Articles

Cancer Stem Cell Treatment

Autologous Dendritic Cell Therapy for Cancer is available at SIRM

Cancer represents one of the major causes of mortality worldwide. More than half of patients suffering from cancer succumb to their condition. The primary approaches to treating cancer are surgical resection followed by radiation therapy and chemotherapy. These treatments have resulted in significant benefits to patients with the majority of tumor types, and the clinical outcomes have become more satisfactory. It is recognized that multidisciplinary treatments should be used in cancer treatments, another option proposed for this is immunotherapy. The combination of the traditional methods of surgery, chemotherapy and radiotherapy with immunotherapy, is a new way for anti-cancer therapies to reduce the mortality of cancer patients. The dysfunction of the antigen-specific T cells required to kill the cancer leads to cancer cells being able to grow in cancer patients. Active and adoptive T cell immunotherapies generate T cells that can target cancer cells.

Dendritic cells (DCs) are immune cells that function as antigen-presenting cells. They are able to activate naive CD4+ T helper cells and unprimed CD8+ cytotoxic T lymphocytes. Active immunotherapy, represented by DC-based regimens, has been used to produce tumor-specific antigen-presenting cells and to generate cytotoxic T lymphocyte responses against cancer cells. DCs can capture antigens, process them, and present them with co-stimulation cytokines/messengers to initiate an immune response, like inducing primary T-cell responses.

Adoptive immunotherapy, as conducted at our facility, is a personalized therapy that uses a patient’s own anti-tumor immune cells to kill cancer cells and may be used to treat several types of cancer, and represents another therapeutic approach against cancer. To date, the adoptive immunotherapy approach is one of the most effective methods for using the body’s immune system to treat cancer. To be used clinically, protocols for the development of these functional DCs must be established for in-clinic use via defined, xenobiotic-free medium conditions.

The purpose of the present study is to determine the cellular immune response in terms of the delayed-type hyper-sensitivity (DTH) skin test and evaluate the subjective clinical outcome and safety of the regimen in cancer patients receiving a DC vaccine.

Vaccination against a single antigen is available using purified and synthetic products, but these have disadvantages because it is unknown which of the identified antigens have the potential to induce an effective antitumor immune response. This study uses unfractionated, autologous, tumor-derived antigens in the form oftumor cell lysates which circumvents this disadvantage.

Tumor lysates as addressed in this protocol, contain multiple known as well as unknown antigens that can be presented to T cells by both MHC class I- and class II-pathways. Therefore, lysate-loaded DCs are more likely to induce the more preferred polyclonal expansion of T cells, including MHC class II restricted T-helper cells. These have been recognized to play an important role in the activation of Cytotoxic T Lymphocytes (CTLs), probably the most important cells in effecting an antitumor immune response. The generation of CTL clones with multiple specificities may be an advantage in heterogeneous tumors and could also reduce the risk of tumor escape variants. Furthermore, lysate from the autologous tumor can be used independently of the HLA type of the patient. A drawback of unfractionated tumor antigens is the possibility of inducing an autoimmune reactivity to epitopes that are shared by normal tissues. However, in clinical trials using lysate or whole tumor cells as the source of antigen, no clinically relevant autoimmune responses have ever been detected.

Personalized dendritic cell vaccines for cancer, via adoptive immunotherapy, are successfully developed and autologously administered to patients coming to Asia, and more specifically, within the Philippines at the Subic Institute for Regenerative Medicine. The results of this case study of cancer and immunotherapy via pulsed dendritic cells, can serve as another example of safety for future cancer vaccine development.

Dendritic Cell Therapy for Cancer:
Related Articles Role of FBXW7 in the quiescence of gefitinib-resistant lung cancer stem cells in EGFR-mutant non-small cell lung cancer. Bosn J Basic Med Sci. 2019 May 28;: Authors: Hidayat M, Mitsuishi Y, Takahashi F, Tajima K, Yae T, Miyahara K, Hayakawa D, Winardi W, Ihara H, Koinuma Y, Wirawan A, Nurwidya F, Kato M, Kobayashi I, Sasaki S, Takamochi K, Hayashi T, Suehara Y, Moriyama M, Moriyama H, Habu S, Takahashi K Abstract Several recent studies suggest that cancer stem cells (CSCs) are involved in intrinsic resistance to cancer treatment. Maintenance of quiescence is crucial for establishing resistance of CSCs to cancer therapeutics. F-box/WD repeat-containing protein 7 (FBXW7) is a ubiquitin ligase that regulates quiescence by targeting the c-MYC protein for ubiquitination. We previously reported that gefitinib-resistant persisters (GRPs) in EGFR-mutant non-small cell lung cancer (NSCLC) cells highly expressed octamer-binding transcription factor 4 (Oct-4) as well as the lung CSC marker CD133, and they exhibited distinctive features of the CSC phenotype. However, the role of FBXW7 in lung CSCs and their resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors in NSCLC is not fully understood. In this study, we developed GRPs from the two NSCLC cell lines PC9 and HCC827, which express an EGFR exon 19 deletion mutation, by treatment with a high concentration of gefitinib. The GRPs from both PC9 and HCC827 cells expressed high levels of CD133 and FBXW7, but low levels of c-MYC. Cell cycle analysis demonstrated that the majority of GRPs existed in the G0/G1 phase. Knockdown of the FBXW7 gene significantly reduced the cell number of CD133-positive GRPs and reversed the cell population in the G0/G1-phase. We also found that FBXW7 expression in CD133-positive cells was increased and c-MYC expression was decreased in gefitinib-resistant tumors of PC9 cells in mice and in 9 out of 14 tumor specimens from EGFR-mutant NSCLC patients with acquired resistance to gefitinib. These findings suggest that FBXW7 plays a pivotal role in the maintenance of quiescence in gefitinib-resistant lung CSCs in EGFR mutation-positive NSCLC. PMID: 31202256 [PubMed - as supplied by publisher]
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Related Articles Combining clustering and classification ensembles: A novel pipeline to identify breast cancer profiles. Artif Intell Med. 2019 Jun;97:27-37 Authors: Agrawal U, Soria D, Wagner C, Garibaldi J, Ellis IO, Bartlett JMS, Cameron D, Rakha EA, Green AR Abstract Breast Cancer is one of the most common causes of cancer death in women, representing a very complex disease with varied molecular alterations. To assist breast cancer prognosis, the classification of patients into biological groups is of great significance for treatment strategies. Recent studies have used an ensemble of multiple clustering algorithms to elucidate the most characteristic biological groups of breast cancer. However, the combination of various clustering methods resulted in a number of patients remaining unclustered. Therefore, a framework still needs to be developed which can assign as many unclustered (i.e. biologically diverse) patients to one of the identified groups in order to improve classification. Therefore, in this paper we develop a novel classification framework which introduces a new ensemble classification stage after the ensemble clustering stage to target the unclustered patients. Thus, a step-by-step pipeline is introduced which couples ensemble clustering with ensemble classification for the identification of core groups, data distribution in them and improvement in final classification results by targeting the unclustered data. The proposed pipeline is employed on a novel real world breast cancer dataset and subsequently its robustness and stability are examined by testing it on standard datasets. The results show that by using the presented framework, an improved classification is obtained. Finally, the results have been verified using statistical tests, visualisation techniques, cluster quality assessment and interpretation from clinical experts. PMID: 31202397 [PubMed - in process]
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Related Articles Veto cells for safer nonmyeloablative haploidentical HSCT and CAR T cell therapy. Semin Hematol. 2019 Jul;56(3):173-182 Authors: Reisner Y, Or-Geva N Abstract Haploidentical donors are a readily available source for mismatched hematopoietic bone marrow transplantation. The application of this regimen is constantly increasing with the advent of methods that overcome T-cell alloreactions that occur due to human-leukocyte-antigen disparity between host and donor. One successful method to overcome both graft rejection and graft-vs-host disease is transplantation of large numbers T-cell-depleted (TCD) haploidentical stem cell grafts (haploSCT), after myeloablative conditioning. The success of stem cell dose escalation is attributed to a unique immunoregulatory cell-property, termed "veto-activity." However, engraftment of mismatched hematopoietic stem cells following reduced-intensity conditioning still represents a major challenge. Here, we describe how the addition of post-transplant high-dose cyclophosphamide can promote immune tolerance induction after megadose TCD haploSCT, following nonmyeloablative conditioning. We also discuss ways of harnessing the immune regulatory properties of adoptively transferred "veto" cells to support mixed chimerism further and confer tolerance to cell-therapies, such as CAR-T cells. These approaches will soon be tested in phase 1-2 clinical studies and may prove to be a safe and efficacious treatment for many disorders such as hemoglobinopathies, autoimmune diseases, and as a prelude for organ tolerance. Moreover, this approach could pave the way for "off-the-shelf" cell-therapy agents, making them cheaper and easily obtainable. PMID: 31202427 [PubMed - in process]
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Related Articles Who is the best donor for haploidentical stem cell transplantation? Semin Hematol. 2019 Jul;56(3):194-200 Authors: Kongtim P, Ciurea SO Abstract Recent advances in haploidentical stem cell transplantation have enabled the use of human leukocyte antigen-half matched related donors for allogeneic stem cell transplantation and helped overcome one of the most important limitation in transplantation, which is donor availability, especially for the non-Caucasian population and mixed race individuals, extending allogeneic stem cell transplant for almost all patients in need. As many multiple potential related donors may now be available, it is increasingly clear that not all of these donors can provide equivalent transplant outcomes. Here we review the current available evidence of donor characteristics known to be associated with transplant outcomes for different types of haploidentical transplants using unmanipulated grafts (with post-transplant cyclophosphamide-based graft-vs-host prophylaxis and G-CSF and anti-thymocyte globulin approach) as well as modified grafts (with either selective or complete T-cell depletion). While various platforms use haploidentical donors, graft manipulation and approach to prevent graft-vs-host post-transplant may impact on donor selection and transplant outcomes. PMID: 31202430 [PubMed - in process]
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Related Articles Basic helix-loop-helix transcription factor Twist1 is a novel regulator of anterior gradient protein 2 homolog (AGR2) in breast cancer. Biochem Biophys Res Commun. 2019 Jun 12;: Authors: Jun SY, Yun J, Kim SJ, Kang S, Kim DY, Kim YJ, Park JH, Jang WB, Ji ST, Ha JS, Hong Van LT, Truong Giang LT, Rethineswaran VK, Kim DH, Song P, Kwon SM Abstract Anterior gradient protein 2 homolog (AGR2) belongs to the disulfide isomerase family of endoplasmic reticulum proteins. Itis overexpressed in several types of solid tumors, including tumors of the prostate, lung, and pancreas. However, the role of AGR2 in breast cancer and the regulatory mechanisms underlying AGR2 protein expressionare not fullyunderstood. We demonstrated that AGR2 levels are increased under hypoxic conditions and in breast cancer tumors. Mechanistically, Twist1 binds to, and activates the AGR2 promoter via an E-box sequence. Under hypoxic conditions, the increased expression of ARG2 is attenuated when Twist1 levels are reduced by shRNA. Conversely, Twist1 overexpression fully reverses decreased AGR2 levels upon HIF-1α knockdown. Notably, AGR2 is required for Twist1-induced proliferation, migration, and invasion of breast cancer cells. Collectively, these findings extend our understanding of AGR2 regulation in breast cancer and may contribute to development of Twist1-AGR2 targeting therapeutics for breast cancer. PMID: 31202462 [PubMed - as supplied by publisher]
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Related Articles Blastemal NCAM+ALDH1+ Wilms' tumor cancer stem cells correlate with disease progression and poor clinical outcome: A pilot study. Pathol Res Pract. 2019 Jun 10;:152491 Authors: Raved D, Tokatly-Latzer I, Anafi L, Harari-Steinberg O, Barshack I, Dekel B, Pode-Shakked N Abstract BACKGROUND: Cancer Stem Cells (CSCs) have been suggested as the culprit responsible for tumor resistance to treatment and disease recurrence. Wilms' tumor (WT) is a paradigm for studying the relation between development and tumorigenesis, showing three main histological elements: undifferentiated blastema, epithelia and stroma, mimicking human kidney development. NCAM + ALDH1+ cells were previously found to contain the cancer stem like-cell population in WT. Thus far, the correlation between histologic characterization of this cell population, clinicopathologic parameters and prognostic outcome has yet been investigated in WT. PROCEDURES: Paraffin-imbedded primary WT specimens from twenty-four patients were immunostained for NCAM and ALDH1. Positivity and histologic compartment localization were determined by two independent observers, blinded to the clinical outcome. Clinicopathologic parameters and prognostic outcomes were determined based on the patients' medical records. The association of NCAM and ALDH1 co-localization with clinicopathologic characteristics was analyzed byχ2-test. Survival analysis was carried out by the log-rank test using Kaplan-Meier method. RESULTS: Blastemal co-localization of NCAM and ALDH1 was observed in 33% of WTs. Metastases, ICE chemotherapy protocol, blastemal predominance following preoperative chemotherapy, recurrence and patient demise were found to significantly correlate with blastemal NCAM + ALDH1+ cell staining (p < 0.05). A significant inverse correlation between blastemal double positive cells, disease-free survival and overall survival was also observed. CONCLUSIONS: WT blastemal NCAM + ALDH1+ CSCs significantly correlate with adverse clinicopathologic parameters and poorer prognosis. These results underscore the role of CSCs in disease progression. Additionally, this pilot study supports the addition of these markers for risk stratification of WTs. PMID: 31202518 [PubMed - as supplied by publisher]
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Related Articles Cytokine release syndrome and neurologic toxicities associated with chimeric antigen receptor T-cell therapy: A comprehensive review of emerging grading models. Hematol Oncol Stem Cell Ther. 2019 Jun 10;: Authors: Chavez JC, Jain MD, Kharfan-Dabaja MA Abstract Advances in the fields of immuno-oncology and T-cell engineering have brought autologous chimeric antigen receptor T-cell (CART) therapies from the bench to the bedside. At present, two CART products that target CD19 are commercially available: tisagenlecleucel and axicabtagene ciloleucel. They have demonstrated remarkable efficacy for their particular indications. One challenge is to compare the safety among commercially available and clinical trial CART treatments due to the use of different grading models to assess the severity of cytokine release syndrome and neurotoxicity. An unmet need exists to harmonize current grading models in order to develop uniform treatment strategies to manage these toxicities. Here, we attempt to summarize the evolution of the various grading systems for cytokine release syndrome and neurotoxicity and also highlight the major differences among them, whenever applicable. PMID: 31202671 [PubMed - as supplied by publisher]
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Related Articles Exploring a Future for PI3K Inhibitors in Chronic Lymphocytic Leukemia. Curr Hematol Malig Rep. 2019 Jun 15;: Authors: Patel K, Pagel JM Abstract PURPOSE OF REVIEW: Treatment for chronic lymphocytic leukemia has changed substantially in the past decade with an increasing shift towards use of targeted therapies, in particular agents targeting the B cell receptor pathway. Inhibition of PI3K, downstream of the B cell receptor pathway, represents an active therapeutic strategy in CLL. Here, we explore the relevance of PI3K inhibition in CLL, examine efficacy and toxicity of approved PI3K inhibitors in CLL, examine barriers to use of PI3K inhibitors, and explore strategies to optimize use of PI3K inhibitors in CLL. RECENT FINDINGS: Current generation PI3K inhibitors are active agents in CLL but their use may be limited by immune-mediated toxicities. Clinical trials of next generation PI3K inhibitors are ongoing and early data suggests these agents are highly active with potentially differentiated toxicity profiles. Furthermore, alternative dosing schedules may reduce toxicities of these agents. Inhibition of PI3K remains an important strategy in management of CLL and novel approaches to limit toxicities of PI3K inhibitors represent an important area of clinical research in CLL. PMID: 31203516 [PubMed - as supplied by publisher]
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