Natural killer (NK) cells have been known to enhance the host immune responses against cancer. NK cell number and cytotoxicity in patients with cancer is often low. Therefore, we developed a large-scale ex vivo NK cell expansion method without feeder layers and introduced NK cell-based autologous immune enhancement therapy (AIET). In this paper, we discuss the epidemiological data that show the relationship between NK activity and cancer incidence, monitoring of NK cell number and activity, anti-cancer activities of NK cells in vitro and in vivo and the effects of the combination of expanded NK cells with monoclonal antibody drugs on cancers through antibody-dependent cellular cytotoxicity. Finally, we also present the clinical cases of NK cell-based AIET and the effect of AIET on advanced stage of pancreatic cancer and on various advanced cancers refractory to conventional therapies. NK cell-based AIET might be a useful strategy in the multidisciplinary approach to cancer.

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NK cell-based autologous immune enhancement therapy (AIET) for cancer

(1) Background: Immune cell therapy recently attracted enormous attention among scientists as a cancer treatment, but, so far, it has been poorly studied and applied in Vietnam. The aim of this study was to assess the safety of autologous immune cell therapy for treating lung, liver, and colon cancers—three prevalent cancers in Vietnam. (2) Method: This was an open-label, single-group clinical trial that included 10 patients with confirmed diagnosis of colon, liver, or lung cancer, conducted between March 2016 and December 2017. (3) Results: After 20–21 days of culture, the average number of cytotoxic T lymphocytes (CTLs) increased 488.5-fold and the average cell viability was 96.3%. The average number of natural killer cells (NKs) increased 542.5-fold, with an average viability of 95%. Most patients exhibited improved quality of life, with the majority of patients presenting a score of 1 to 2 in the Eastern Cooperative Oncology Group (ECOG) performance status (ECOG/PS) scale, a decrease in symptoms on fatigue scales, and an increase in the mean survival time to 18.7 months at the end of the study. (4) Conclusion: This method of immune cell expansion met the requirements for clinical applications in cancer treatment and demonstrated the safety of this therapy for the cancer patients in Vietnam.

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Phase I Clinical Trial Using Autologous Ex Vivo Expanded NK Cells and Cytotoxic T Lymphocytes for Cancer Treatment in Vietnam.

Ex vivo-expanded natural killer cells kill cancer cells more effectively than ex vivo-expanded γδ T cells or αβ T cells

Immune cell-based therapies are emerging as a promising tool to tackle malignancies, both solid tumors and selected hematological tumors. Vast experiences in literature have documented their safety and added survival benefits when such cell-based therapies are combined with the existing treatment options. Numerous methodologies of processing and in vitro expansion protocols of immune cells, such as the dendritic cells, natural killer (NK) cells, NKT cells, αβ T cells, so-called activated T lymphocytes, γδ T cells, cytotoxic T lymphocytes, and lymphokine-activated killer cells, have been reported for use in cell-based therapies. Among this handful of immune cells of significance, the NK cells stand apart from the rest for not only their direct cytotoxic ability against cancer cells but also their added advantage, which includes their capability of (i) action through both innate and adaptive immune mechanism, (ii) tackling viruses too, giving benefits in conditions where viral infections culminate in cancer, and (iii) destroying cancer stem cells, thereby preventing resistance to chemotherapy and radiotherapy. This review thoroughly analyses the sources of such NK cells, methods for expansion, and the future potentials of taking the in vitro expanded allogeneic NK cells with good cytotoxic ability as a drug for treating cancer and/or viral infection and even as a prophylactic tool for prevention of cancer after initial remission.

Natural killer cells as a promising tool to tackle cancer-A review of sources, methodologies, and potentials.

Background/objective: Gut dysbiosis is one of the major pathologies in children with autism spectrum disorder (ASD). In previous studies, Aureobasidium pullulans (i.e., black yeast AFO-202-produced beta glucan found in Nichi Glucan) yielded beneficial clinical outcomes related to sleep and behaviour. Evaluation of gut microbiota of the subjects in the present randomized pilot clinical study was undertaken and compared with an aim of gaining a mechanistic insight.
Methods: The study involved 18 subjects with ASD who were randomly allocated: six subjects in the control group (Group 1) underwent conventional treatment comprising remedial behavioural therapies and L-carnosine 500 mg per day, and 12 subjects (Group 2) underwent supplementation with Nichi Glucan 0.5 g twice daily along with the conventional treatment for 90 days. The subjects stool samples were collected at baseline and after the intervention. Whole genome metagenome (WGM) sequencing was performed.
Results: WGM sequencing followed by bioinformatic analysis in 13 subjects who completed the study showed that among genera of relevance, the abundance of Enterobacteria was decreased almost to zero in Group 2 after intervention, whereas it increased from 0.36% to 0.85% in Group 1. The abundance of Bacteroides increased from 16.84% to 19.09% in Group 1, whereas it decreased from 11.60% to 11.43% in Group 2. The abundance of Prevotella increased in both Group 1 and Group 2. The decrease in abundance of lactobacillus was significant in Group 2 compared to Group 1. Among species, a decrease was seen in Escherichia coli, Akkermansia muciniphila CAG:154, Blautia spp., Coprobacillus sp., and Clostridium bolteae CAG:59, with an increase of Faecalibacterium prausnitzii and Prevotella copri, which are both beneficial.
Conclusion: AFO-202 beta 1,3-1,6 glucan was able to balance the gut microbiome, which is considered beneficial in children with ASD. Effective control of curli-producing enterobacteria that leads to α-synuclein (αSyn) misfolding and accumulation, which apart from being advantageous in alleviating ASD symptoms, may have a prophylactic role in Parkinsons and Alzheimers diseases where the Alpha Syn misfolding and amyloid deposition are central to their pathogenesis. Additionally, stimulation of natural killer cells to help clear accumulated Alpha Syn amyloids, beneficial microbiome reconstitution, and microglial rejuvenation lead us to recommend larger clinical studies in neurodevelopmental and neurodegenerative diseases of this safety-proven food supplement.

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Beneficial reconstitution of gut microbiota and control of alpha-synuclein and curli-amyloids-producing enterobacteria, by beta 1,3-1,6 glucans in a clinical pilot study of autism and potentials in neurodegenerative diseases

Radiotherapy is the primary form of treatment in patients with locally advanced cervical carcinoma. However for residual disease in the form of the persistent lymph nodes, surgery or chemotherapy is recommended. As surgery is not acceptable by every patient and chemotherapy has associated side effects, we hereby report the positive outcome of in vitro expanded natural killer cell and activated T lymphocyte based autologous immune enhancement therapy (AIET) for the residual lymphadenopathy in a patient with locally advanced cervical cancer after radiation. After six transfusions of AIET, there was complete resolution of residual lymph nodes and there was no evidence of local lesion. The patient also reported improvement in quality of life. As AIET has been reported as the least toxic among the available therapies for cancer, combining AIET with conventional forms of therapy in similar patients might not only improve the outcome but may also help the patients achieve a good quality of life.

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Cell Based Autologous Immune Enhancement Therapy (AIET) after Radiotherapy in a Locally Advanced Carcinoma of the Cervix.

Background Autism spectrum disorders (ASDs) are a wide range of behavioural disabilities for which there are no definite interventional modalities available. Remedial therapies remain the only option but with varying outcomes. We have evaluated the childhood autism rating scale (CARS) and alpha-synuclein levels in this parallel-group, multiple-arm pilot clinical study after supplementation with a biological response modifier beta-glucan food supplement (Nichi Glucan). Methods Six subjects with ASD (n = 6) Gr. 1 underwent conventional treatment comprising remedial behavioural therapies and L-carnosine 500 mg per day, and 12 subjects (n = 12) Gr. 2 underwent supplementation with the Nichi Glucan 0.5 g twice daily along with the conventional treatment. Results There was a significant decrease in the CARS score in all of the children of the Nichi Glucan Gr.2 compared to the control (p-value = 0.034517). Plasma levels of alpha-synuclein were significantly higher in Gr. 2 (Nichi Glucan) than in the control group Gr. 1 (p-value = 0.091701). Conclusion Improvement of the behavioural pattern CARS score and a correlating alpha-synuclein level, followed by a safe beta-glucan food supplement, warrants further research on other parameters, such as gut-microbiota evaluation, and relevant neuronal biomarkers which is likely to cast light on novel solutions.

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Improvement of behavioural pattern and alpha-synuclein levels in autism spectrum disorder after consumption of a beta-glucan food supplement in a randomized, parallel-group pilot clinical study

Vidyasagar Devaprasad Dedeepiya

Papers

Cell Based Autologous Immune Enhancement Therapy (AIET) after Radiotherapy in a Locally Advanced Carcinoma of the Cervix.

Improvement of behavioural pattern and alpha-synuclein levels in autism spectrum disorder after consumption of a beta-glucan food supplement in a randomized, parallel-group pilot clinical study