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We have shown that antigen escape tumor cell variants prevail in glioblastoma (GBM)
recurring after treatment with chimeric antigen receptor (CAR) T cells with a single
specificity. Recurrent tumors preserve alternative non-targeted tumor associated antigens.
We thus hypothesize that a bispecific CAR will mitigate antigen escape, enhancing
the antitumor activity of T cells. Two validated glioma-associated antigens, HER2
and IL13Rα2 are currently targeted in phase I GBM trials using CAR T cells. We used
computational modeling to design and create a bispecific CAR molecule with a HER2-specific
scFv joined in tandem to an IL13Rα2-binding moiety in the CAR exodomain (Tandem CAR)
and a CD28.ζ signaling endodomain. GBM patients' Tandem CAR T cells showed distinct
binding to soluble HER2 and IL13Rα2 and killed primary autologous GBM cells. Tandem
CAR T cells exhibit significantly enhanced activation dynamics when compared to conventional
HER2 or IL13Rα2 CAR T cells and better controlled established GBM xenografts in an
orthotopic murine model by offsetting both HER2 and IL13Rα2 escape. To investigate
if the Tandem CAR T cells were ‘bispecific’ in nature, we determined the localization
of the tumor antigens at the CAR T-cell/GBM contact point, also referred to as the
immunological synapse (IS). Three-dimensional reconstitution and quantification of
confocal images of the Tandem CAR T-cell/tumor interface revealed enhanced bi-functional
IS compared to conventional CARs. Further interrogation of the tumor antigen co-clustering
at the IS using Stimulated Emission Depletion (STED) microscopy revealed the size
resolution for the dual clusters to be at a 100–200 nm range, suggesting their co-docking
with the Tandem CAR receptor at the IS. (Figure 1, Figure 2)
