335 IL-18R equipped CAR T cells against oncofetal Tenascin C for pediatric solid and brain tumor immunotherapy

• DOI: 10.1136/jitc-2024-sitc2024.0335
• Publication Date: 2024-11-05T14:58:58Z
• Authors: Elizabeth Wickman; Shannon Lange; Jessica Wagner; Jorge Ibanez; Liqing Tian; Meifen Lu; Heather Sheppard; Jason Chiang; Selene Koo; Matthew Bell; Timothy I Shaw; Giedre Krenciute; Jinghui Zhang; Stephen Gottschalk
• Keywords: Tenascin C

<h3>Background</h3> A critical limitation for solid tumor CAR T cell therapy is the lack of safe, targetable antigens. Splice variants extracellular matrix proteins provide a unique class protein candidates chimeric antigen therapy. One such target, oncofetal Tenascin C, was previously identified having high expression in tissues as osteosarcoma (OS) and glioma.¹ Here, we evaluate cells redirected to alternatively spliced C domain (C.TNC). <h3>Methods</h3> Using RTqPCR IHC assays, determined C.TNC pediatric brain tumors. We designed second-generation 28ζ target C.TNC, retroviral transduction healthy donor PBMCs yielded C.TNC-CAR cells. were evaluated their effector function against lines. <i>In vivo</i>, antitumor activity NSG mice bearing either LM7 or DIPG007 <h3>Results</h3> highly expressed sarcoma glioma lines, evaluation primary tumors revealed strong stromal deposition C.TNC. The efficiently on had antigen-dependent IFNγ production cytolysis. exhibited limited expansion transient which conferred minimal survival advantage. To improve cells, cell-intrinsic, constitutively active IL-18 receptor (Zip18R). Evaluation C.TNC-CAR.Zip18R compared repeat stimulation assay enhanced when cocultured that produced more Type I II cytokines well chemokines 48 hours post Determination cytokine chemokine profile after four stimulations illustrated Zip18R could sustain secretome over time. cell-treated significant advantage Out ten mice, 3 rechallenged with fresh able prevent growth, suggesting persistence <h3>Conclusions</h3> have can be targeted Although efficacy transient, transgenic bolsters confer Thus, warrant further exploration immunotherapy expressing <h3>Reference</h3> Shaw TI,<i> et al</i>. Discovery targets by exon-level expression. <i>Nat. Commun</i>. 2024;<b>15</b>:3732.