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Collaboration MAKNA-HUKM

Project Title

Development of Dendritic-Cell Based Vaccine

Principal Researcher Professor Dr Cheong Soon Keng
Research Team Prof Madya Dr S Fadilah Abdul Wahid
Prof Madya Dr Leong Chooi Fun
Amount Allocated RM500,000.00
Project Duration July 2002 – December 2006

Introduction

 

Despite advances in chemotherapy, radiotherapy and stem cell transplantation, only 50% of the leukemias & lymphomas and 30% of other cancers are cured of the disease. Thus it is imperative to search for new modalities of treatment. Our research team focus on the development of dendritic-cell (DC) based vaccine for the treatment of leukemias and other cancers.

 

Objectives

  1. To isolate DC from monocytes and haemopoietic stem cells in murine and human sources and evaluate their properties in-vitro.
  2. To isolate DC from human leukemic cells and evaluate their properties in-vitro.
  3. To generate DC vaccines and evaluate their activities in-vitro
  4. To evaluate the efficacy and toxicity of DC vaccines in a murine model.
  5. To produce clinical grade DC vaccine in large quantities for clinical application
  6. To evaluate the efficacy and toxicity of DC vaccine in a clinical setting.

Hypotheses

  1. DC vaccines could be developed from monocytes, bone marrow stem cells and also leukemic cells.
  2. DC vaccines  could inhibit tumour progression  in a murine model.
  3. DC vaccines could be developed in large quantities for clinical use
  4. DC vaccines could cause tumour regression in leukemias and lymphomas.

Findings

We had successfully generated DC from monocytes and haemopoietic stem cells from murine and human sources. DC could also be generated directly from leukemic cells. When these DC were exposed to tumour antigen, they were converted to tumour vaccines which showed anti-tumour activity in-vitro and inhibited tumour progression in-vivo in a murine model. Using serum-free culture media and clinical grade reagents, we were able to generate DC in large quantities from monocytes or leukemic cells for active immunotherapy. We are currently evaluating the efficacy and toxicity of DC vaccines in patients with refractory leukemias and lymphomas and relapse after stem cell transplantation.

ANNUAL REPORT 2006

FINAL REPORT of Leukemia Vaccine Project
Research Team:
Principal Investigator Professor Dr Cheong Soon Keng
Collaborators Prof Madya Dr S Fadilah Abdul Wahid
Prof Madya Dr Leong Chooi Fun
Amount Allocated RM500,000.00
Project Duration July 2002 – December 2006

 

Project Summary

 

Introduction

 

Despite advances in chemotherapy, radiotherapy and stem cell transplantation, only 50% of the leukemias & lymphomas and 30% of other cancers are cured of the disease. Thus it is imperative to search for new modalities of treatment. Our research team focus on the development of dendritic-cell (DC) based vaccine for the treatment of leukemias and other cancers.

 

Objectives:

  1. To isolate DC from monocytes and haemopoietic stem cells in murine and human sources and evaluate their properties in-vitro.

  2. To isolate DC from human leukemic cells and evaluate their properties in-vitro.

  3. To generate DC vaccines and evaluate their activities in-vitro
  4. To evaluate the efficacy and toxicity of DC vaccines in a murine model.
  5. To produce clinical grade DC vaccine in large quantities for clinical application
  6. To evaluate the efficacy and toxicity of DC vaccine in a clinical setting.

Hypotheses:

  1. DC vaccines could be developed from monocytes, bone marrow stem cells and also leukemic cells.
  2. DC vaccines  could inhibit tumour progression  in a murine model.
  3. DC vaccines could be developed in large quantities for clinical use
  4. DC vaccines could cause tumour regression in leukemias and lymphomas.

Findings

 

Phase I

We had successfully generated DC from monocytes and haemopoietic stem cells from murine and human sources. DC could also be generated directly from leukemic cells. When these DC were exposed to tumour antigen, they were converted to tumour vaccines which showed anti-tumour activity in-vitro and inhibited tumour progression in-vivo in a murine model. Using serum-free culture media and clinical grade reagents, we were able to generate DC in large quantities from monocytes or leukemic cells for active immunotherapy.

 

Phase II

In Phase II of the project, a proposal to conduct human clinical trial was submitted to the Research and Ethics Committee of Universiti Kebangsaan Malaysia in year 2004, and permission to carry out the project was granted in late 2004. As it is a totally new treatment, only terminal or refractory leukemia cases are allowed for recruitment to test the efficacy and safety of the treatment method.

 

In escalating the project from bench to clinical trial, Good Manufacturing Practice (GMP) is strictly observed. We initially encountered contamination problem of the clinical grade vaccine product (culture proven) and there was a delay in patient recruitment until the contamination problem was resolved.

 

By 2006, we had recruited a total of 3 patients who had undergone GMP grade DC vaccine preparation. These autologous vaccines were stored in small aliquots in a liquid nitrogen tank for the treatment programme, which would last 6 months for every patient.

 

Two patients (One with acute myeloid leukemia, the other with chronic myeloid leukemia) had passed away before the completion of the vaccination programme. Although leukemia vaccine was produced and cryopreserved for the third patients, the patient subsequently changed her mind and the vaccine was not used.

 

In 2006, Hospital UKM has acquired an instrument Elutra (RM150,000) for production of dendritic-cell based tumour vaccine. The research group has decided to terminate the clinical trial and transfer the technology to the new Cellular Therapy Unit established and operated under MAKNA-HUKM Cancer Institute. The DC based vaccines will from now on be a routine clinical service open to all patients with cancers including leukemias requiring such treatment.

 

Outcome of the Project

 

a) Scientific Publications in Indexed Journal

  1. MN Lim, CF Leong, SK Cheong, HF Seow.  Generation of dendritic cells from acute myeloid leukaemia cells and monocytes: our local experience. Malays J Pathol. 2003; 25(2):107-12.

  2. SK Cheong. Vaccination against cancer –does it work ? Med J Malaysia 2003; 58 (S E): 67.

  3. LM Looi, Z Zubaidah, PL Cheah, SK Cheong et al. Research on cancer diagnosis in Malaysia: current status. Malays J Pathol. 2004; 26(1):13-27.

  4. GC Sim, R Ammu, SK Cheong. Generation and characterization of murineCD4-CD8- dendritic cellsform bone marrow cultures. Cytotherapy 2005; 7(S1): 130.

  5. GC Sim, R Ammu, SK Cheong. Dysfunction of DC and not the impairment of T cells may contribute to low IFN-gamma production. Cytotherapy 2005; 7(S1): 131.

b) Abstracts of Presentation at Scientific Meetings

  1. MN Lim, CF Leong, SK Cheong. Generation of dendritic cells from monocytes and acute myeloid leukemic cells. 3rd CpathAMM Annual Scientific Meeting, 21-23 June 2002, Melaka.

  2. A Habsah, CF Leong, NH Hamidah, O Ainoon, SK Cheong. Enumeration of absolute counts of myeloid and lymphoid dendritic cells in peripheral blood using flow cytometry. The First Joint Congress of the College of Pathologists AMM and the Malaysian Institute of Medical Laboratory Sciences, 16-18 December 2003, Kuala Lumpur

  3. GC Sim, R Ammu, SK Cheong. In vitro expansion and differentiation of dendritic cells from peripheral blood CD34+ haemopoietic stem cells. The First Joint Congress of the College of Pathologists AMM and the Malaysian Institute of Medical Laboratory Sciences, 16-18 December 2003, Kuala Lumpur

  4. SK Cheong, MN Lim, CF Leong. Generation of dendritic cells from human monocytes. (C6 UKM P8). Research and Devlopment Exposition 2003, Putra World Trade Centre, Kuala Lumpur.

  5. GC Sim, R Ammu, SK Cheong. Dendritic cells pulsed with tumour lysate caused tumour regression of breast cancer in a murine model. 5th Malaysian National Haematology Scientific Meeting, 9-11 April 2004, Putrajaya.

  6. GC Sim, R Ammu, SK Cheong. Comparison of the ability of cryopreserved and fresh dendritic cells to inhibit tumour growth using a murine model. 10th Annual Scienctific Meeting of Internaltional Society of Cellular Therapy, 7-10 May 2004, Dublin, Ireland.

  7. GC Sim, R Ammu, SK Cheong. In-vitro generation and IFN-gamma production of murine bone marrow derived CD4-CD8- dendritic cells. First Malaysia-Indonesia Medical Sciences Conference, 21-23 July 2005, Kuala Lumpur.

  8. AA Mimi, SK Cheong, A Habsah. Dendritic cell sunsets in non-Hodgkin’s B-cell lymphoma. Proceedings of 6th Malaysian National Haematology Scientific Meeting, 28-30 April 2006, Kota Bharu, pg  49.

  9. YF Tan, GC Sim, A Habsah, CF Leong, SK Cheong. Experimental production of clinical grade leukemic vaccine. Proceedings of 7th Annual Scientific Meeting, College of Pathologists, Academy of Medicine of Malaysia, 2-4 June 2006, Kuantan, pg 14.

c) Contribution of the Project to Expertise Development

 

Name Nationality Area of Expertise Degree Year Graduated
Lim Moon Nian Malaysian Biotechnology MSc (UPM) 2004
Mimi Azura Malaysian Haematology MPath (UKM) 2005
Sim Geok Choo Malaysian Biotechnology MSc   (IMU) 2006

 

d) Contribution of the Project to MAKNA’s Reputation.

 

We received the following awards for the project:
 

1.      Best Poster Presentation (2nd Prize), Minggu Penyelidikan Ke-VI, Fakulti Perubatan UKM, 19-24 July 2004.

2.      Bronze Medal in Ekspo Penyelidikan & Inovasi 2004, UKM, 15-18 July 2004.

3.      Best Oral Presentation Award. 6th Malaysian National Haematology Scientific Meeting, 28-30 April 2006, Kota Bharu.

 

Reported by Professor Dr Cheong Soon Keng, 27 December 2006.

 

Mesenchymal Stem Cell for Cancer Management

 

(JAn-DEC 2006)
PROJECT 1 – ISOLATION & PROPAGATION OF MSC FROM DISCARDED HUMAN TISSUES.

 

In this project, it is proposed to isolate MSC from placental or cord blood or discarded tissues after surgery such as eye surgery.

 

MSC-like cells were confirmed to be isolated from discarded corneal tissues after surgery. These corneal tissues were kindly provided by an eye surgeon, Dr Kong Then, from Birmingham Hospital of the United Kingdom. This finding has now been accepted for publication and would be published in Cytotherapy, the official journal of International Society of Cellular Therapy, based in USA.

 

This finding was also presented in the 7th Annual Scientific Meeting, College of Pathologists, Academy of Medicine of Malaysia, 2-4 June 2006, at Kuantan and it received the Best Oral Presentation Award.

 

The research finding was the basis of a MSc thesis and the research officer had successfully defended her thesis

 

PROJECT 2 – Application of MSC to repair injured spinal cord.

 

In this project, we propose to carry out an in-vivo study of using MSC isolated from human bone marrow to repair injured spinal cord in rats.

 

MSC were successfully isolated and characterised in at least 29 human bone marrow samples from patients with non-malignant disorders. These MSC are cryopreserved for the next stage of in-vivo study in rats. The in-vivo experiments are planned for 2007.

PROJECT 3 – GENETICALLY-MODIFIED MSC FOR TREATMENT OF ANAEMIA OF CANCERS.

In this project, we propose to carry out an in-vivo study of human MSC inserted with erythropoietin gene and transplanted into mice with anaemia due to cancer.

 

We have conducted different methods of transferring erythropoietin gene into MSC. So far, transduction with MIDGE-encoded EPO gene using non-viral means appeared to be the most successful. Experiments were also be carried out to label MSC with PKH26 dye for cell tracking in future in-vivo study. The animal studies would be carried out in 2007.

 

PROPOSED BUDGET FOR YEAR 2007

 

The budget estimate (3 projects) for year 2007 is as in the table below:

 

 Research Requirements

Jan – Dec 2007

a.

Temporary & Contract Personnel

(2 research scientific officers)

          RM  60,000

b.

Travel & Transportation

          RM    5,000

c.

Research Materials & Supplies

RM 110,000

d.

Minor Modifications & Repairs

          RM   10,000

e.

Special Services (Animal house charges)

          RM    5,000

f.

Minor Equipment & Accessories

          RM   10,000

Grand Total

RM 200,000

 

Professor Dr Cheong Soon Keng, 4 January, 2007.

 

 

Please CLICK HERE to download Professor Dr Cheong Soon Keng's Presentaion (PDF Format)

 


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