The Battle within: AML´s p53 Strategies to Evade T-Cell Attack

Bispecific T-cell recruiting antibody constructs (BsAb) have shown clinical efficacy with Blinatumomab, a CD3xCD19 BiTE ® construct used for the treatment of relapsed or refractory B-cell precursor ALL. Despite the success of BsAbs in B-cell malignancies, the translation to a myeloid setting has been unsuccessful, independently of the chosen target antigen. For example, targeting CD33 has failed to provide long-term benefits. Several reports have demonstrated that the diverse genetic makeup of AML confers resistance to T-cell based immunotherapy. Mutations of TP53occur in 5-10% of patients with de novoAML and up to 50% in older patients with therapy related AML, thus highlighting its role as a potential resistance mechanism. We hypothesize, that genetic aberrations of TP53in AML contribute to cell intrinsic and cell extrinsic resistance against T-cell based immunotherapy approaches.