Ongoing Malignant Melanoma Research

Research and New Therapies for Melanoma - Update August 2008

For reasons that are not entirely clear, melanoma has proven to be responsive to therapies involving the immune system. These therapies are termed immunotherapy and tend to focus upon the use of biological agents (substances or materials generally found within the body) that can stimulate the patients’ immune system to recognise and eradicate the tumour. To date, the most common form of immunotherapy involves the use of cytokines such as interferons, which are produced in very small levels within the body but are used at higher doses in order to stimulate the tumour fighting capacity of the immune system. Further therapies based upon stimulating the patients’ own immune system are at various stages of development. Examples include cancer vaccines and other cytokines such as interleukin-2.

An alternative approach that has been explored involves the infusion of tumour specific immune cells into the patient’s blood system. Once in the patients’ bloodstream, these cells travel around the patient’s body and eventually arrive at the site of tumour where it is hoped that they recognise and challenge the tumour. This approach is termed adoptive cell therapy and has generally involved the use of T-cells isolated from the patient. T-cells are important members of the immune system playing a pivotal role in protecting against harmful pathogens such as viruses. T-cells are generated in the bone marrow before being matured in the thymus and released to patrol the body within the blood and lymphatic system. T-cells can move into sites of infection within tissues where they either kill infected cells or produce cytokines that can further amplify the immune response. The combination of these properties makes T-cells highly attractive as a cancer therapy since they can patrol the body and specifically home into tumours.

The development of T-cells as an adoptive cell therapy for melanoma has been largely driven by researchers under the leadership of Dr Steven Rosenberg at the Surgery Branch of the National Institutes of Health, Washington, DC. Over an extended period of time, this group has carried out a series of trials examining the potency of adoptively transferred T-cells with recent reports documenting some highly encouraging clinical responses driven by T-cells against melanoma.

Other clinical research groups within the United States are also actively pursing translational studies focused upon the development of adoptive cellular therapies for melanoma. Our aim here in Manchester is to develop the technology and facilities in order to drive our research and to pursue trials of adoptive T-cell therapies for melanoma and other potential cancer targets.

The Basis of Adoptive T-cell Therapy

The initial problem concerning T-cell therapies is where to source the T-cells. T-cells have been isolated from both blood and tumour biopsies and subsequently cultured in the laboratory to achieve numbers which are suitable for clinical use. The use of T-cells derived from tumour (Tumour Infiltrating Lymphocytes – TIL’s) has proven effective in challenging the growth of melanoma. Reasons for this may include the expanded T cells maintaining several of the characteristics that caused them to migrate to the tumour in the first place. Protocols to isolate and expand the TIL’s have been optimised in Dr Rosenberg’s laboratory and are currently being replicated within the Christie Hospital. Once characterised and expanded, the TIL’s are re-infused into the patient generally after the patients have had their own white cells temporarily depleted by the use of chemotherapy. This is important since the absence of competing immune cells, including T-cells, appears to allow the tumour specific T cells to engraft and function more effectively. In order to aid the survival of the T cells, cytokines such as interleukin-2 may also be given.

The process though is technically demanding and requires a period of time to harvest and culture the T cells before the therapy can be administered to the patient. One of the major reasons for this time delay is the fact that tumour specific T-cells are generally present only at very low frequencies within the patients’ blood or tumour. More recent experimental work has focused upon the use of gene-therapy in order to more rapidly generate tumour specific T-cells. The gene therapy procedure involves the introduction of DNA into the T-cells at an early stage of culture that results in producing a protein on their surface and facilitates the specific targeting of tumour. In this case of ex-vivo gene therapy, the gene transfer vector is administered to the T-cells and is washed away before the cells are returned to the patient. In theory, this ensures that tumour specific T-cells can be generated more rapidly thereby potentially reducing the length of time required to generate the T-cells for therapy.

Clinical Developments in Manchester

The University Department of Medical Oncology based at Christie Hospital and the Paterson Institute for Cancer Research has been working upon the development of gene-modified T cells for cancer therapy. Two phase I clinical trials of T cells targeted against colorectal cancer and B-cell lymphoma have recently opened. Underpinning these trials has been the development of the infrastructure to deliver cell therapies and, consequently, we are now collaborating with Dr Rosenberg’s group to develop TIL therapies. The development of this therapy has been also driven by the collaborative effort between Medical Oncology and the Department of Surgery based at Christie’s and we are currently performing developing our in-house protocols in order to submit proposals for phase I trial to the Regulatory agencies. We are also currently initiating studies aimed at developing gene-modified T cells for melanoma therapy again in collaboration with Dr Rosenberg and colleagues.