In this interview, we sit down with Mario Marcondes from Nektar Therapeutics to explore the advancements and potential of NKTR-255 in treating solid tumors and hematological cancers. Mario shares insights into clinical trials, challenges, and future milestones, highlighting NKTR-255’s role in the evolving landscape of cancer therapies.

Moe: How is NKTR-255 advancing treatment for solid tumors and hematological cancers?

NKTR-255, an IL-15 receptor agonist, is making significant strides toward treating solid tumors and hematological cancers by focusing on expanding NK and CD8 cells, which are crucial for anti-tumor response. For instance, the RESCUE trial is pivotal, leveraging the ability to rescue these cells post-chemo radiation in non-small cell lung cancer or NSCLC patients. This is a Nektar-sponsored study to research NKTR-255’s ability to reverse radiation-induced lymphopenia in patients with NSCLC. When combined with the checkpoint inhibitor durvalumab, NKTR-255 showed significant improvement in lymphocyte recovery, a key prognostic factor for survival in

Mario Marcondes, VP Head Of Clinical Development Nektar Therapeutics

such cancers. This combination was well-tolerated by patients, suggesting its potential to enhance immunotherapy outcomes​ for multiple indications, including Glioblastoma and other solid tumor indications where chemo-radiation is employed.

Additionally, we are exploring combinations with other therapies, such as avelumab in bladder cancer, to enhance systemic responses—our focus on safety and efficacy positions NKTR-255 as a promising candidate in oncology. NKTR-255 aims to improve treatment outcomes and offer new hope for patients with limited options by addressing key challenges in immune cell recovery. This strategic approach underscores our commitment to advancing cancer treatment through innovative solutions.

Moe: What insights have been gained from NKTR-255’s phase two trial, especially with CAR-T therapies?

The phase two trial of NKTR-255 has provided valuable insights into its safety and efficacy, particularly in synergy with CAR-T therapies. Compared to high-dose IL-2, IL-15 offers cellular expansion with a manageable safety profile. Our trials have shown enhanced NK and CD8 T cell expansion, which are crucial for CAR-T cell therapies. This aligns with unmet needs for durable responses in cancer treatment by potentially overcoming limitations in persistence and durability of response, especially in Large B cell Non Hodgkins Lymphoma.

Collaborations with Dr. Crystal Mackall at Stanford and Dr. Cameron Turtle from Seattle have shown that NKTR-255 can overcome CAR-T cell persistence limitations, a significant challenge in treating lymphoma. This synergy with CAR-T therapies addresses a critical gap in hematological malignancies, offering hope for improved long-term outcomes.

Moe: How does NKTR-255 address limitations in immunotherapy, like cell persistence and response durability?

NKTR-255 addresses key limitations in immunotherapy by enhancing cell persistence and response durability. Administering it at day 14 to 21 can re-expand CAR-T cells, improving their tenacity. This addresses the limitation of CAR-T cell therapies, which often struggle with persistence. Our data indicates a significant improvement in response durability, which is crucial for patients with limited treatment options post-CAR-T cell therapy.

Data from the Fred Hutchinson collaboration suggests that NKTR-255 can create a second peak of CAR-T cell elevation, improving the area under the curve and, thus the long-term efficacy of the treatment. This capability is critical in solid tumors, where maintaining a robust immune response is challenging. By enhancing immune cell recovery, NKTR-255 aims to improve treatment outcomes and offer new hope for patients with limited options, potentially transforming the cancer treatment landscape.

Moe: What challenges or unexpected findings emerged during the phase two trial, and how did you adapt?

Executing complex trials like NKTR-255’s phase two study presented challenges, requiring substantial resources and patient screening due to strict inclusion criteria. We also faced issues with proprietary assays for CAR-T cell PK. We enhanced collaboration and expertise in this field by leveraging relationships with academic centers. Our proprietary polymer conjugation technology allowed us to administer NKTR-255 less frequently, overcoming the short half-life of endogenous IL-15. The early NCI’s IL-15 molecule researched and published by Dr. Kevin C. Conlon had some issues with very short half-life, requiring frequent administration, which is not commercially feasible. Our approach allows for administration every 21 to 28 days, making it more practical for clinical use.

Moe: What role do you envision for NKTR-255 in combination cancer therapies?

NKTR-255 can potentially enhance endogenous reconstitution of NK and CD8 cells, not only in CAR-T cell therapies but also in combination with checkpoint inhibitors and other modalities. Its non-immunogenic nature and lack of tachyphylaxis make it suitable for long-term use, potentially up to two years, without the safety concerns seen with other agents. We are actively seeking partnerships to expand its application in the immuno-oncology space. Our collaboration with EMD Serono in the JAVELIN Medley trial is exploring its use in combination with avelumab, aiming to deliver robust systemic responses in bladder cancer. This integration with existing therapies could significantly enhance treatment efficacy and patient outcomes.

Moe: What are the key milestones for NKTR-255’s development, and how will they shape its trajectory?

Key milestones for NKTR-255 include upcoming data presentations at conferences, such as new efficacy and PD analysis for the Breyanzi NKTR-255 combination, which we are aiming to present at a Scientific Meeting in the middle of this year, and results from our collaboration with EMD Serono in the JAVELIN Medley trial. We also anticipate presenting preliminary data in non-small cell lung cancer in a Scientific Symposium later this year. These milestones will be crucial for attracting strategic partners and advancing NKTR-255 toward registration trials, ultimately shaping its clinical and commercial trajectory.

The data from Dr. Cameron Turtle and Dr. Alex Herrera on large B-cell lymphoma will provide critical insights into its efficacy and safety, potentially influencing its adoption in clinical practice. Our ongoing efforts to seek strategic partnerships and licensing deals will further enhance its commercial potential.

Moe: Is there anything else you’d like to add that I might have missed?

NKTR-255 is poised to deliver significant cellular boosts crucial for immuno-oncology and cellular therapies. Its safety profile and lack of T regulatory cell expansion make it an ideal candidate for combination therapies. We are excited to continue advancing this work in partnership with others in the field. The ability to provide a safe and effective cytokine boost without the complications associated with other treatments positions NKTR-255 as a promising asset in the fight against cancer.

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Moe Alsumidaie is Chief Editor of The Clinical Trial Vanguard. Moe holds decades of experience in the clinical trials industry. Moe also serves as Head of Research at CliniBiz and Chief Data Scientist at Annex Clinical Corporation.