using the terms " uterine carcinosarcoma " , " uterine Malignant Mixed Müllerian Tumors " , " target therapies " , " angiogenesis therapy " , " cancer stem cell therapy " , " prognostic biomarker " , and " novel antibody-drug ". Based on our results, the differential expression and accessibility of epithelial cell adhesion molecule-1 on metastatic/chemotherapy-resistant CS cells in comparison to normal tissues and Human Epidermal Growth Factor Receptor 2 (HER2) open up new possibilities in the field of target therapy. Nevertheless, future investigations are needed to clarify the impact of these new therapies on survival rate and medium-/long-term outcomes.

- by Salvatore Giovanni Vitale and +7
- •
- Genetics, Cancer Immunotherapy, Epigenetics, Gynecologic Oncology

Mura G, Verdelli B. The features of peritoneal metastases from gastric cancer. J Cancer Metastasis Treat 2016;2:365-74. Peritoneal Carcinomatosis (PC) from metastasization of Gastric Cancer (GC), either present at first diagnosis of GC or as recurrence, is considered a fatal disease with no hope of definitive cure. Although newer agents like S1 and docetaxel have shown some promise, the median overall survival with the current first line chemotherapy is only 8 to 14 months, and is not greatly improved by adding targeted therapy. A multi-modal approach with cytoreductive surgery (CRS) associated with hyperthermic intraperitoneal chemotherapy (HIPEC) has been developed along the last two decades in order to tackle this problem. It's an aggressive, combined treatment still under investigation. Studies coming from Europe and Far East reported long-term survival with 5-year survival rates up to nearly 25% in case of complete cytoreduction. Prophylactic/adjuvant setting is the most evidence-based indication for HIPEC in advanced-stage GC patients without PC, in order to prevent peritoneal recurrence and to improve overall survival. The rationale for immuno treatment in patients with gastric PC is strong. A randomized phase II study, combining complete CRS with intraperitoneal catumaxomab is ongoing. The detection of free peritoneal cancer cells is the more realistic and practical way for the identification of patients at risk of carcinomatosis after surgery. The routine use of techniques of molecular detection in peritoneal washing appears to be the more sensitive method. Such patients are potential candidate for multimodal and locoregional treatments in order to prevent the peritoneal recurrence.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the liver, with poor prognosis and high mortality. Traditional treatments for patients with HCC have shown poor efficacy especially for advanced liver cancer. Compared with other organs, the liver has more natural immune cells such as Kupffer cells, natural killer cells and natural killer T cells. Immunotherapy for liver cancer has become the focus in current research. The theoretical basis of immunotherapy rests on immune tolerance and suppression in the tumor microenvironment. Common immunotherapy methods include vaccines, cytokines, adoptive cell therapies, immune checkpoint inhibitors, and oncolytic viruses. Compared with traditional treatment, immunotherapy can enhance the body's immune function, delay tumor progression, and prolong survival. This article reviews the HCC microenvironment and immunotherapy both in the clinical and basic research aspects.

- by Hepatoma Research and +1
- •
- Immune response, Cancer Immunotherapy, Hepatology, Gastroentrology & Hepatology

Moleküler biyoloji ve genetik modifikasyon teknoloji ve olanaklarının gelişmesi ve ucuzlaması yıllardır kemoterapiye sınırlı olan kanser tedavilerinde bir çağın kapanıp yeni bir çağın açılmasına sebep oldu. Kemoterapide kullanılan ilaçlar ile sadece kanserli hücrelerin değil; vücuttaki sağlıklı hücrelerinde ölmesinden dolayı bilim insanları kanserli hastaya özel kişisel terapi teknikleri geliştirmek üzere yoğun çaba gösteriyorlar. Bu girişimlerden en umut verici sonuçlar alınan biri de ‘Genetiği Değiştirilmiş CAR-T Hücre Terapisi’...

Chronic viruses and cancers thwart immune responses in humans by inducing T cell dysfunction. Using a murine chronic virus that models human infections, we investigated the function of the adhesion molecule, P-selectin glycoprotein ligand-1(PSGL-1), that is upregulated on responding T cells. PSGL-1-deficient mice cleared the virus due to increased intrinsic survival of multifunctional effector T cells that had downregulated PD-1 as well as other inhibitory receptors. Notably, this response resulted in CD4+-T-cell-dependent immunopathology. Mechanistically, PSGL-1 ligation on exhausted CD8+ T cells inhibited T cell receptor (TCR) and interleukin-2 (IL-2) signaling and upregulated PD-1, leading to diminished survival with TCR stimulation. In models of melanoma cancer in which T cell dysfunction occurs, PSGL-1 deficiency led to PD-1 down regulation, improved T cell responses, and tumor control. Thus, PSGL-1 plays a fundamental role in balancing viral control and immunopathology and also functions to regulate T cell responses in the tumor microenvironment.

- by Roberto Tinoco and +1
- •
- Immunology, Immune response, Tumor Immunology, Cancer Immunotherapy

The development of cancer immunotherapy in the last decade has followed a vertiginous rhythm. Nowadays, immune checkpoint inhibitors (ICI) which include anti-CTLA4, anti-PD-1 and anti-PD-L1 antibodies are in clinical use for the treatment of numerous cancers. However, approximately only a third of the patients benefit from ICI therapies. Many efforts have been made for the identification of biomarkers allowing patient stratification into potential responders and progressors before the start of ICI therapies or for monitoring responses during treatment. While much attention is centered on biomarkers from the tumor microenvironment, in many cases biopsies are not available. The identification of systemic immune cell subsets that correlate with responses could provide promising biomarkers. Some of them have been reported to influence the response to ICI therapies, such as proliferation and activation status of CD8 and CD4 T cells, the expression of immune checkpoints in peripheral blood cells and the relative numbers of immunosuppressive cells such as regulatory T cells and myeloid-derived suppressor cells. In addition, the profile of soluble factors in plasma samples could be associated to response or tumor progression. Here we will review the cellular subsets associated to response or progression in different studies and discuss their accuracy in diagnosis.

- by David Escors
- •
- Cancer, Biomarkers, Cancer Immunotherapy, Lung Cancer

Cancer affects all animals containing eukaryote cells. Less is known about the cancers that affect wild animals, since they move around and may not be easily observed for a long period of time. This review about cancers in wild animals contains useful data for the study of human cancers as well. Certain cancers in dinosaurs show that this metabolic disease is primitive and may have been around since the beginning of the multicellular organisms. This data also shows there has been some cancer types in naked mole rats and wild sharks as well. Nowadays, Tasmanian Devils are plagued by an infectious cancer known as Tasmanian devil facial tumor disease (DFTD). Since the emergence of the disease in 1996, the population has declined by more than 60 percent. This type of cancer has an allograft transmission. It seems earthworms contain an anti-cancer agent which could be of great interests in the treatment of cancer. In the discussion part of our review we have discussed how

- by Sorush Niknamian
- •
- Evolutionary Biology, Animal Science, Molecular Biology, Cell Biology

CAR-T hücre tedavisini Türkiye’de üretmek ve başarmak genetik bilimimizin uygulanmaya dönüştürülmesi ve biyoteknolojik tıp konusunda yerlileşme ve dışa bağımlılığımızı azaltma noktasında çok mühim. Bunun yanında ülkemiz sağlık turizminde Amerika ve diğer ülkelere kıyasla çok ucuz olmasından ötürü çekici bir özelliğe sahip. CAR-T hücre tedavisinin ucuza yerli imkanlarla gerçekleştirilmesi, bu tedavinin yüz binlerce doları bulduğu göz önüne alındığında sağlık turizminde elimizi güçlendirecektir.