Nix MA, Mandal K, Geng H, Paranjape N, Lin YT, Rivera J, Marcoulis M, White KL, Whitman JD, Bapat SP, Parker KR, Ramirez J, Deucher A, Phojanokong P, Steri V, Fattahi F, Hann B, Satpathy AT, Manglik A, Stieglitz E, Wiita AP.
Cancer Discovery, 16 March 2021

Alternate strategies are needed for B-cell malignancy patients relapsing after CD19-targeted immunotherapy. Here, cell surface proteomics revealed CD72 as an optimal target for poor-prognosis KMT2A/MLL1-rearranged (MLLr) B-ALL, which we further found to be expressed in other B-cell malignancies. Using a recently-described, fully-in vitro system we selected synthetic CD72-specific nanobodies, incorporated them into CARs, and demonstrated robust activity against B-cell malignancy models, including CD19 loss. Taking advantage of CD72’s role in inhibiting B-cell receptor signaling, we found that pharmacologic SHIP1 inhibition increased CD72 surface density. We establish CD72-nanobody CAR T’s as a promising therapy for MLLr B-ALL.