Exploring NKTR-255: Using the IL-15 Pathway for Potentiation of CAR-T Therapies

For some patients with certain types of blood cancers, the invention of chimeric antigen receptor T (CAR-T) cell therapy has been a blessing. Even during early clinical trials at the National Cancer Institute, University of Pennsylvania and Memorial Sloan-Kettering, oncologists proclaimed that tumors literally “melted away” in some patients for whom other previous therapies were ineffective. Thus, industry was not surprised in the least when CAR-T cell regimens from Novartis and Kite Pharma (acquired by Gilead) gained approval by the FDA.

CAR-T cells are T cells taken from either the patient’s own blood (i.e., autologous) or a healthy donor (i.e., allogeneic) that are genetically modified to identify a target present on the surface of cancer cells, thereby enabling CAR-T cells to seek and destroy tumor cells.

A patient with a difficult-to-treat blood cancer seeking CAR-T cell treatment will first visit an approved clinic that provides therapeutic apheresis services. Blood taken from the patient is frozen and sent to specialized CAR-T cell manufacturing facilities. Once there, laboratory technicians separate the T cells from the collected blood, then transfect those T cells with an attenuated virus that carries the genetic code to modify the cells ex vivo (i.e., outside of the body). The cells are incubated, washed, and cultured to increase their numbers, before being injected back into the patient. Currently, autologous CAR-T regimens are approved by the FDA to treat B-cell precursor acute lymphoblastic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and multiple myeloma.

Results after receiving CAR-T therapy are, at first, impressive. Some clinical trials initially reported 70-80% overall response rates, with complete response rates as high as 65%, in lymphoma patients who were refractory to chemotherapy or relapsed after stem cell transplantation [1-2]. While there remain some challenges including long manufacturing times and high costs that currently prevent the wider adoption of CAR-T cell therapies, for some patients CAR-T cell therapy undoubtedly is lifesaving.

Unfortunately, long term remission does not materialize with CAR-T cell therapy for many patients. In fact, studies have shown that as many as 53% of patients who achieved an objective response after receiving CAR-T cell therapy subsequently relapse within 6 months [3]. Therefore, there is a high unmet need to provide both an extended duration of response and drive a higher frequency of complete responses with CAR-T cell therapies.

IL-15 pathway could address the need for deeper and more durable responses in CAR-T cell therapies

At Nektar Therapeutics, we are trying to address these problems by leveraging the unique properties of a cytokine called Interleukin (IL) 15.

Our understanding of the role that IL-15 plays in antitumor immunity has grown in recent years. IL-15 is a pleiotropic cytokine that is produced by immune cells and is key in the activation and proliferation of natural killer (NK) cells and CD8+ T cells, which are important components of the antitumor immune response in attacking cancer cells [4-5].

As a potent cytokine that stimulates the proliferation and maintenance of T cells, IL-15 may also play a role in enhancing CAR-T cell survival and therapeutic efficacy. Studies have shown, for example, that high levels of IL-15 correlate with enhanced tumor volume shrinkage in patients treated with CAR-T cell therapies [6]. High peak concentrations of IL-15 also correlate with deeper and more durable responses after CAR-T cell therapy is administered in a patient [7].

At Nektar, we have developed a polyethylene glycol (PEG)-conjugated recombinant IL-15 protein, NKTR-255, that leverages advanced polymer chemistry to enhance its pharmacological properties. Native IL-15 has limitations as a therapy: it is rapidly cleared from the body, meaning any therapeutic dose would have to be high and frequent, thus limiting its utility due to potential toxicity and inconvenience of use. NKTR-255 was specifically designed for optimal activation of the IL-15 signaling pathway such that lower and less frequent doses are required while still maintaining its durable effects.

We are particularly interested in the unique properties of NKTR-255 that could make it an excellent cell therapy potentiator. As preclinical data show, NKTR-255 is adept at driving CAR-T and CD8+ T cell expansion, persistence of CAR-T cells after administration, and their infiltration into the tumor tissue. Preclinical studies have also found that combining NKTR-255 and CAR-T cell therapy is far more effective than CAR-T cell therapy alone in clearing tumors.

Based on promising preclinical data thus far, Nektar’s external collaborators at the Stanford Center for Cancer Cell Therapy and Fred Hutchinson Cancer Center have begun testing CAR-T cell therapies (including experimental candidates that are not commercially available) plus NKTR-255 in patients. At last year’s American Society of Hematology (ASH) conference, Nektar presented preliminary findings from an ongoing Phase I clinical trial showing that administering NKTR-255 in patients who had previously received CAR-T cell therapies, some over a year earlier, led to an increase in circulating CAR-T cells.

Our Path Forward: ASH 2022

At this year’s ASH conference in New Orleans, we presented the trial design of our own, Nektar-sponsored Phase 2/3 clinical trial evaluating NKTR-255 following CAR-T cell therapy in patients with relapsed or refractory diffused large B-cell lymphoma. We are looking forward to initiating the study shortly.

Cancer immunotherapy today looks nothing like it did a decade ago thanks to new emerging therapies like CAR-T cell therapies. In pursuit of better therapies, we at Nektar strive to research and develop more efficacious and safer treatments for patients in need. If you would like to inquire about our new clinical trial evaluating NKTR-255 following CAR-T cell therapy, or any of our other therapeutic candidates currently in development, please visit Nektar.com.

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[1] Kochenderfer JN, et al. J Clin Oncol (2017) 35(16):1803-1813. Lymphoma Remissions Caused by Anti-CD19 Chimeric Antigen Receptor T Cells Are Associated With High Serum Interleukin-15 Levels.

[2] Locke FL, et al. N Engl J Med (2022) 386(7):640-654. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma.

[3] Meng J, et al. Front Oncol (2021) 26;11:698607. Efficacy and Safety of CAR-T Cell Products Axicabtagene Ciloleucel, Tisagenlecleucel, and Lisocabtagene Maraleucel for the Treatment of Hematologic Malignancies: A Systematic Review and Meta-Analysis.

[4] Grabstein KH, et al. Science (1994) 13;264(5161):965-8. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor.

[5] Robinson TO and Schluns KS. Immunol Lett (2017) 190:159-168. The potential and promise of IL-15 in immuno-oncogenic therapies.

[6] Rossi J, et al. Blood (2018) 132(8):804-814. Preinfusion polyfunctional anti-CD19 chimeric antigen receptor T cells are associated with clinical outcomes in NHL.

[7] Ogasawara K, et al. Clin Pharmacokinet (2021) 60(12):1621-1633. Population Cellular Kinetics of Lisocabtagene Maraleucel, an Autologous CD19-Directed Chimeric Antigen Receptor T-Cell Product, in Patients with Relapsed/Refractory Large B-Cell Lymphoma.