Abstract 3112: Pralsetinib induces opportunistic infection in RET fusion-positive NSCLC patients via inhibition of IL-2 production by blocking Jak3/Stat5 activation
Abstract
Oncogenic alteration in RET, representing 1-2% of NSCLC, is an important target. Pralsetinib is a selective RET inhibitor targeting RET fusions. We present a case series on opportunistic infections and the mechanism of immunosuppression.
From October 2021 to March 2022, we administered pralsetinib to a total of 15 patients with NSCLC harboring RET fusion. We retrospectively analyzed the clinical efficacy and adverse events related to pralsetinib. To investigate pralsetinib’s impact on T-cells, we examined cytokine release using ELISA from Jurkat T (JT) cells after pralsetinib treatment. To test if Stat5 binds to the IL-2 promoter, we conducted Chromatin Immunoprecipitation (ChIP).
Out of 18 patients with measurable disease, 14 (93%) achieved a partial response. With a median follow-up duration of 8.7 months, four cases of opportunistic infections occurred. Notably, three patients (16.6%) experienced invasive pulmonary aspergillosis, and one patient (5.5%) experienced cytomegalovirus pneumonia. To investigate mechanisms behind these observations, we aimed to replicate conditions similar to those of activated T cells. Thus, JT cells were treated with PMA and ionomycin to induce IL-2 release through NFAT, AP-1, and NF-κB binding to the IL-2 promoter. After ∼2 weeks of pralsetinib treatment, Jak3 signaling was inhibited, leading to decreased IL-2 release by downregulating transcription factors associated with IL-2 production, such as JunB/c-Jun and Stat5, which are downstream…
How strong is the evidence?
Evidence Hub reads this as a case series, done in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health. Reported size: 18 participants or records.
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