IOV-3001, a modified interleukin-2 fusion protein, for potential use in tumor-infiltrating lymphocyte cell therapy regimens.

Authors

null

Michelle R. Abelson

Iovance Biotherapeutics, Inc., San Carlos, CA

Michelle R. Abelson , Sadie Johnson , Joanna Poprawski , Jamie L. Blauvelt , Sean Hall , Hequn Yin

Organizations

Iovance Biotherapeutics, Inc., San Carlos, CA, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, Iovance Biotherapeutics, Inc., Tampa, FL

Research Funding

Iovance Biotherapeutics (San Carlos, CA, USA)

Background: Tumor-infiltrating lymphocyte (TIL) cell therapy has shown promising efficacy in patients with solid tumor malignancies. Interleukin-2 (IL-2) administration after TIL infusion supports persistence and survival of infused TIL. Aldesleukin is a synthetic IL-2 with a short half-life administered every 8–12 hours, to support the expansion and persistence of the TIL in vivo. IOV-3001 is a modified dimeric IL-2 fused to palivizumab that has a longer half-life and potentially better safety profile, compared with aldesleukin. Here, we describe the preclinical activity, pharmacokinetics (PK), pharmacodynamics (PD), and in vivo safety profile of IOV-3001. Methods: Binding of IOV-3001 and aldesleukin to the IL-2 receptor (IL-2R), IL-2R-mediated activation via STAT5 phosphorylation, and T cell proliferation were assessed. Pharmacological activities of IOV-3001 and aldesleukin were evaluated in B16-F10 mice infused with pmel-1 T cells. Safety after a single dose of IOV-3001 (0.01–9.0 mg/kg) was assessed in cynomolgus monkeys across 3 independent studies. PK and PD parameters, clinical pathology, hematology, and histopathology were assessed. Results: Both IOV-3001 and aldesleukin induced comparable STAT5 phosphorylation and proliferation of T-cell subsets. Mice infused with pmel-1 T cells and subsequently treated with IOV-3001 or aldesleukin showed similar reductions in tumor burden. The half-life of IOV-3001 in cynomolgus monkeys ranged from 5–8 hours. IOV-3001 was well tolerated in monkeys across the dose range studied except for 1 animal administered IOV-3001 at the highest tested dose level, with recovery by Day 29. Inflammatory cytokines (IL-12 p40, IL-6, MCP-1) increased from 4 hours to ≤3 days after dosing and returned to baseline by Day 29. Fibrinogen, bilirubin, and triglycerides increased on Day 3 and returned to baseline by Day 29. No signs of capillary leak were observed. Increased numbers of hematopoietic cells were found in the bone marrow, spleen, and lymph nodes 3 days post dosing. During the 4-week recovery, these changes diminished or resolved, while bone marrow showed differential dose-dependent effects. IL-2–induced proinflammatory PD effects were observed, including >10-fold peak CD8+ T cell expansion in peripheral blood mononuclear cells at Day 5 versus preacclimation in most cynomolgus monkeys treated with IOV-3001. Conclusions: IOV-3001 exhibited a similar mechanism of action (MoA) to that of aldesleukin in vitro and has a longer half-life in vivo. PD effects were consistent with the MoA of IL-2. IOV-3001 showed a favorable preclinical safety profile. These results suggest a potentially improved safety profile for IOV-3001 with less frequent dosing compared with aldesleukin. These features of IOV-3001 strongly advocate for its development in TIL cell therapy regimens.

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Abstract Details

Meeting

2024 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Developmental Therapeutics—Immunotherapy

Track

Developmental Therapeutics—Immunotherapy

Sub Track

Cellular Immmunotherapy

Citation

J Clin Oncol 42, 2024 (suppl 16; abstr 2552)

DOI

10.1200/JCO.2024.42.16_suppl.2552

Abstract #

2552

Poster Bd #

31

Abstract Disclosures