Stem Cell Institute Philippines

novel inductions for the future...

Natural Killer Cells Attack Cancer and Virus

Autologous Dendritic Cell Therapy for Cancer is available at ASCI.

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 Asian Stem Cell Institute in Manila. 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 Human CD40 ligand deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-γ. J Allergy Clin Immunol. 2017 Mar;139(3):900-912.e7 Authors: Cabral-Marques O, Ramos RN, Schimke LF, Khan TA, Amaral EP, Barbosa Bomfim CC, Junior OR, França TT, Arslanian C, Carola Correia Lima JD, Weber CW, Ferreira JF, Tavares FS, Sun J, D'Imperio Lima MR, Seelaender M, Garcia Calich VL, Marzagão Barbuto JA, Costa-Carvalho BT, Riemekasten G, Seminario G, Bezrodnik L, Notarangelo L, Torgerson TR, Ochs HD, Condino-Neto A Abstract BACKGROUND: CD40 ligand (CD40L) deficiency predisposes to opportunistic infections, including those caused by fungi and intracellular bacteria. Studies of CD40L-deficient patients reveal the critical role of CD40L-CD40 interaction for the function of T, B, and dendritic cells. However, the consequences of CD40L deficiency on macrophage function remain to be investigated. OBJECTIVES: We sought to determine the effect of CD40L absence on monocyte-derived macrophage responses. METHODS: After observing the improvement of refractory disseminated mycobacterial infection in a CD40L-deficient patient by recombinant human IFN-γ (rhIFN-γ) adjuvant therapy, we investigated macrophage functions from CD40L-deficient patients. We analyzed the killing activity, oxidative burst, cytokine production, and in vitro effects of rhIFN-γ and soluble CD40 ligand (sCD40L) treatment on macrophages. In addition, the effect of CD40L absence on the macrophage transcriptome before and after rhIFN-γ treatment was studied. RESULTS: Macrophages from CD40L-deficient patients exhibited defective fungicidal activity and reduced oxidative burst, both of which improved in the presence of rhIFN-γ but not sCD40L. In contrast, rhIFN-γ and sCD40L ameliorate impaired production of inflammatory cytokines. Furthermore, rhIFN-γ reversed defective control of Mycobacterium tuberculosis proliferation by patients' macrophages. The absence of CD40L dysregulated the macrophage transcriptome, which was improved by rhIFN-γ. Additionally, rhIFN-γ increased expression levels of pattern recognition receptors, such as Toll-like receptors 1 and 2, dectin 1, and dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin in macrophages from both control subjects and patients. CONCLUSION: Absence of CD40L impairs macrophage development and function. In addition, the improvement of macrophage immune responses by IFN-γ suggests this cytokine as a potential therapeutic option for patients with CD40L deficiency. PMID: 27554817 [PubMed - indexed for MEDLINE]
Related Articles Targeting C-type lectin receptors: a high-carbohydrate diet for dendritic cells to improve cancer vaccines. J Leukoc Biol. 2017 Jul 20;: Authors: van Dinther D, Stolk DA, van de Ven R, van Kooyk Y, de Gruijl TD, den Haan JMM Abstract There is a growing understanding of why certain patients do or do not respond to checkpoint inhibition therapy. This opens new opportunities to reconsider and redevelop vaccine strategies to prime an anticancer immune response. Combination of such vaccines with checkpoint inhibitors will both provide the fuel and release the brake for an efficient anticancer response. Here, we discuss vaccine strategies that use C-type lectin receptor (CLR) targeting of APCs, such as dendritic cells and macrophages. APCs are a necessity for the priming of antigen-specific cytotoxic and helper T cells. Because CLRs are natural carbohydrate-recognition receptors highly expressed by multiple subsets of APCs and involved in uptake and processing of Ags for presentation, these receptors seem particularly interesting for targeting purposes. PMID: 28729358 [PubMed - as supplied by publisher]
Related Articles Cytokine-Induced Killer Cells As Pharmacological Tools for Cancer Immunotherapy. Front Immunol. 2017;8:774 Authors: Gao X, Mi Y, Guo N, Xu H, Xu L, Gou X, Jin W Abstract Cytokine-induced killer (CIK) cells are a heterogeneous population of effector CD3(+)CD56(+) natural killer T cells, which can be easily expanded in vitro from peripheral blood mononuclear cells. CIK cells work as pharmacological tools for cancer immunotherapy as they exhibit MHC-unrestricted, safe, and effective antitumor activity. Much effort has been made to improve CIK cells cytotoxicity and treatments of CIK cells combined with other antitumor therapies are applied. This review summarizes some strategies, including the combination of CIK with additional cytokines, dendritic cells, check point inhibitors, antibodies, chemotherapeutic agents, nanomedicines, and engineering CIK cells with a chimeric antigen receptor. Furthermore, we briefly sum up the clinical trials on CIK cells and compare the effect of clinical CIK therapy with other immunotherapies. Finally, further research is needed to clarify the pharmacological mechanism of CIK and provide evidence to formulate uniform culturing criteria for CIK expansion. PMID: 28729866 [PubMed]
Turbocharging vaccines: emerging adjuvants for dendritic cell based therapeutic cancer vaccines. Curr Opin Immunol. 2017 Jul 18;47:35-43 Authors: Saxena M, Bhardwaj N Abstract Development of therapeutic cancer vaccines has been hindered by the many pro-tumorigenic mechanisms at play in cancer patients that serve to suppress both antigen presenting cells and T cells. In face of these obstacles, cancer vaccines are most likely to promote anti-tumorigenic immune responses only when formulated with strong adjuvants, and in combination with new immune interventions designed to reverse immune suppression and exhaustion of T cells in the tumor microenvironment. Dendritic cells (DCs) are often termed 'nature's adjuvant' due to their exceptional capacity for initiating both innate and adaptive immune responses. Hence, the past decade has witnessed a flurry of activity in testing DC based immunotherapies for cancer intervention. In this review we will discuss advances in conventional adjuvants and provide insight into new adjuvants as they pertain to DC cancer therapy. PMID: 28732279 [PubMed - as supplied by publisher]