Long-term in vivo microscopy of CAR T cell dynamics during eradication of CNS lymphoma in mice
Menée à l'aide d'un modèle murin de lymphome primitif du système nerveux central et à l'aide de la microscopie par excitation à deux photons, cette étude met en évidence l'intérêt thérapeutique de l'injection intracérébrale de lymphocytes CAR-T anti-CD19
Primary central nervous system lymphoma (PCNSL) is a highly malignant brain tumor with limited treatment options. Here, we show that genetically engineered T cells, expressing a chimeric antigen receptor, thoroughly infiltrate these tumors in mice. Combining intravital 2-photon microscopy with chronic cranial windows, we were able to visualize their intratumoral proliferation and intracerebral persistence for up to 159 d, leading to the eradication of large, established PCNSL and to long-term survival.T cells expressing anti-CD19 chimeric antigen receptors (CARs) demonstrate impressive efficacy in the treatment of systemic B cell malignancies, including B cell lymphoma. However, their effect on primary central nervous system lymphoma (PCNSL) is unknown. Additionally, the detailed cellular dynamics of CAR T cells during their antitumor reaction remain unclear, including their intratumoral infiltration depth, mobility, and persistence. Studying these processes in detail requires repeated intravital imaging of precisely defined tumor regions during weeks of tumor growth and regression. Here, we have combined a model of PCNSL with in vivo intracerebral 2-photon microscopy. Thereby, we were able to visualize intracranial PCNSL growth and therapeutic effects of CAR T cells longitudinally in the same animal over several weeks. Intravenous (i.v.) injection resulted in poor tumor infiltration of anti-CD19 CAR T cells and could not sufficiently control tumor growth. After intracerebral injection, however, anti-CD19 CAR T cells invaded deeply into the solid tumor, reduced tumor growth, and induced regression of PCNSL, which was associated with long-term survival. Intracerebral anti-CD19 CAR T cells entered the circulation and infiltrated distant, nondraining lymph nodes more efficiently than mock CAR T cells. After complete regression of tumors, anti-CD19 CAR T cells remained detectable intracranially and intravascularly for up to 159 d. Collectively, these results demonstrate the great potential of anti-CD19 CAR T cells for the treatment of PCNSL.