Work

263 Effects of resorcinyl isoprenyl benzene derivative IPI201 on natural killer cell cytotoxicity and tumor cell viability in human colorectal adenocarcinoma cells

Year: 2026

Type: conference-abstract

Abstract: Background Natural killer (NK) cells play a critical role in anti-tumor immunity, yet their cytotoxic efficacy can be limited by tumor resistance. Resorcinyl isoprenyl benzene derivatives have previously shown anti-tumor activity, but effects on NK cell-mediated cytotoxicity remain unclear. IPI201 is a synthetic resorcinyl isoprenyl benzene derivative. We evaluated whether IP201 augments NK cell cytotoxicity and explored potential mechanisms.Methods Cytotoxicity assays were performed using HT-29 colorectal carcinoma cells co-cultured with either standard NK cells or engineered NK cells (CAR-NK) under conditions of IPI201 pre-treatment or co-treatment. Cancer cell lysis was quantified over time to assess total cytolysis (AUC), maximum rate of killing (V max), and time to 50% maximal cytolysis (T50). NK activation markers were assessed by flow cytometry. NK cell survival following IPI201 exposure was assessed over 7 days using cell density quantification.Results IPI201 enhanced NK cell-mediated cytotoxicity against colorectal cancer cells. Pre-treatment increased overall cytolysis and killing rates by 625% in standard NK cells and 50% in CAR-NK cells ( P < 0.05). Co-treatment similarly increased tumor cell lysis (P < 0.05). IPI201 alone induced rapid tumor cell death, outperforming standard NK cells alone in overall cytolysis, killing rate, and time to peak effect (P < 0.05). Enhanced cytotoxicity was not associated with changes in NK activation markers. Instead, IPI201 increased NK cell survival across doses, with the highest dose increasing Day 7 density by 117% in standard NK cells and 214% in CAR-NK cells (P < 0.05) (figure 1). Further, IPI201 sensitized tumor cells to NK-mediated killing following tumor cell pre-treatment (+130% in both NK cell types; P < 0.05) (figure 2).Conclusions IPI201 induces tumor cell death independent of NK cells and enhances NK cell-associated cytotoxicity during pre- or co-treatment. These effects may arise from increased NK cell survival and/or heightened tumor cell susceptibility to immune-mediated killing. To our knowledge, IPI201 is now the third known molecule, alongside IL-2 and IL-15, that is independently sufficient to support NK cell survival. These findings support further investigation of IPI201 as a multifunctional immunomodulatory and cytotoxic agent in combination cell-based cancer therapies.Abstract 263 Figure 1Pre-treatment results: (A) IPI201 pre-treatment improves standard- and CAR-NK-mediated cancer cell death. (B) Pre-treatment improves NK cell survivalAbstract 263 Figure 2Co-treatment results

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.0263