Carpenter, BJM; (2014) Targeting Therapeutic T Cells To Tumour Niches. Doctoral thesis , UCL (University College London).

Abstract

CXCR4 and CXCL12 are known to work in concert to mediate cell proliferation, survival and migration. These functions have a bearing on physiological cellular events such as haematopoietic cell recruitment to, and survival within, the bone marrow (BM) compartment. This axis can mediate analogous functions within a malignant setting, helping to organize tumour niches and promoting tumour cell survival and disease progression. Adoptive T cell therapy is well established in the treatment of haematopoietic cancers, and is under investigation for solid malignancies. Barriers to these therapies include off target toxicities such as GVHD and loss of T cell function or persistence. Approaches to target transferred therapeutic T cells to the sites of disease and increase their function and engraftment are desirable. I have constructed a retroviral vector to enable transduction of murine T cells to produce constitutive over-expression of CXCR4. This construct was used alongside control vectors, to investigate the therapeutic potential of CXCR4 over-expressing T (TCXCR4) cells. In vitro, murine TCXCR4 cells exhibited stable expression of CXCR4 and increased chemotaxis to CXCL12. Further in vivo studies observed preferential accumulation of T cells within the BM from 24hrs after transfer. By 2 weeks, TCXCR4 cells outcompete control counterparts in BM accumulation 15-fold. To further track TCXCR4 cells within the BM, intra-vital imaging experiments in osteoblast (Collagen-1α-GFP) mice identified preferential homing to the endosteal niche. In murine tumour models, allogeneic TCXCR4 cells mediated greater anti-tumour responses against sub-cutaneous CXCR4+ tumour. Of note, greater graft-versus-lymphoma (GVL) effect was achieved without the induction of greater graft-versus-host disease. This approach has also demonstrated preferential control of splenic metastasis of BM disease in a further murine model of CXCR4+ malignancy. In memory recall experiments, performed using OT-I CD8+ T as donor cells, TCXCR4 cells once transferred in vivo maintained higher proportions of CD44Hi CD62LHi CD127+ phenotype cells, underwent higher levels of proliferation and produced higher levels of IFN-γ, early post vaccination with relevant antigen. In conclusion, over-expression of CXCR4 in T cells increases their engraftment in the BM and the induction of GVL. This initial data suggests that the strategy of inducing CXCR4 over-expression in therapeutic T cells is an attractive approach to enhance malignant disease targeting and favour long-term engraftment of transferred cells.

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