Early this year at the ASCO Genitourinary Cancers 2017 meeting, Hurwitz et al. (2017) presented clinical data from a Phase I clinical trial of the oncology agent NKTR-214 in patients with renal cell carcinoma (RCC) showing encouraging evidence of anti-tumour activity, and a favourable safety and tolerability profile. NKTR-214 was developed by Nektar Therapeutics to expand specific cancer-fighting immune cells in the tumour environment and increase expression of the cell surface receptor PD-1 on these immune cells.
NKTR-214 is a CD122-biased cytokine agonist conjugated with multiple releasable chains of polyethylene glycol and designed to provide sustained signalling through the heterodimeric IL-2 receptor pathway (IL-2Rβγ) to preferentially activate and expand effector CD8+ T and natural killer (NK) cells – usually cancer-fighting immune cells – over T regulatory cells (Tregs) – immunosuppressive cells that usually limit anti-tumour response.
A dose escalation trial of NKTR-214 was initiated to assess the safety, tolerability and explore immune changes in the blood and tumour microenvironment in patients with RCC. NKTR-214 was administered IV every 2 or 3 weeks. Pre and post treatment blood and tumour samples were collected and analysed for immune phenotyping, gene expression and changes in the tumour microenvironment by immunohistochemistry.
Among 25 patients dosed, 15 had RCC. Treatment with single-agent NKTR-214 was well tolerated and the maximum tolerated dose (MTD) was not reached. There were no autoimmune-related adverse events or organ related inflammation. 6 out of the 15 RCC patients, with prior tyrosine kinase inhibitor (TKI) treatments, experienced tumour shrinkage. Analysis of the tumour microenvironment revealed several significant immunological changes post treatment, including increase in total and proliferating NK, CD8+, and CD4+ T cells. There was good correlation between increase in activated CD4+ and CD8+T cells in peripheral blood with an increase in T cell infiltrates within the tumour tissue. There was a greater abundance of CD8+ T cell compared to Treg immune suppressive cells accumulating in the tumour tissue. NKTR-214 also increased cell-surface expression of PD-1 on CD4+ and CD8+ T cells.
NKTR-214 increased immune infiltration in the tumour and anti-tumour activity in patients who previously progressed on TKIs, with a favourable safety profile. The ability to alter the immune environment and increase PD-1 expression on effectors T cells may improve the effectiveness of anti-PD-1 blockade. A trial combination of NKTR-214 and nivolumab is being evaluated. The Phase 1/2 clinical program will enrol up to 260 patients and will evaluate the potential for the combination of Opdivo (nivolumab) and NKTR-214 to show improved and sustained efficacy and tolerability above the current standard of care in melanoma, kidney, triple-negative breast cancer, bladder and non-small cell lung cancer patients.
The NKTR-214 clinical trial is currently recruiting participants, you can find more information here.