Combining daratumumab with CD47 blockade prolongs survival in preclinical models of pediatric T-ALL

Acute lymphoblastic leukemia (ALL) is the most common malignant disease affecting children. Although therapy strategies improved, T-cell acute lymphoblastic leukemia (T-ALL) relapse is associated with chemoresistance and a poor prognosis. One strategy to overcome this obstacle is the application of monoclonal antibodies. Here, we show that leukemic cells from T-ALL patients express surface CD38 and CD47, both attractive targets for antibody therapy. We therefore investigated the commercially available CD38 antibody daratumumab (Dara) in combination with a proprietary modified CD47 antibody (Hu5F9-IgG2σ) in vitro and in vivo. Compared to single treatments, this combination significantly increased in vitro antibody-dependent cellular phagocytosis (ADCP) in T-ALL cell lines as well as in random de novo and in relapsed/refractory T-ALL patient derived xenograft (PDX) samples. Similarly, enhanced ADCP was observed when combining Dara with pharmacological inhibition of CD47 interactions using a glutaminyl cyclase inhibitor. Phase II-like preclinical in vivo trials using T-ALL PDX samples in experimental minimal residual disease like (MRD-like) and overt leukemia models revealed a high anti-leukemic efficacy of CD47 blockade alone. However, T-ALL xenograft mice subjected to chemotherapy first (post-chemo MRD) and subsequently co-treated with Dara and Hu5F9-IgG2σ displayed significantly reduced bone marrow infiltration as compared to single treatments. In relapsed and highly refractory T-ALL PDX combined treatment with Dara and Hu5F9-IgG2σ was required to substantially prolong survival as compared to single treatments. These findings suggest that combining CD47 blockade with Dara is a promising therapy for T-ALL, especially for relapsed/refractory disease harbouring a dismal prognosis in patients.