2545 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 activated NK cells genetically modified to produce soluble IL-15 (sIL15 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 (T 50 ). 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 sIL15 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 sIL15 NK cells ( P <0.05). Further, IPI201 sensitized tumor cells to NK-mediated killing following tumor cell pre-treatment (+130% in both NK cell types; P <0.05). 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.
Lanier et al. (Wed,) studied this question.