Article Text

Download PDFPDF

724 A phase I study of HCW9218, a bifunctional TGF-β Antagonist/IL-15 protein complex, in advanced solid tumors
  1. Melissa Geller1,
  2. Manish Patel1,
  3. Hing Wong2,
  4. Peter Rhode2,
  5. Philip Arlen2,
  6. Pallavi Chaturvedi2,
  7. Jack Egan2,
  8. Giles Leclerc2,
  9. Martin Felices1,
  10. Shannon Lunn1,
  11. Bethany Hanke1,
  12. Deepa Kolseri1,
  13. Rose Wangen1 and
  14. Jeffrey Miller1
  1. 1University of Minnesota, St. Paul, MN, USA
  2. 2HCW Biologics, Miramar, FL, USA


Background HCW9218 is a bifunctional protein complex comprising dimeric extracellular domains of the human transforming growth factor beta (TGF-β) receptor II and human interleukin-15 (IL-15). HCW9218 acts to (1) stimulate immune effector cells and (2) sequester soluble immunosuppressive TGF-β.1, 2 The primary objective of this Phase I first-in-human clinical trial is to determine the maximum tolerated dose of HCW9218 in advanced solid tumors.

Methods HCW9218 is administered subcutaneously in the outpatient setting once every 3 weeks for a minimum of two cycles. HCW9218 dose range was established through extensive nonclinical studies using the MABEL approach. Patients’ assigned dose levels range from 0.25 mg/kg (DL1) to 1.2 mg/kg (DL4). Correlative analyses include HCW9218 immunogenicity and pharmacokinetic profiles, serum cytokine levels and lymphocyte number, phenotype and function.

Results Since 4/2022, three patients have been dosed. Patient #1 had a recurrent GI stromal tumor, received one dose but elected to discontinue due to metastatic bone pain. He experienced an injection site reaction lasting >72 hours requiring dose expansion to 3 subjects. Patient #2 had recurrent colon cancer, received 2 doses and discontinued due to unrelated grade 3 ascites requiring paracentesis and disease progression. Patient #3 had recurrent ovarian cancer and has received 2 doses to date. There has been one grade 3 adverse event (AE). The most common AEs have been grade 1-2 injection site reactions. Unexpectedly, patients at the DL1 level exhibit consistent and robust immune activity for at least 2 weeks after a single dose (figure 1). PBMNC and serum were collected prior to dose 1, and at 2 to 15 days after dosing. All subjects had a robust increase in NK cell proliferation (81% Ki-67+ by day 8 after dosing vs.12.6% pre-dosing), which corresponded to an increased mean percent of NK cells to 34% of lymphocytes (12.6% pre-dosing). These responses were sustained through day 15, a biologic effect beyond that previously observed for other IL-15 agonists. By day 14, 44% of NK cells were CD56bright. Additionally, there was a modest increase in Ki-67+ CD8+ T cells at day 8. No treatment-mediated effects were seen on serum IL-1α, IL-1β, IL-6, IFN-γ or TNFα, whereas levels of TGF-β1 and TGF-β2 were reduced (as expected) and MCP-1 was elevated. Preliminary pharmacokinetic analysis showed a Cmax at 20-73h post-dosing and half-life of ~78h.

Conclusions HCW9218 safely and robustly expands NK cells after a single dose and escalation continues as planned to DL2 (0.5 mg/kg).

Trial Registration NCT05322408


  1. Liu B, Zhu X, Kong L, et al. Bifunctional TGF-beta trap/IL-15 protein complex elicits potent NK cell and CD8(+) T cell immunity against solid tumors. Mol Ther. 2021;29:2949–62.

  2. Chaturvedi P, George V, Shrestha N, et al. Immunotherapeutic HCW9218 augments anti-tumor activity of chemotherapy via NK cell-mediated reduction of therapy-induced senescent cells. Mol Ther. 2022;30:1171–87.

Ethics Approval This study was approved by the University of Minnesota’s Institutional Review Board; approval number: 00015102. All participants gave informed consent before taking part in this clinical trial.

Consent Written informed consent was obtained from the patients for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Abstract 724 Figure 1

NK cell proliferation following administration of HCW9218Following subcutaneous administration of 0.25 mg/kg of HCW9218 there is robust proliferation of NK cells measured by Ki67, with maximum levels seen on Day 8 (81%) which corresponds to a mean of 34% of the lymphocytes.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.