Expert Addresses Rationale for Evaluating NKTR-255 in Multiple Myeloma

Nikhil C. Munshi, MD

NKTR-255 is a polymer-conjugated human interleukin (IL)-15–modified compound, the purpose of which is agent is to elongate the effect of IL-15. Preclinical data suggest this agent may have a role in the treatment of patients with multiple myeloma.

The effect of NKTR-255 is mainly upon natural killer (NK) cells, which play an important role in the immune system for an antitumor effect. IL-15 encourages tumor site killing. Patients with multiple myeloma tend to be deficient in NK cells, but these cells are needed to reject tumor cells and infected cells. Because NKTR-255 is known to increase NK cell immediate killing, this agent may be effective as treatment in patients with multiple myeloma.

Overall, NKTR-255 appears superior to IL-15, so investigators are now evaluating the role of this agent in patients with multiple myeloma, says Nikhil C. Munshi, MD, who spoke to the evolution of this agent at the 2019 American Society of Hematology Annual Meeting.

The molecule will be evaluated in a clinical trial in combination with another antibody, such as either daratumumab or elotuzumab. By combining these agents in myeloma, investigators hypothesize that the treatment regimen may induce superior tumor cell killing.

In an interview with Targeted Oncology, Munshi, director of Basic and Correlative Science, Jerome Lipper Multiple Myeloma Center, Kraft Family Chair, senior physician, Dana-Farber Cancer Institute, and professor of medicine, Harvard Medical School, discussed the rationale for evaluating NKTR-255 as treatment of patients with multiple myeloma.

TARGETED ONCOLOGY: What was the rationale for evaluating this agent in patients with multiple myeloma?

Munshi: NKTR-255 is a IL-15–modified compound. The way it is modified increases the IL-15 life that does not occur as frequently, etc. Its purpose is to have a longer effect of IL-15. Its effect is mainly on NK cells, and NK cells are very important immune cells for antitumor effect in antitumor therapy. The purpose of this molecule is to excite the NK cells to have the tumor cell killing.

We looked at this molecule in our lab in a preclinical model to evaluate in myeloma patients what the impact of this molecule is on NK cells and if they can have an antitumor effect. We found encouraging [results]. This molecule leads to the activation of NK cells. It does not expand in NK cells, but it activates NK cells, so the activation markers have gone up and they function better. An inhibitory marker of NK cells goes down, so the inhibitory effects are less. These effects combined together can lead to better and higher-end NK cell-mediated killing of myeloma cells compared to when they cells are not used with NK cells. We compared it with IL-15, and this molecule performs equally well or even better sometimes and has similar effect. With the very improve pharmacokinetics of the agent and also the effect that is antitumor. It is a very exciting molecule to be utilized in patients.

TARGETED ONCOLOGY: How is the trial being designed for NTRK-255?

Munshi: The main goal of NKTR-255 would be to give it to patients in a dosage that will be very easy, such as once every 3 weeks or so, then get the NK cell expansion and get the antitumor effect without significant toxicities. Looking at the preclinical animal data, it looks like those 3 things might be achievable.

TARGETED ONCOLOGY: In your expert opinion, what would be the next steps?

Munshi: The next step would be to first utilize this agent in a phase I/II study. We would look at the tolerability, which is predicted to be good, and see what the toxicities are, as well as any indication for efficacy. That is the first component.

The second component will be to see what we can combine it with. NK cells play a very important role in myeloma. There are many agents that can affect NK cell function, so can we combine NCTR-255 with antibodies, such as daratumumab or elotuzumab. Data that showed when we combine NCTR-255 with daratumumab or elotuzumab, we get much superior tumor cell killing. The next step would be to do a combination study combining NCTR-255 with daratumumab or elotuzumab to see if we can get better cell killing. The combination is going to be very exciting as a study in the future.

TARGETED ONCOLOGY: What makes NKTR-255 unique compared with other molecules?

Munshi: [NTRK-255 is unique because of] the ease of administration, the infrequency of administration, and how it functions through the immune cell, so the tolerability would be better. Immune-mediated mechanism always provides better tumor cell killing and sometimes more sustained tumor cell killing. That is what we are hoping will happen when 1 or more of these can be combined to make it more attractive.