CD19/CD22 targeting with co-transduced CAR T-cells to prevent antigen negative relapse after CAR T-cell therapy of B-ALL
Sara Ghorashian, Giovanna Lucchini, Rachel Richardson, Kyvi Nguyen, Craig Terris, Aleks Guvenel, Macarena Oporto Espuelas, Jenny Yeung, Danielle Pinner, Jan Chu, Lindsy Williams, Ka-Yuk Ko, Chloe Walding, Kelly Watts, Sarah Inglott, Rebecca Thomas, Christopher Connor, Stuart Paul Adams, Emma Gravett, Kimberley C Gilmour, Alka Lal, Bilyana Popova, Sangeetha Kunaseelan, Andre Lopes, Yenting Ngai, Allan Hackshaw, Evangelia K Kokalaki, Milena Balasch-Carulla, Khushnuma Mullanfiroze, Arina Lazareva, Vesna Pavasovic, Anupama Rao, Jack Bartram, Ajay Vora, Robert Chiesa, Juliana M Furtado Silva, Kanchan Rao, Denise Kathleen Bonney, Robert Wynn, Martin Pule, Rachael E Hough, Persis J. Amrolia- Cell Biology
- Hematology
- Immunology
- Biochemistry
CD19-negative relapse is a leading cause of treatment failure after Chimeric antigen receptor (CAR) T-cell therapy for ALL. We investigated a CAR T-cell product targeting CD19 and CD22 generated by lentiviral co-transduction with vectors encoding our previously-described fast-off rate CD19CAR (AUTO1) combined with a novel CD22CAR capable of effective signalling at low antigen density. Twelve patients with advanced B-ALL were treated (CARPALL study, NCT02443831), a third of whom had failed prior licensed CAR therapy. Toxicity was similar to that of AUTO1 alone, with no cases of severe cytokine release syndrome. Ten of 12 patients (83%) achieved a Measurable Residual Disease (MRD) negative complete remission at 2 months post infusion. Of 10 responding patients, 5 had emergence of MRD (2) or relapse (3) with CD19 and CD22 expressing disease associated with loss of CAR T-cell persistence. With a median follow-up of 8.7 months there were no cases of relapse due to antigen-negative escape. Overall survival was 75% (95%CI: 41-91%) at 6 and 12 months. Six and 12-month event free survival (EFS) were 75% (95%CI: 41-91%) and 60% (95%CI: 23-84%). These data suggest dual targeting with co-transduction may prevent antigen negative relapse after CAR T-cell therapy.