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Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary new therapeutic breakthrough in cancer treatment. Approved immunotherapies with CD19-targeting or BCMA-targeting CAR T cells have been shown to achieve complete or partial remission in patients with advanced hematologic malignancies. However, about half of patients will either fail to achieve remission or will relapse, thus indicating that durability of response remains a challenge. Strategies are being explored to further improve the efficacy and durability of CAR T-cell therapies.

Correlative clinical studies support the potential role for IL-15 in better outcomes for patients receiving CAR T-cell therapies. Several studies have shown that for patients treated with CD19 CAR T cells, higher serum IL-15 concentration was associated with higher probabilities of response to therapy and higher CAR T cell expansion and persistence.

Recombinant IL-15 has limited applicability in the clinic due to poor pharmacokinetic (PK) properties, requiring frequent dosing at high dose levels which can result in toxicities. Although there are many attempts to develop IL-15/IL-15 receptor alpha molecules to improve the PK profile of unmodified IL-15, those molecules have different biological profiles from naïve IL-15.

In contrast to other IL-15 approaches in development, NKTR-255 is a polymer-conjugated IL-15 that retains binding affinity to IL-15Rα and maintains the full spectrum of IL-15 biology. NKTR-255 exhibits improved pharmacokinetics thereby providing sustained pharmacodynamic responses without the need for daily dosing.

Preclinical evidence for NKTR-255 to play a role with CAR T-cell therapy

Preclinical data generated in collaboration with the Fred Hutchinson Cancer Center has demonstrated the promise of combining NKTR-255 with CD19-targeted CAR T-cell therapies. At ASH 2019, the addition of NKTR-255 to a CD19-targeted CAR T-cell regimen in preclinical models of B cell lymphoma was shown to increase survival of CAR T cells and reduce tumor growth as compared to either treatment alone. At EHA 2019, researchers showed that in vivo treatment with NKTR-255 and CAR T cells resulted in rejection of a tumor re-challenge.

At the 2022 Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, data with anti-MCAM CAR modified Natural Killer (NK) cells in preclinical models of Ewing sarcoma, osteosarcoma and neuroblastoma showed that the addition of NKTR-255 resulted in enhanced anti-MCAM CAR NK anti-tumor effect by stimulating proliferation and expansion of NK cells (Luo Separate data showed that NKTR-255 also enhanced the anti-tumor effect of ex-vivo expanded anti-CD19 CAR NK cells against Burkitt’s Lymphoma when combined with anti-CD20 or anti-CD79 therapeutic antibodies (Chu et al.).

Clinical findings for NKTR-255 and effects on CAR-T cell persistence

Our clinical safety and pharmacodynamic report on the effect of NKTR-255 on CAR T cell counts in patients with relapsed/refractory Non-Hodgkin Lymphoma or Multiple Myeloma patients was the first such report for any IL-15 agent and was presented at the 63rd American Society of Hematology (ASH) Annual Meeting in 2021 (Hirayama, A., et al). Of the patients with detectable CAR T cells at the time of entry in the study, 100% of patients (4/4) showed an increase of CD3+ CAR T cells following treatment with NKTR-255.

The reported patients had minimal levels of detectable CAR T cells at baseline prior to the study and three of the patients were well over a year past their CAR T-cell infusion at the time they began treatment with NKTR-255. In brief, NKTR-255 induced proliferation and increase of the CAR-T compartment and more importantly an increase of the CD8+ cell fraction in patients. These data suggest that NKTR-255 represents a potentially novel means of CAR T augmentation through enhancement and persistence of CD8+ T cells and provides promising evidence of CAR T cell rescue.

Clinical studies planned or ongoing for NKTR-255 with CAR T-cell therapies

Clinical studies are ongoing or planned to evaluate NKTR-255 as a potential strategy to enhance the efficacy of CAR T-cell therapy. The first is an ongoing Stanford-sponsored study evaluating CD19/CD22 CAR T cells combined with NKTR-255 treatment in adults with recurrent or refractory acute lymphocytic leukemia.

A separate study at Fred Hutchinson Cancer Center is being initiated to evaluate the efficacy and safety of NKTR-255 in combination with an approved CD19 CAR T-cell therapy in patients with relapsed or refractory diffuse large B cell lymphoma.

Nektar-sponsored studies of NKTR-255 in combination with other cell therapies are also being planned.

To learn more about the continued clinical development of the IL-15 agonist, NKTR-255, visit our website.