IMMUNOTHERAPY AND IMMUNE REGULATION IN CHILDHOOD CANCERS
Our group's aims are to develop and implement innovative treatments for childhood cancer through modulation of the host immune system, and to understand basic biological processes in tumour cells relevant to the design of effective treatments.
Chimeric antigen receptor modified T cells for recurrent neuroblastoma
Funding: Cancer Research UK; New Agent Committee (co-investigators: Anderson, Pule and Straathof); Action Medical Research
Chimeric antigen receptors (CAR) combine the specificity of monoclonal antibodies with potent T cell signal transduction. In this way, a gene therapy vector can encode a single polypeptide chain that forms a surface receptor and activates a transduced T cells specifically in the presence of a target antigen. Because the antigen recognition component is derived from an antibody, T cells can recognize brightly expressed surface tumour antigens in an MHC-unrestricted manner.
We are investigating CAR technology in relation to neuroblastoma, which expresses the ganglioside antigen GD2 brightly and homogeneously. With CRUK grant support and in collaboration with the CRUK Drug Development Office we have developed a new phase I/II clinical trial to open in 2014 pending regulatory approvals.
Gamma delta T cell biology and immunotherapy
Funding: Leukaemia and Lymphoma Research, Wellcome Trust, SPARKS/DuBois Children's Cancer Fund, Cromwell clinical fellowship scheme.
In 2012 we demonstrated that human blood gamma delta T cells' ability to function as professional antigen presenting cells is dependent on interaction with IgG antibodies on the surface of opsonized targets cells and this "licensing" is dependent on CD16 ligation (Himoudi et al Journal of Immunology (2012) 188(4):1708-16.). This observation has led us to explore the potential use of therapeutic monoclonal antibodies in combination with gamma delta T cells in the immunotherapy of childhood cancers. Grants from the Wellcome Trust and LLR are enabling us to explore these possibilities in neuroblastoma and in leukaemia/lymphoma respectively. Grants from the ICH/Cromwell fellowship scheme are enabling us to evaluate the role of CMV specific gamma delta T lymphocytes in control of paediatric cancers, and to evaluate the clinical potential of CAR-transduced γδT cells in paediatric cancer immunotherapy.
New antibody targets in neuroblastoma and high grade glioma (Straathof, Pule Anderson)
With grant support from Children with Cancer-UK, Great Ormond Street Children's Charity, and the GOSH Biomedical Centre, we are developing new antibodies against the extracellular component of ALK, which is deregulated in a high proportion of children with neuroblastoma. Through our collaboration with the UCL Cancer Institute we are developing single chain variable fragments and chimeric antigen receptors against a range of antigenic targets for childhood cancer. For example, in collaboration with the Institute of Cancer Research Sutton, we are investigating combinations with new ALK inhibitors and ALK antibodies to test in transgenic models of the disease.
Translational Cancer Research Collaboration
Work on biomarkers and developments in Gene and Cell therapy of childhood cancers is done in partnership with the TCRC within the cancer section.