AUTO2

The APRIL CAR was well tolerated, but the clinical responses observed in AUTO2 were disappointing. Subsequently, when comparing the APRIL CAR to other BCMA CARs, we observed in vitro functional deficiencies due to reduced target binding by cell-expressed ligand.

Patients received lymphodepletion with fludarabine (30mg/m2 for 4 days) and cyclophosphamide (500mg/m2 for 2 days) (Flu/Cy) prior to AUTO4 infusion... AUTO4 treatment was well tolerated with no DLT. Early responses are encouraging, although no CAR T cell expansion was seen in peripheral blood which may translate to responses that are not durable. To address this, optimisation of the AUTO4 manufacturing process has been performed, resulting in a product with a more naïve phenotype.

Building on these properties, we developed AUTO1/22 an autologous CAR T cell product co-transduced with two different lentiviral vectors encoding our existing CD19 CAR and a novel CD22CAR designed to recognise targets with low antigen density...Following fludarabine/cyclophosphamide lymphodepletion, patients received 1x106 /kg CAR+ T cells...Six of 12 patients had relapsed post allogeneic SCT, 6 had received prior Blinatumomab/Inotuzumab and 4 had relapsed after prior Tisagenlecleucel...Cytokine release syndrome (CRS) occurred in 11/12 patients (grade 1 n=5, grade 2 n=6) requiring Tocilizumab in 5 cases, but severe (≥ grade 3) CRS was not seen and no patients required ICU admission for CRS... Our data show that dual CD19/22 targeting CAR T cells generated by co-transduction show a favorable safety profile, with robust expansion/persistence and early efficacy in a heavily pre-treated cohort. To date with we have not observed antigen negative relapse. This contrasts to an incidence of 5/6 CD19 negative relapses in the 12 responders treated with single CD19 targeting CAR T cells (AUTO1) in an earlier cohort and suggests dual targeting may be effective in preventing antigen escape.

All patients receive lymphodepletion with 30 mg/m2/day fludarabine and 300 mg/m2/day cyclophosphamide for 3 days prior to AUTO2 infusion...Median age was 61 years (range 45-69 years), median 5 prior lines of treatment (range 3-6) ,73% had prior autologous transplant, 100% were refractory to a PI or IMiD, 80% were refractory to both and 45% were refractory to daratumumab...Tocilizumab was given to 3 patients (27%)... AUTO2 is a novel CAR-T therapy, with a manageable safety profile at doses up to 900x10e6 CAR-T cells.