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 Myeloid cells as a target for oligonucleotide therapeutics: turning obstacles into opportunities. Cancer Immunol Immunother. 2017 Feb 18;: Authors: Kortylewski M, Moreira D Abstract Immunotherapies emerged as an alternative for cancer treatment, yet their clinical efficacies are still limited, especially in case of solid tumors. Myeloid immune cells, such as macrophages and myeloid-derived suppressor cells (MDSCs), are often hijacked by tumors and become pivotal inhibitors of antitumor immunity. Immunosuppressive functions of tumor-associated myeloid cells result from the activity of Signal Transducer and Activator of Transcription 3 (STAT3), a transcription factor with well-defined tumorigenic and tolerogenic roles in human cancers. To overcome challenges in the development of pharmacological STAT3 inhibitors, we recently developed oligonucleotide-based strategies for cell-selective, in vivo STAT3 targeting. Conjugation of a STAT3siRNA or decoy STAT3 inhibitors to synthetic Toll-like Receptor 9 (TLR9) agonists, CpG oligonucleotides, allowed for selective delivery into TLR9-positive cells. Cellular target for CpG-STAT3 inhibitors include non-malignant, tumor-associated myeloid cells, such as polymorphonuclear MDSCs, as well as cancer cells in acute myeloid leukemia, B cell lymphoma and in certain solid tumors. The chemically modified CpG-STAT3 inhibitors resist serum nucleases and thus can be administered intravenously. Their potency relies on the intracellular gain-of-function effect: release of the central immune checkpoint regulator (STAT3) to unleash proinflammatory signaling (CpG/TLR9) in the same antigen-presenting cell. At the cellular level, CpG-STAT3 inhibitors exert two-pronged effect by rescuing T cells from the immune checkpoint control while decreasing survival of cancer cells. In this article, we review the preclinical data on CpG-STAT3 inhibitors and discuss perspectives of using TLR9-targeted delivery of oligonucleotide therapeutics for the generation of novel, more effective and safer cancer immunotherapies. PMID: 28214929 [PubMed - as supplied by publisher]

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