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By Willem W. Overwijk, Ph.D., Vice President Oncology Research, Nektar Therapeutics

Over the last 20 years, a new era of innovation has led to vast improvements in clinical outcomes for people with cancer. We’ve made major strides in harnessing the immune system’s natural mechanisms to stage a multi-pronged defense against the disease. Two major advancements have been checkpoint inhibitors, which release a natural brake on the immune system to allow immune cells to recognize and attack tumors, and chimeric antigen receptor (CAR) T cell therapy, in which the patients’ own T cells are engineered to specifically recognize and destroy cancer cells. Checkpoint inhibitors and CAR T cell therapies have proven to be lifesaving for patients with previously untreatable cancers. Unfortunately, there are limits to their widespread clinical utility. CAR T cell therapies, for example, require an expensive, individualized manufacturing process for each patient and a perfect match with protein targets on the cancer cells. Immune checkpoint inhibitor therapy induces tumor reduction in a variety of cancers, but most patients eventually still succumb to their disease. We are therefore discovering new ways to activate the immune system’s natural ability to fight cancer and exploring combination therapies with synergistic mechanisms to improve treatment outcomes.

Unlocking the Power of NK Cells to Combat Cancer

One promising new approach to oncology immunotherapy is activating natural killer (NK) cells to attack cancer. NK cells can directly recognize and kill abnormal cells, as well as modulate the body’s adaptive immune response against foreign invaders and cancer. IL-15 is a naturally occurring cytokine that stimulates and promotes the production, survival and activity of NK cells. However, its therapeutic application has been limited: since native IL-15 is rapidly cleared from the body, it has to be administered frequently in high doses, which can cause toxic side effects. Repeated dosing also leads to desensitization and a loss of response over time.

At Nektar Therapeutics, we have taken a unique approach to address the limitations of native IL-15 with the development of NKTR-255. NKTR-255 is a novel investigational therapy designed to bind to the IL-15 receptor complex and increase the proliferation, activity and survival of NK cells without leading to immunogenicity. NKTR-255 also has the potential to improve the survival of other immune cells, such as CD8+ T cells, creating long-term immunological memory, which could lead to a sustained anti-tumor response. NKTR-255 is an engineered version of native IL-15 employing advanced polymer chemistry to alter its pharmacokinetic profile while preserving the natural binding to endogenous IL-15R alpha, beta and gamma subunits. This lets NKTR-255 remain active in the bloodstream longer, improving tolerability and allowing for administration once every 2 to 4 weeks.

By targeting IL-15 and increasing the number and activity of cancer-killing NK cells, we believe NKTR-255 may be able to enhance the patient’s own tumor-fighting response. This could lead to improved response rates and prolonged survival. NKTR-255 is currently being evaluated in a Phase 1 study in adults with relapsed/refractory non-Hodgkin lymphoma or relapsed/refractory multiple myeloma (NCT04136756) and in a Phase 1b/2 study in combination with cetuximab as a salvage regimen for solid tumors.

Nektar is applying its deep understanding of immunology to fuel the discovery of novel therapies that selectively modulate the immune system to advance the treatment of cancer, autoimmune disorders, and chronic inflammatory conditions. To learn more, visit