Genetically Modified Cell Therapy for the Treatment of Malignant Pleural Mesothelioma
Lead Research Organisation:
University College London
Department Name: Medicine
Abstract
Malignant pleural mesothelioma is an incurable cancer strongly linked to asbestos exposure. It is usually found in the lining of the lungs, and symptoms of breathlessness and pain are very disabling. Unfortunately treatment options are limited. Mesenchymal stem cells (MSCs) are usually found within our bone marrow but travel within the blood stream towards cancers and can infiltrate into them. These cells can be modified to carry a therapy called TRAIL that on contact kills cancer cells without damaging surrounding healthy cells. We can switch this therapy on and off using a common antibiotic. Our previous studies have shown that MSCs carrying TRAIL can be sent to lung cancer and cause death of the cancer cells. In all cases cancer growth was reduced and in 40% cancers were eliminated.
In initial experiments I have shown these MSCs carrying TRAIL kill malignant pleural mesothelioma cancer cells. I now wish to examine how widely effective this new therapy is and whether it can be further improved by combining it with existing chemotherapy drugs. If these experiments are successful this treatment could easily be delivered to patients through a tube directly to the cancer in the space surrounding the lungs.
In initial experiments I have shown these MSCs carrying TRAIL kill malignant pleural mesothelioma cancer cells. I now wish to examine how widely effective this new therapy is and whether it can be further improved by combining it with existing chemotherapy drugs. If these experiments are successful this treatment could easily be delivered to patients through a tube directly to the cancer in the space surrounding the lungs.
Technical Summary
Malignant pleural mesothelioma (MPM) is an aggressive and fatal cancer caused largely by previous exposure to asbestos fibres. Treatment options are limited to either radical surgery or combination chemotherapy and the average survival is four to eighteen months. Novel therapies are desperately needed. Mesenchymal stem cells (MSCs) are known to migrate to sites of tumours and incorporate into tumour stroma making them potentially good vehicles for the delivery of anti-cancer therapies. TNF-related apoptosis inducing ligand (TRAIL) is a transmembrane protein that selectively induces apoptosis in malignant cells without affecting healthy tissues.
I hypothesise that MSCs genetically modified to produce TRAIL can be delivered locally to malignant mesothelioma calls and induce apoptosis. I have three key objectives:
1. To establish the sensitivity of primary and established MPM cell lines to MSCTRAIL cell therapy
2. To determine whether the combination of chemotherapy or radiotherapy with TRAIL increases death of MPM cells compared to TRAIL alone in both resistant and sensitive MPM cells
3. To determine whether the delivery of MSCTRAIL reduces or eliminates MPM tumour growth in vivo
Previous data from Dr Janes‘ group shows that human MSCs can be stably transduced with a lentiviral vector to conditionally express TRAIL in the presence of tetracycline. These modified stem cells induce apoptosis and cell death in a number of cancer cell lines both in vitro and in an in vivo metastatic model. My experiments will examine the sensitivity of MPM cell lines and primary cultures to MSCTRAIL therapy. TRAIL resistance is recognised in some MPM cell lines and I will explore both the mechanism of this and examine improving tumour cell killing by combining the cellular therapy with commonly used cytotoxic chemotherapies and irradiation. I will finally examine the effects of MSCTRAIL therapy in an in vivo xenograft model of MPM. This will explore both the biology of MSC infiltration into tumours within a body cavity after direct introduction and evaluate the effect of the therapy in a clinically relevant model. I believe my experiments will delineate a possible role for combined cell and gene therapy in this otherwise uniformly fatal disease.
I hypothesise that MSCs genetically modified to produce TRAIL can be delivered locally to malignant mesothelioma calls and induce apoptosis. I have three key objectives:
1. To establish the sensitivity of primary and established MPM cell lines to MSCTRAIL cell therapy
2. To determine whether the combination of chemotherapy or radiotherapy with TRAIL increases death of MPM cells compared to TRAIL alone in both resistant and sensitive MPM cells
3. To determine whether the delivery of MSCTRAIL reduces or eliminates MPM tumour growth in vivo
Previous data from Dr Janes‘ group shows that human MSCs can be stably transduced with a lentiviral vector to conditionally express TRAIL in the presence of tetracycline. These modified stem cells induce apoptosis and cell death in a number of cancer cell lines both in vitro and in an in vivo metastatic model. My experiments will examine the sensitivity of MPM cell lines and primary cultures to MSCTRAIL therapy. TRAIL resistance is recognised in some MPM cell lines and I will explore both the mechanism of this and examine improving tumour cell killing by combining the cellular therapy with commonly used cytotoxic chemotherapies and irradiation. I will finally examine the effects of MSCTRAIL therapy in an in vivo xenograft model of MPM. This will explore both the biology of MSC infiltration into tumours within a body cavity after direct introduction and evaluate the effect of the therapy in a clinically relevant model. I believe my experiments will delineate a possible role for combined cell and gene therapy in this otherwise uniformly fatal disease.