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An IL-15 superagonist enables anti-tumor efficacy of NK cells against all molecular variants of small cell lung cancer (SCLC)

Open AccessPublished:November 18, 2022DOI:https://doi.org/10.1016/j.jtho.2022.11.008
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      Abstract

      Background

      Small cell lung cancer (SCLC) is a highly aggressive tumor with a 5-year survival rate of less than 6%. A heterogenous disease, SCLC is classified into four subtypes that include tumors with neuroendocrine (NE) and non-NE features. Immune checkpoint blockade (ICB) therapy has been recently added for the front-line treatment of SCLC; ICB, however, has only led to modest clinical improvements. The lack of clinical benefit in a cancer type known to have a high tumor-mutational burden has been attributed to poor T-cell infiltration and low expression of MHC-class I in most SCLC tumors. In an attempt to devise a more effective immunotherapeutic regimen, this study investigated an alternate approach based on the use of the clinical stage IL-15 superagonist, N-803.

      Methods

      Preclinical models of SCLC spanning all molecular subtypes were used to evaluate the susceptibility of SCLC to NK-mediated lysis in vitro, including NK cells activated via N-803. Anti-tumor activity of N-803 was evaluated in vivo with a xenograft model of SCLC.

      Results

      In vitro and in vivo data revealed differences in susceptibility of SCLC subtypes to lysis by NK cells and demonstrated that NK cells activated via N-803 effectively lyse SCLC tumor cells across all variant subtypes, regardless of their expression of MHC-class I.

      Conclusions

      These findings highlight the potential of a novel immune-based intervention utilizing a cytokine-based therapeutic option for the treatment of SCLC. We hypothesize that N-803 may provide benefit to the majority of SCLC patients, including those with immunologically cold tumors lacking MHC expression.

      Keywords