Al's Comment:
This is just a proposal but seems like a very good idea. To limit the toxcicity of CAR-T cells, they propose to create a new type of CAR-T cell that has to bind to 2 targets before it can kill the cell. That has been tried before, but the new idea is the logic part: there has to be EGFRvIII AND (Il-13Ra2 OR CD133). This may be a big improvement, however, as I understand it, only about 1/3 of GBMs have EGFRvIII and it is possible that in the natural course of the disease, even those that are EGFvIII positive can turn EGFRvIII negative. CD133 is a marker found on all of the GBM stem cells, which are the most important cells to target, but most non stem cells in the tumor won't have it. IL13Ra2 is overexpressed in a little over 1/2 of the GBMs but not distributed uniformly through the tumor. So the OR part should target most of the tumor cells, but the AND part might not be enough. Perhaps find a way to require (EGFRvIII or ???) AND (Il-13Ra2 OR CD133) where we have to figure out what the best target for ??? is! This is a complex math problem that can be solved and variations can be tested and perhaps even personalized to the patient.
Posted on: 02/03/2020
Med Hypotheses. 2020 Jan 13;137:109559. doi: 10.1016/j.mehy.2020.109559. [Epub ahead of print]
Proposing a tandem AND-gate CAR T cell targeting glioblastoma multiforme.
Sabahi M1, Jabbari P2, Alizadeh Haghighi M3, Soltani S4, Soudi S5, Rahmani F6, Rezaei N7.
Author information:
1. Neurosurgery Research Group (NRG), Student Reaserch Committee, Hamadan University of Medical Sciences, Hamadan, Iran; Neuroimaging Network (NIN), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
2. Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
3. Neurosurgery Research Group (NRG), Student Reaserch Committee, Hamadan University of Medical Sciences, Hamadan, Iran.
4. Student Reaserch Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran.
5. Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
6. Neuroimaging Network (NIN), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.
7. Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: rezaei_nima@tums.ac.ir.
Abstract
CAR T cell therapy is suggested as an effective method to treat hematological malignancies. However, high recurrence rates and in vivo toxicities have limited their widespread use. In order to reduce toxicity and improve tumor specificity, we propose a CAR T cell targeting glioblastoma multiforme utilizing the synNotch receptor pathway linked to a tandem CAR T cell. The extracellular domain of the synNotch receptor is replaced by a single chain fragment variable specific for the EGF receptor variant III (scfv-EGFRvIII), and covalently bonded to a IL-13Rα2-CD133-tandem CAR. This would produce an AND-gate CAR-T cell, which requires activation of both signals from synNotch receptor binding to EGFRvIII and then binding of the tandem CAR to either of the two IL-13Rα2 or CD133 ligands-specific antigens for glioblastoma stem cells. SynNotch receptor activation along with the 4-1BB costimulatory domain results in CAR T cell expression under the TRE promoter, culminating in a tri-specific and effective tumor stem cell recognition and elimination of glioblastoma multiforme.
Copyright © 2020 Elsevier Ltd. All rights reserved.
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