A novel in vivo chemoselection strategy for genetically modified hematopoietic stem cells

Abstract

leukocyte antigens (HLA) displayed on cancer cells, but absent on normal neuroglia in the CNS. AlloCTL migrate through tumors, and at high effectorto-target (E:T) cell ratios achieve selective alloreactive killing, mediating a localized immunorejection effect. Adoptive alloCTL immunotherapy for glioma is also currently being evaluated in a Phase I study (www.clinicaltrials.gov, NCT01144247). Mixed lymphocyte-target cell assays demonstrated that alloCTL-based RRV producer cells (alloCTL/RRV) maintain migratory and effector function, and efficiently transmitted RRV to co-cultured cancer cells even at E:T ratios as low as 1:100. Combining alloCTL adoptive immunotherapy and RRV prodrug activator gene therapy in vivo showed both early tumor growth inhibition aswell as continued regression upon prodrug administration, achieving significantly improved therapeutic efficacy compared to either treatment alone in orthotopic brain tumor models. Thus, alloCTL/RRV can act both as immunotherapeutic effector cells that directly kill targets at high E:T ratios, and as motile cellular ‘carriers’ that release RRV and facilitate virus spread to unkilled targets at low E:T ratios.