By Jonathan Zalevsky, PhD, Chief Research & Development Officer, Nektar Therapeutics
For decades, researchers have worked to harness the potential of the body’s immune system to fight cancer. One novel approach being explored is the use of IL-15 agonists, given IL-15 is a cytokine that has been shown to trigger the induction of natural killer (NK) and CD8+ T cells in experimental models. However, past attempts to administer recombinant human (rhIL-15) itself have been hindered by rhIL-15’s short half-life in the body, which limits the ability to administer it effectively. With this in mind, our research team began exploring ways to harness the full spectrum of IL-15 biology across a variety of tumor types.
We have taken a fresh look at native IL-15 and engineered a new IL-15 agonist that incorporates advanced polymer chemistry. The new molecule has an altered pharmacokinetic and pharmacodynamic profile that allows rhIL-15 to be administered with antibody-like dosing schedules. Our investigational candidate, NKTR-255, also preserves physiological binding to all three endogenous IL-15 receptor sub-units to capture the full spectrum of IL-15 biology, a molecular design which was outlined by my colleague Willem Overwijk, PhD, vice president of oncology research at Nektar, in a STAT column last year. Our initial data in preclinical models, published earlier this year by Takahiro Miyazaki, senior vice president and head of research at Nektar, and now in the clinic, have shown sustained IL-15 receptor engagement and prolonged proliferation of NK cells in vivo following treatment with NKTR-255. In addition to NK cell proliferation, we have observed survival and expansion of CD8+ effector and memory T cells, which are also critical components of an anti-cancer immune response, further contributing to NKTR-255’s promise in this space.
Because rhIL-15 based-immunotherapies engage NK cells and other immune cells that are specialized in recognizing abnormal cells and killing them, this pathway can have broad application in a variety of cancers. Through IL-15 pathway activation, NK cells can be effective against liquid, or hematological tumors, possibly because they are in close contact with these cancer cells in the bloodstream and lymphoid organs, a rationale detailed in a recent interview with Dr. Overwijk. NK cells are also effective at recognizing tumor cells coded in tumor-binding antibodies, making the combination of NKTR-255 with mechanisms that use antibody-dependent cellular cytotoxicity (ADCC) an attractive development pathway.
Currently, Nektar is focused on studying NKTR-255 in combination with leading approved antibodies that use the mechanism of ADCC to kill cancer cells through the action of functional NK cells. Research has shown that long-term expansion of NK cells through activation of the IL-15 pathway can greatly enhance the activity of these ADCC agents.
Over this past year, we have continued to build upon this momentum with our first NKTR-255 clinical trial in patients with relapsed/refractory hematologic malignancies, a disease area with a high unmet need. According to the Leukemia & Lymphoma Society, over 100,000 people are projected to be diagnosed with either multiple myeloma (MM) or non-Hodgkin’s lymphoma (NHL) in 2021. We plan to complete the dose escalation monotherapy portion of our Phase 1/2 study later this year and expand into several arms that will evaluate NKTR-255 as a monotherapy or in combination with rituximab in NHL, and as a monotherapy or in combination with daratumumab in MM.
We have also initiated a new trial in patients with head and neck squamous cell carcinoma (HNSCC) or colorectal cancer (CRC), with multiple milestones for both this study and the trial in hematologic malignancies expected in the next year. This Phase 1/2 clinical study is evaluating NKTR-255 in combination with cetuximab in two distinct groups of highly refractory late-line patients with metastatic CRC or HNSCC, which have approximately 150,000 and 68,000 annual U.S. diagnoses, respectively, according to the National Cancer Institute. Cetuximab monotherapy has a response rate of about 10-15% in these disease settings, which provides an opportunity to enhance the activities of an ADCC antibody, such as cetuximab, and to improve upon the response rates in late-line HNSCC. We expect to have initial data from the dose-finding portion of this study later in 2021 and then expand into dedicated cohorts for CRC and HNSCC patients.
We were also pleased with the recent announcement that we have entered into a new clinical collaboration with Merck KGaA Darmstadt, Germany and Pfizer Inc. to combine NKTR-255 with BAVENCIO® (avelumab), a PD-L1 inhibitor, in the recently-designed JAVELIN Bladder Medley study to evaluate the combination’s potential as a maintenance therapy in patients with locally advanced or metastatic urothelial carcinoma. Bladder cancer has nearly 573,000 new diagnoses worldwide per year, according to the GLOBOCAN 2020 estimates. Avelumab has been shown in preclinical studies to not only block immunosuppressive PD-1/PD-L1 interactions, but also induce direct lysis of tumor cells via ADCC. This indicates a potential additional mechanism of action for this checkpoint inhibitor and provides a unique opportunity for possible synergy when combined with an NK cell stimulator, such as NKTR-255. The study will compare the combination of NKTR-255 with avelumab to avelumab treatment alone. We look forward to investigating the potential synergies between these drugs in our clinical research.
As we look to what is ahead for the development of NKTR-255, we are excited to continue developing and expanding the clinical development program across different patient populations in both liquid and solid tumors. To learn more about how we are bringing hope to millions of patients with cancer and autoimmune diseases by using new chemistry approaches to make better medicines, visit nektar.com.