[HTML][HTML] Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies

M Ruella, DM Barrett, SS Kenderian… - The Journal of …, 2016 - Am Soc Clin Investig
M Ruella, DM Barrett, SS Kenderian, O Shestova, TJ Hofmann, J Perazzelli, M Klichinsky…
The Journal of clinical investigation, 2016Am Soc Clin Investig
Potent CD19-directed immunotherapies, such as chimeric antigen receptor T cells (CART)
and blinatumomab, have drastically changed the outcome of patients with
relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). However, CD19-negative
relapses have emerged as a major problem that is observed in approximately 30% of
treated patients. Developing approaches to preventing and treating antigen-loss escapes
would therefore represent a vertical advance in the field. Here, we found that in primary …
Potent CD19-directed immunotherapies, such as chimeric antigen receptor T cells (CART) and blinatumomab, have drastically changed the outcome of patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). However, CD19-negative relapses have emerged as a major problem that is observed in approximately 30% of treated patients. Developing approaches to preventing and treating antigen-loss escapes would therefore represent a vertical advance in the field. Here, we found that in primary patient samples, the IL-3 receptor α chain CD123 was highly expressed on leukemia-initiating cells and CD19-negative blasts in bulk B-ALL at baseline and at relapse after CART19 administration. Using intravital imaging in an antigen-loss CD19-negative relapse xenograft model, we determined that CART123, but not CART19, recognized leukemic blasts, established protracted synapses, and eradicated CD19-negative leukemia, leading to prolonged survival. Furthermore, combining CART19 and CART123 prevented antigen-loss relapses in xenograft models. Finally, we devised a dual CAR-expressing construct that combined CD19- and CD123-mediated T cell activation and demonstrated that it provides superior in vivo activity against B-ALL compared with single-expressing CART or pooled combination CART. In conclusion, these findings indicate that targeting CD19 and CD123 on leukemic blasts represents an effective strategy for treating and preventing antigen-loss relapses occurring after CD19-directed therapies
The Journal of Clinical Investigation