1516 Advancing immunotherapy through patient-identified regulators of T cell stemness

• DOI: 10.1136/jitc-2023-sitc2023.1516
• Publication Date: 2023-10-31T14:57:11Z
• Authors: Caitlin Zebley; Tae Gun Kang; Tian Mi; Shanta Alli; Grace Ward; Anoop Babu Vasandan; Shala Carson; Xin Lan; Peter Jones; Stephen Baylin; Kristen Groenbæk; Casey O’Connell; Benjamin Youngblood
• Keywords: Adoptive Cell Transfer; Cell therapy

<h3>Background</h3> The success of CAR T-cell immunotherapy depends on the differentiation status and metabolic fitness product. In current CART manufacturing protocols, activation leads to irreversible differentiation. Our recent work showed that nonactivated T-cells can be generated within 24 hours, eliminating need for or <i>ex vivo</i> expansion. We assert this process retains maximal Interleukin 18 (IL-18) is a proinflammatory cytokine regulates adoptively transferred T-cells, IL-18 supports survival persistence, an important determinant efficacy following adoptive transfer.^{1 2} enhances cytotoxic activity as well their ability produce IFNγ, which further amplify immune response. <h3>Methods</h3> first-in-human clinical trial, we show CD19-specific expanded 3 days only, co-expressing human (CART19-IL18), result in 100% overall response rates patients had relapsed after refractory prior therapy.³ Building these promising results, examined if potency xenograft models hematologic solid tumor malignancies. <h3>Results</h3> anti-tumor function durability non-activated compared with expressing control transgene (CART-GFP). To understand mechanisms underlying functional benefit IL-18, metabolite content CART19-GFP those (CART19-IL18). Using untargeted metabolomic screen, IL18-expressing 2-hydroxyglutarate (2HG) 8-fold higher than T-cells. LC-MS, also serum metabolome before receiving, 7 T infusion. found glycolytic intermediates glyceraldehyde 3-phosphate (G3P) dihydroxyacetone phosphate (DHAP) were significantly enriched receiving IL-18-expressing Remarkably, end product glycolysis-lactic acid, was similar pre post (day 7) These findings imply efficient path glucose metabolism (potentially mitochondrial) limits production systemic accumulation lactic acid. <h3>Conclusions</h3> Understanding how will improve therapeutic potential CARTs further. Developing approaches boost long-term persistence raise its impact Importantly, our studies have accessibility therapy cancer patients. <h3>References</h3> Chmielewski M, Abken H. cells releasing convert T-Bet(high) FoxO1(low) effectors exhibit augmented against advanced tumors. <i>Cell Rep.</i> 2017;<b>21</b>:3205–3219. Hu B, <i>et al</i>. Augmentation antitumor immunity by mouse secreting IL-18. 2017;<b>20</b>:3025–3033. Svoboda J, Interleukin-18 autologous anti-CD19 (huCART19-IL18) non-hodgkin lymphomas therapy. <i>Blood.</i> 2022;<b>140</b>:4612–4614.