Overcoming CAR-Mediated CD19 Downmodulation and Leukemia Relapse with T Lymphocytes Secreting Anti-CD19 T-cell Engagers

Medientyp: E-Artikel

Titel: Overcoming CAR-Mediated CD19 Downmodulation and Leukemia Relapse with T Lymphocytes Secreting Anti-CD19 T-cell Engagers

Beteiligte: Blanco, Belén; Ramírez-Fernández, Ángel; Bueno, Clara; Argemí-Muntadas, Lidia; Fuentes, Patricia; Aguilar-Sopeña, Óscar; Gutierrez-Agüera, Francisco; Zanetti, Samanta Romina; Tapia-Galisteo, Antonio; Díez-Alonso, Laura; Segura-Tudela, Alejandro; Castellà, Maria; Marzal, Berta; Betriu, Sergi; Harwood, Seandean L.; Compte, Marta; Lykkemark, Simon; Erce-Llamazares, Ainhoa; Rubio-Pérez, Laura; Jiménez-Reinoso, Anaïs; Domínguez-Alonso, Carmen; Neves, Maria; Morales, Pablo; Paz-Artal, Estela; [...]

Erschienen: American Association for Cancer Research (AACR), 2022

Sprache: Englisch

DOI: 10.1158/2326-6066.cir-21-0853

ISSN: 2326-6066; 2326-6074

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Beschreibung: Abstract Chimeric antigen receptor (CAR)–modified T cells have revolutionized the treatment of CD19-positive hematologic malignancies. Although anti-CD19 CAR-engineered autologous T cells can induce remission in patients with B-cell acute lymphoblastic leukemia, a large subset relapse, most of them with CD19-positive disease. Therefore, new therapeutic strategies are clearly needed. Here, we report a comprehensive study comparing engineered T cells either expressing a second-generation anti-CD19 CAR (CAR-T19) or secreting a CD19/CD3-targeting bispecific T-cell engager antibody (STAb-T19). We found that STAb-T19 cells are more effective than CAR-T19 cells at inducing cytotoxicity, avoiding leukemia escape in vitro, and preventing relapse in vivo. We observed that leukemia escape in vitro is associated with rapid and drastic CAR-induced internalization of CD19 that is coupled with lysosome-mediated degradation, leading to the emergence of transiently CD19-negative leukemic cells that evade the immune response of engineered CAR-T19 cells. In contrast, engineered STAb-T19 cells induce the formation of canonical immunologic synapses and prevent the CD19 downmodulation observed in anti-CD19 CAR-mediated interactions. Although both strategies show similar efficacy in short-term mouse models, there is a significant difference in a long-term patient-derived xenograft mouse model, where STAb-T19 cells efficiently eradicated leukemia cells, but leukemia relapsed after CAR-T19 therapy. Our findings suggest that the absence of CD19 downmodulation in the STAb-T19 strategy, coupled with the continued antibody secretion, allows an efficient recruitment of the endogenous T-cell pool, resulting in fast and effective elimination of cancer cells that may prevent CD19-positive relapses frequently associated with CAR-T19 therapies.

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