CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma
Monica Casucci, Benedetta Nicolis di Robilant, Laura Falcone, Barbara Camisa, Margherita Norelli, Pietro Genovese, Bernhard Gentner, Fabiana Gullotta, Maurilio Ponzoni, Massimo Bernardi, Magda Marcatti, Aurore Saudemont, Claudio Bordignon, Barbara Savoldo, Fabio Ciceri, Luigi Naldini, Gianpietro Dotti, Chiara Bonini, Attilio Bondanza, Monica Casucci, Benedetta Nicolis di Robilant, Laura Falcone, Barbara Camisa, Margherita Norelli, Pietro Genovese, Bernhard Gentner, Fabiana Gullotta, Maurilio Ponzoni, Massimo Bernardi, Magda Marcatti, Aurore Saudemont, Claudio Bordignon, Barbara Savoldo, Fabio Ciceri, Luigi Naldini, Gianpietro Dotti, Chiara Bonini, Attilio Bondanza
Abstract
Genetically targeted T cells promise to solve the feasibility and efficacy hurdles of adoptive T-cell therapy for cancer. Selecting a target expressed in multiple-tumor types and that is required for tumor growth would widen disease indications and prevent immune escape caused by the emergence of antigen-loss variants. The adhesive receptor CD44 is broadly expressed in hematologic and epithelial tumors, where it contributes to the cancer stem/initiating phenotype. In this study, silencing of its isoform variant 6 (CD44v6) prevented engraftment of human acute myeloid leukemia (AML) and multiple myeloma (MM) cells in immunocompromised mice. Accordingly, T cells targeted to CD44v6 by means of a chimeric antigen receptor containing a CD28 signaling domain mediated potent antitumor effects against primary AML and MM while sparing normal hematopoietic stem cells and CD44v6-expressing keratinocytes. Importantly, in vitro activation with CD3/CD28 beads and interleukin (IL)-7/IL-15 was required for antitumor efficacy in vivo. Finally, coexpressing a suicide gene enabled fast and efficient pharmacologic ablation of CD44v6-targeted T cells and complete rescue from hyperacute xenogeneic graft-versus-host disease modeling early and generalized toxicity. These results warrant the clinical investigation of suicidal CD44v6-targeted T cells in AML and MM.
Source: PubMed