Integrating Proteomics and Transcriptomics for Systematic Combinatorial Chimeric Antigen Receptor Therapy of AML

Abstract

Chimeric antigen receptor (CAR) therapy targeting CD19 has yielded remarkable outcomes in patients with acute lymphoblastic leukemia. To identify potential CAR targets in acute myeloid leukemia (AML), we probed the AML surfaceome for overexpressed molecules with tolerable systemic expression. We integrated large transcriptomics and proteomics datasets from malignant and normal tissues, and developed an algorithm to identify potential targets expressed in leukemia stem cells, but not in normal CD34CD38 hematopoietic cells, T cells, or vital tissues. As these investigations did not uncover candidate targets with a profile as favorable as CD19, we developed a generalizable combinatorial targeting strategy fulfilling stringent efficacy and safety criteria. Our findings indicate that several target pairings hold great promise for CAR therapy of AML.

Inefficient ZAP70-Signaling Blunts Antigen Detection by CAR-T-Cells

“…The emergence of antigen escape tumor variants with reduced or even complete loss of antigen expression constitutes a severe complication associated with current CAR-T-cell based therapies (Evans et al, 2015;Orlando et al, 2018;Ruella and Maus, 2016). In particular, targeting cancers with highly heterogeneous TAA-expression via state-of-the-art CAR-T-cells remains to this date a challenge (Fry et al, 2018;Perna et al, 2017). While the strategy to "hit hard and early" through the transfer of larger numbers of CARmodified central memory T-cells may -if applicable -help to increase overall survival rates, it does not provide full protection from outgrowth of tumor variants with low TAA expression.…”

Adoptive immunotherapy with CAR modified T cells in cancer current landscape and future perspectives

“…Albeit no antigen with characteristics as favorable as CD19 was found, some promising targets, namely ADGRE2, CCR1, CD70, and LILRB2, were identified (75). Besides, a recent proof-of-concept publication showed that also intracellular peptides can be targeted and that the efficacy of CAR T cells can be boosted by vaccination.…”

The EURE‐CART project as a prototype model for CAR T‐cell immunotherapy in Europe

“…Although extensive studies using genomics and proteomics did not identify a candidate target with a profile as favourable as CD19, recent efforts have shed some light on this topic. In fact, a generalizable combinatorial targeting strategy fulfilling stringent efficacy and safety criteria has recently been suggested to overcome this obstacle . Alternatively, novel targets can be considered in the process of identification of an ideal, single, surface target for CAR T‐cell therapy in AML.…”