Abstract:
˝Engineered T cell-based therapy is an advanced cancer immunotherapy approach with genetically modified T cells. Currently, the two most commonly used immune receptors that introduce tumor specificity and functionality to engineered T cells are the tumor-reactive Chimeric Antigen Receptor (CAR) and the T-cell Receptor (TCR). To date, CAR T cells directed against CD19 have emerged as the most successful cellular immunotherapy approach. Clinical trials in relapsed or refractory pediatric acute lymphoblastic leukemia (ALL) and high-grade B-cell lymphoma in adults have shown that CAR T-cell immunotherapy can mediate efficacious, long-lasting, and overall unprecedented clinical responses. CD19-targeted CAR T cells were approved by the U.S. Food and Drug Administration in 2017 and by the European Medicines Agency in 2018.The success of CAR T cells has been met with challenges regarding efficacy in solid tumors and in hematologic malignancies that induce dysfunctional T cell states. To overcome some of these challenges, we have developed a genetic approach that combines activation-inducible production of an accessory molecule along with constitutive CAR expression in a single lentiviral vector called Uni-Vect. By knocking out the endogenous TCR using the CRISPR/Cas9 method, we made CAR signaling an exclusive activator of the system. Here, we present two distinct therapeutic implementations of Uni-Vect. In a first therapeutic approach, we introduced inducible expression of IL -12 (ilL-12 CAR T) and demonstrated a remarkably enhanced anti-tumor response in established solid tumors in vivo.
In a second therapeutic approach, we modulated CAR T cell-intrinsic properties by transient activation-inducible transcription factor expression (iTF-CAR T) and demonstrated improved therapeutically relevant T cell states and in vivo expansion. Overall, our work provides a foundation for clinically applicable next-generation cellular immunotherapies.˝


Vljudno vabljeni! Seminar bo potekal v angleškem jeziku. / You are kindly invited! The seminar will be held in English.  


Vse, ki boste prisostvovali predavanju, prosimo, da med predavanjem izključite mikrofone in kamere. / Participants are kindly asked to turn off microphones and cameras during the talk.


Dodatne informacije/Additional information: dr. Anže Smole, anze.smole@nib.si.