NKTR-214 is an investigational immunotherapy being developed by Nektar to treat solid tumors. The therapy is being assessed in studies in collaboration with Bristol Meyers-Squibb (BMS) and Takeda Oncology.
How NKTR-214 works
NKTR-214 is a type of immunotherapy, meaning that it acts by boosting the immune response to encourage the patient’s own body to fight cancer.
The immune system is capable of identifying and destroying infected or abnormal cells, including cancer cells. One way it does this is by producing “tumor-infiltrating lymphocytes” (TILs), a type of immune cell capable of moving into a tumor and targeting the cancerous cells. Two types of TILs are T-cells and natural killer (NK) cells. NKTR-214 stimulates an increased immune response by expanding the numbers of activated T-cells and NK cells available to attack the tumor.
TILs produce a protein called interleukin-2 receptor (IL-2R), which can send a signal to increase their production. This signal is sent when a particular cell signaling molecule, called interleukin-2 (IL-2), binds to IL-2R and activates it.
NKTR-214 is a prodrug, as it is delivered to the body in an inactive form. The body breaks down the prodrug to produce a signaling molecule that is biased toward binding to and activating CD122, a subunit of IL-2R. When NKTR-214 binds to CD122, it triggers an increase in the number of TILs. It is believe that this mobilization of TILs will heighten the immune response against a tumor and result in a reduction in tumor size.
NKTR-214 in clinical trials
NKTR-214 is being investigated in four ongoing clinical trials, assessed alone and in combination with other anti-cancer drugs.
The first-in-human open-label Phase 1/2 clinical trial, called Excel, (NCT02869295) aims to investigate the safety, tolerability, and preliminary efficacy of NKTR-214 in 40 patients with advanced solid tumors at three locations across the U.S. The trial is ongoing, but no longer recruiting participants.
Preliminary trial results were presented at the 2016 Annual Meeting of the Society for Immunotherapy of Cancer and suggested that NKTR-214 has anti-tumor activity. Out of 18 evaluable patients, 12 (67 percent) achieved stable disease after eight weeks, and seven of them showed reduced tumor size. The therapy appeared safe and well-tolerated with no immune-related adverse effects. Three patients experienced severe hypotension (extremely low blood pressure), but the symptoms were quickly reversed with increased fluid intake.
NKTR-214 is predicted to act well in combination with immune system checkpoint inhibitors, and it is believed that a combination approach will make for a stronger immune response against tumors. Several trials are underway to test NKTR-214 in combination with these therapies.
The Phase 1/2 PIVOT trial (NCT02983045), being carried out in collaboration with BMS, aims to test NKTR-214 in combination with Opdivo (nivolumab) at 63 sites across North America and Europe. The trial aims to recruit 250 patients with selected advanced cancers, including advanced non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), melanoma, triple negative breast cancer, and urothelial carcinoma. It is still open for recruitment; more information is available by clicking on the trial’s identification number.
Preliminary results from this study were presented at the 2017 American Society of Clinical Oncology Annual Meeting and showed that the combined therapy appeared to have a clinical benefit. Of four patients treated for melanoma, three responded to the treatment. Six patients with RCC were also evaluated and showed either a partial response or achieved stable disease.
A Phase 1/2 trial (NCT03138889), called PROPEL, aims to investigate NKTR-214 in combination with Tecentriq (atezolizumab). The study aims to enroll 36 patients with NSCLC or advanced urothelial bladder cancer and is still enrolling at three sites across the U.S.
Memorial Sloan Kettering Cancer Center is carrying out an open-label Phase 2 clinical trial (NCT03282344), in collaboration with the MD Anderson Cancer Center, investigating NKTR-214 in combination with Opdivo in 60 patients with advanced sarcoma. The trial is still recruiting participants and is being carried out at the Memorial Sloan center in New York City.
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