NiSCELL has been collaborating with University Putra Malaysia (UPM) to produce GMP-grade human umbilical cord-derived mesenchymal stem cells for therapeutic use.
Mesenchymal stem cells (MSCs)
Stem cells have become a new and potentially revolutionary treatment modality for diseases that were once considered as terminal. Among all sources of stem cells, mesenchymal stem cells (MSCs), the adult tissue-resident stem cells, have seized the attention of many clinicians and researchers due to its ability to repair and regenerate damaged tissues and organs. The use of MSCs as cell-based products for therapeutic purposes requires an optimised protocol for isolation, expansion, cryopreservation and reliable quality control procedures to warrant a high-quality product that meets the demands of clinical applications. To date, most of the mesenchymal stem cell culture and preservation protocols that currently used for the regenerative medicine are not in accordance with the criteria of stringent good manufacturing practice (GMP) guidelines and lack quality control parameters. The clinical grade production necessitates adhering to GMP to ensure the delivery of a "cell drug" which is safe, reproducible and efficient. In view of the potential application of MSCs in regenerative medicine, anti-ageing and aesthetic therapy, there is a growing need for developing a standardised protocol that allows expansion of stem cells without compromising its therapeutic efficacy.
Importance of GMP
GMP-compliant cell manufacturing involves several issues to provide a quality assurance system during translation from the primary stem cell sciences into clinical investigations and applications. On the other hand, advanced cellular therapy requires extensive validation, process control, and documentation. It also emphasises the critical importance of production methods and probable risks. Therefore, implementation of quality management and assurance system in accordance with GMP guidelines can greatly reduce risks particularly in the higher-risk category or "more than minimally manipulated" products.
GMP non-compliance issues
Wrong labelling, cross-contamination, document manipulations, non-instrument calibration, and entry of unqualified personnel in proper hygienic environment are considered as non-GMP compliance issues.
General objective of our collaboration
To optimize the GMP culture conditions to produce safe and high quantity of umbilical cord-derived Mesenchymal Stem Cells (UC-MSCs)
To optimise culture conditions for efficient and large-scale production of GMP-grade UC-MSCs in a cost- and time-effective manner with less manipulation and passages.
To determine the stability and stemness of in vitro expanded GMP-grade UC-MSCs.
To evaluate the safety, toxicity and tumorigenicity potential of GMP-grade UC-MSCs in an immune compromised mice model.
Identify an optimized culture condition for efficient and large-scale production of GMP-grade UC-MSCs in a cost- and time-effective manner with less manipulation and passages.
NiSCELL has been collaborating with Universiti Sains Malaysia (USM) to study the technical feasibility, safety and efficacy of cellular immunotherapy in metastatic human breast cancer mouse model in a project funded by MOSTI.
Breast cancer is the most commonly diagnosed malignancy and the second highest leading cause of cancer-related death among women worldwide. In 2012, nearly 1.7 million new cases were diagnosed and there were nearly 600,000 deaths globally, which represent about 12% of all new cancer cases and 25% (one in four) of all cancers in women. The incidence of breast cancer has risen more than 20 % in the past 5 years. In the year 2008, it accounted for 31.3% of the total number of the new cases of cancer among Malaysian women. Treatment of the metastatic patient is a very complex issue with patients frequently developing resistance to the available chemotherapeutic agents. After exhausting the first- or second-line metastatic treatment, there have been usually limited chemotherapeutic options available or patients may not be fit for further chemotherapy due to the toxicities of the treatment undergone. At this stage further treatment may significantly increase the morbidities and any further survival or symptomatic benefits may be minimal. Therefore, there is a desperate need to establish new therapeutic strategies to improve the outcomes in metastatic breast cancer patients.
General objective of our collaboration
To evaluate the therapeutic potential of intravenous injection of in vitro expanded human peripheral blood derived dendritic cell activated CTLs (Antigen specific CTLs) and NK cells in metastatic breast cancer mouse model (xenograft).
1. To analyse the safety (dose and route) and technical feasibility of autoimmune enhanced therapy (AIET) in metastatic breast cancer mouse model.
2. To evaluate the clinical efficacy of intravenous injection of tumour specific CTLs and activated NK cells in metastatic breast cancer mouse model.
To use an optimal dose of CTL and NK cells for the treatment of metastatic breast cancer
NiSCELL has been collaborating with Universiti Teknologi MARA to study the mechanism of the enhancement of immune cells sensitization and trafficking in osteosarcoma by spironolactone (SPIR) and rosiglitazone (RGZ) towards adaptive immunotherapy in mice.
Osteosarcoma (OS) is a frequently observed non-hematologic primary malignant tumour which occurs about 50 per cent more frequently in males than in females. Due to the high genetic heterogeneity and genetic variability, the current standard therapies are of limited efficacy and the overall five-year survival rate (SR) of patients with osteosarcoma (OS) has not considerably improved in past two decades. The outcome is worse if the patient is diagnosed with pulmonary metastasis which is associated with an overall all five-year SR of 30% only.
To find an alternative therapeutic module, adoptive immunotherapy or adoptive immune enhancement therapy (AIET) has shown the effectiveness for several types of advanced tumours, including OS. AIET holds several clinical advantages over conventional therapeutic regimens as well as over new other target therapies. Several experimental (in vitro) and pre-clinical studies provided an important insight and the clinical endpoints also supported the probability that AIET could be a potential therapeutic regimen to treat many types of advanced cancer. At present, different types of anti-tumour immune cells (DCs, or antigen specific or tumour specific T cells, or NK cell or mixed population) have been practiced as AIET for most of the metastatic cancer. However, the disease progression was widely varied based on the source, type and mode of administration of immune cells.
Despite AIET having the ability to kill or eradicate the OS cells, the clinical outcome is still limited. This is because of poor capacity of adoptively transferred DC activated T cell (CD8+) and NK cells to home to the tumours. Immune sensitization and trafficking are the two crucial factors to determine the homing property of immune cells towards the tumour site. In general, anti-tumour immune cells (especially, NK and T cell) trafficking is mediated by precise chemokine receptors expression on immune cells; whereas, the immune sensitization can be induced by stimulating the immune cell recognizing ligands on cancer cells.
General objective of our collaboration
Enhancement of adoptively transferred human osteosarcoma-specific cytotoxic T lymphocyte and activated NK cells therapy by stimulating the sensitization and trafficking of immune cells to home to tumors, as an in vitro and in vivo analysis.
1. To evaluate the SPIR and RGZ immunosensitization and trafficking effects of NK and T cells to OS by measuring the expression of NKG2DL in OS and the CXCR2 in NK and T cells.
2. To study the safety and feasibility of adaptive immune therapy in xenograft osteosarcoma mice model.
3. To impact the therapeutic potential of adaptive immune therapy combined with SPIR in advanced human osteosarcoma using NOD.SCID gamma mice as a humanized xenograft model.
SPIR and RGZ can be used as immunosensitisation and trafficking agents in AIET to target the OS cells in cell-based therapy