First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation

Abstract

New therapies for patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) are needed. Interleukin 15 (IL-15) is a cytokine that stimulates CD8 T-cell and natural killer (NK) cell antitumor responses, and we hypothesized this cytokine may augment antileukemia/antilymphoma immunity in vivo. To test this, we performed a first-in-human multicenter phase 1 trial of the IL-15 superagonist complex ALT-803 in patients who relapsed >60 days after allo-HCT. ALT-803 was administered to 33 patients via the IV or subcutaneous (SQ) routes once weekly for 4 doses (dose levels of 1, 3, 6, and 10 μg/kg). ALT-803 was well tolerated, and no dose-limiting toxicities or treatment-emergent graft-versus-host disease requiring systemic therapy was observed in this clinical setting. Adverse events following IV administration included constitutional symptoms temporally related to increased serum IL-6 and interferon-γ. To mitigate these effects, the SQ route was tested. SQ delivery resulted in self-limited injection site rashes infiltrated with lymphocytes without acute constitutional symptoms. Pharmacokinetic analysis revealed prolonged (>96 hour) serum concentrations following SQ, but not IV, injection. ALT-803 stimulated the activation, proliferation, and expansion of NK cells and CD8 T cells without increasing regulatory T cells. Responses were observed in 19% of evaluable patients, including 1 complete remission lasting 7 months. Thus, ALT-803 is a safe, well-tolerated agent that significantly increased NK and CD8 T cell numbers and function. This immunostimulatory IL-15 superagonist warrants further investigation to augment antitumor immunity alone and combined with other immunotherapies. This trial was registered at www.clinicaltrials.gov as #NCT01885897.

Interleukin-15 (dys)regulation of lymphoid homeostasis: Implications for therapy of autoimmunity and cancer

“…ALT-803 (IL-15 mutant/IL-15Rα/Ig1fusion protein) was administered i.v. or s.c. to 33 patients with hematological malignancies once weekly for four doses (Romee et al, 2018), and pharmacokinetic analysis revealed prolonged serum concentrations following s.c. compared with i.v. infusion.…”

Reduced-Intensity Conditioning Followed by Related and Unrelated Allografts for Hematologic Malignancies: Expanded Analysis and Long-Term Follow-Up

“…20 Lastly, immune modulation post-HCT could diminish relapse risk. Based on recently published data highlighting successful IL-15 superagonist (ALT-803) induced NK cell and CD8+ T cell expansion in patients relapsing post allogeneic transplant, 21 we are now utilizing ALT-803 prophylaxis post RIC allogeneic transplant for patients with AML and MDS in attempts to minimize relapse risk. Combining pre-transplant disease status specific requirements, personalized conditioning intensity approaches, and post-HCT maintenance pathways for high relapse risk diseases will improve long-term outcomes.…”

Adaptive NK cell responses in HIV/SIV infections: A roadmap to cell-based therapeutics?

“…62 Several studies targeting NKG2A in order to enhance NK and CD8+ T cell functions using the NKG2A blocking antibody, Monalizumab, are now underway for cancer therapy. 63,64 Anti-NKG2A antibody treatment has also been shown to improve NK cell cytotoxicity and viral clearance in and Romee et al 71 ). Further, ALT-803 is being tested in concert with other checkpoint inhibitors such as anti-PD-1 therapy in patients with metastatic nonsmall cell lung cancer.…”

“…ALT‐803 (now N803) is a fusion complex of IL‐15 and IL‐15Rα with IgG1 Fc that has enhanced IL‐15 biologic activity through a single amino acid mutation in IL‐15 . ALT‐803 has been shown to be well tolerated in patients with relapsed hematologic malignancies with augmented NK and T cell responses (ClinicalTrials.gov ID: NCT01885897 and Romee et al …”