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 Asian Stem Cell Institute, 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 Reciprocal regulation of integrin β4 and KLF4 promotes gliomagenesis through maintaining cancer stem cell traits. J Exp Clin Cancer Res. 2019 Jan 18;38(1):23 Authors: Ma B, Zhang L, Zou Y, He R, Wu Q, Han C, Zhang B Abstract BACKGROUND: The dismal prognosis of patients with glioma is largely attributed to cancer stem cells that display pivotal roles in tumour initiation, progression, metastasis, resistance to therapy, and relapse. Therefore, understanding how these populations of cells maintain their stem-like properties is critical in developing effective glioma therapeutics. METHODS: RNA sequencing analysis was used to identify genes potentially involved in regulating glioma stem cells (GSCs). Integrin β4 (ITGB4) expression was validated by quantitative real-time PCR (qRT-PCR) and immunohistochemical (IHC) staining. The role of ITGB4 was investigated by flow cytometry, mammosphere formation, transwell, colony formation, and in vivo tumorigenesis assays. The reciprocal regulation between Integrin β4 and KLF4 was investigated by chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, immunoprecipitation, and in vivo ubiquitylation assays. RESULTS: In this study, we found that ITGB4 expression was increased in GSCs and human glioma tissues. Upregulation of ITGB4 was correlated with glioma grades. Inhibition of ITGB4 in glioma cells decreased the self-renewal abilities of GSCs and suppressed the malignant behaviours of glioma cells in vitro and in vivo. Further mechanistic studies revealed that KLF4, an important transcription factor, directly binds to the promoter of ITGB4, facilitating its transcription and contributing to increased ITGB4 expression in glioma. Interestingly, this increased expression enabled ITGB4 to bind KLF4, thus attenuating its interaction with its E3 ligase, the von Hippel-Lindau (VHL) protein, which subsequently decreases KLF4 ubiquitination and leads to its accumulation. CONCLUSIONS: Collectively, our data indicate the existence of a positive feedback loop between KLF4 and ITGB4 that promotes GSC self-renewal and gliomagenesis, suggesting that ITGB4 may be a valuable therapeutic target for glioma. PMID: 30658712 [PubMed - in process]
Related Articles Blockade of a laminin-411 - Notch axis with CRISPR/Cas9 or a nanobioconjugate inhibits glioblastoma growth through tumor-microenvironment crosstalk. Cancer Res. 2019 Jan 18;: Authors: Sun T, Patil R, Galstyan A, Klymyshyn D, Ding H, Chesnokova A, Cavenee WK, Furnari FB, Ljubimov VA, Shatalova ES, Wagner S, Li D, Mamelak AN, Bannykh SI, Patil CG, Rudnick JD, Hu J, Grodzinski ZB, Rekechenetskiy A, Falahatian V, Lyubimov AV, Chen YL, Leoh LS, Daniels-Wells TR, Penichet ML, Holler E, Ljubimov AV, Black KL, Ljubimova JY Abstract There is an unmet need for the treatment of glioblastoma multiforme (GBM). The extracellular matrix (ECM), including laminins, in the tumor microenvironment is important for tumor invasion and progression. In a panel of 226 patient brain glioma samples, we found a clinical correlation between the expression of tumor vascular laminin-411 (α4β1γ1) with higher tumor grade and with expression of cancer stem cell (CSC) markers including Notch pathway members, CD133, Nestin, and c-Myc. Laminin-411 overexpression also correlated with higher recurrence rate and shorter survival of GBM patients. We also showed that depletion of laminin-411 α4 and β1 chains with CRISPR/Cas9 in human GBM cells led to reduced growth of resultant intracranial tumors in mice, and significantly increased survival of host animals compared to mice with untreated cells. Inhibition of laminin-411 suppressed Notch pathway in normal and malignant human brain cell types. A nanobioconjugate potentially suitable for clinical use and capable of crossing blood-brain barrier was designed to block laminin-411 expression. Nanobioconjugate treatment of mice carrying intracranial GBM significantly increased animal survival and inhibited multiple CSC markers including the Notch axis. This study describes an efficient strategy for GBM treatment via targeting a critical component of the tumor microenvironment largely independent of heterogeneous genetic mutations in glioblastoma. PMID: 30659021 [PubMed - as supplied by publisher]
Related Articles MNK1/NODAL signaling promotes invasive progression of breast ductal carcinoma in situ. Cancer Res. 2019 Jan 18;: Authors: Guo Q, Li VZ, Nichol JN, Huang F, Yang W, Preston SEJ, Talat Z, Lefrère H, Yu H, Zhang G, Basik M, Gonçalves C, Zhan Y, Plourde D, Su J, Torres J, Marques M, Al Habyan S, Bijian K, Amant F, Witcher M, Behbod F, McCaffrey L, Alaoui-Jamali MA, Giannakopoulos NV, Brackstone M, Postovit LM, Del Rincón SV, Miller WH Abstract The mechanisms by which breast cancers progress from relatively indolent ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) are not well understood. However, this process is critical to the acquisition of metastatic potential. MAP kinase-interacting serine/threonine-protein kinase 1 (MNK1) signaling can promote cell invasion. NODAL, a morphogen essential for embryogenic patterning, is often re-expressed in breast cancer. Here we describe a MNK1/NODAL signaling axis that promotes DCIS progression to IDC. We generated MNK1 knockout (KO) or constitutively active MNK1 (caMNK1)-expressing human MCF-10A-derived DCIS cell lines, which were orthotopically injected into the mammary glands of mice. Loss of MNK1 repressed NODAL expression, inhibited DCIS to IDC conversion, and decreased tumor relapse and metastasis. Conversely, caMNK1 induced NODAL expression and promoted IDC. The MNK1/NODAL axis promoted cancer stem cell properties and invasion in vitro. The MNK1/2 inhibitor SEL201 blocked DCIS progression to invasive disease in vivo. In clinical samples, IDC and DCIS with microinvasion expressed higher levels of phospho-MNK1 and NODAL versus low grade (invasion-free) DCIS. Cumulatively, our data support further development of MNK1 inhibitors as therapeutics for preventing invasive disease. PMID: 30659022 [PubMed - as supplied by publisher]
Related Articles Impressive response of CD30-negative, treatment-refractory mycosis fungoides to brentuximab vedotin. Dermatol Ther. 2019 Jan 19;:e12835 Authors: Goyal-O'Leary A, Hordinsky M, Lazaryan A Abstract Brentuximab vedotin is a CD30-antibody/drug conjugate which has demonstrated excellent response in treating CD30-positive mycosis fungoides (MF) and anaplastic large cell lymphoma (ALCL). In this report, we present a patient with CD30-negative MF refractory to multiple other lines of therapy who demonstrated a dramatic response to brentuximab. This paradoxical response may be due to inadequate detection of CD30 expression by immunohistochemical techniques. From this case we see that even in the setting of apparent CD30 negativity, brentuximab may be a viable treatment option for patients who require bridging to stem cell transplant or seek successful palliation. This case highlights the point that rigid inclusion criteria for MF trials without use of more sensitive techniques to confirm lack of CD30 expression may inappropriate. This article is protected by copyright. All rights reserved. PMID: 30659762 [PubMed - as supplied by publisher]
Related Articles MODELING MALIGNANCIES USING INDUCED PLURIPOTENT STEM CELLS: FROM CHRONIC MYELOID LEUKEMIA (CML) TO HEREDITARY CANCERS. Exp Hematol. 2019 Jan 16;: Authors: Turhan AG, Foudi A, Hwang JW, Desterke C, Griscelli F, Bennaceur-Griscelli A Abstract During the last decade, the possibility of reprogramming malignant cells to a pluripotent state has been achieved in several hematological malignancies, including myeloproliferative neoplasms, myelodysplastic syndromes and chronic myeloid leukemia (CML). It has been shown that it is readily possible to generate iPSC from several types of primary CML cells and generate progenitors and differentiated cells with variable efficiency. Although these experiments have brought some new insights in the understanding of CML pathophysiology, the ultimate goal of generating induced leukemic stem cells (LSC) with long-term multilineage potential has not yet been demonstrated. Experiments underway will determine whether additional signaling events are required to induce the emergence of bona fide LSCs. iPSC modeling offers however the unique possibility to generate pluripotent cells harboring cancer predisposing mutations using patient-derived non-cancerous cells as has been shown in Li-Fraumeni syndrome, BRCA-1 associated breast or RET-mutated medullary thyroid carcinomas. In these conditions, mutated iPSCs can then be used to study the mutational history that precedes the appearance of the malignant transformation and develop novel drug screening strategies. The ability to induce a successful differentiation program towards the tissue in which a given cancer develops or to generate tissue-specific cancer organoids in which the full oncogenic potential can be revealed, remains a major challenge in the field. Similarly, in hematological malignancies a significant hurdle remains owing to the lack of adequate technology to induce the emergence of leukemic stem cells that resemble LSCs, which hinders our ability to study the mechanisms of therapy resistance. PMID: 30659851 [PubMed - as supplied by publisher]

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