767 Pre-clinical and first-in-human studies of HCW9218, a bifunctional TGF-β antagonist/IL-15 protein complex, in advanced solid tumors

Background

HCW9218 is a bifunctional protein complex comprising dimeric extracellular domains of human transforming growth factor beta (TGF-β) receptor II and interleukin-15 (IL-15). HCW9218 1) stimulates immune effector cells and 2) sequesters soluble immunosuppressive TGF-β.^{1 2} The objectives of our pre-clinical and first-in-human studies are to explore the antitumor mechanism of action (MOA) and determine the RP2D.

Methods

Two syngeneic mouse tumor models were used to explore the MOA of HCW9218. A phase I dose escalation study (NCT05322408) of HCW9218 monotherapy (Q3W, subcutaneous) has been completed in adult patients (n=12) with refractory advanced/metastatic solid tumors and is expanding at the highest dose level (1.2mg/kg).³ Correlative analyses included pharmacokinetics, serum cytokines, blood lymphocytes, and cellular/molecular profiling of tumors.

Results

In B16F10 melanoma and 4T1 breast cancer murine models, HCW9218 promotes proliferation and activation of progenitor exhausted (Tpex) and exhausted transitory effector (Tem) CD8⁺ T cells in draining lymph nodes, and CD8⁺ memory T cells and NK cells in peripheral blood. HCW9218 increases tumor infiltrating Tpex, Tem, and memory CD8⁺ T cells and enhances antitumor potency of immune checkpoint blockade therapy, likely due to stimulation of Tpex and Tem cells. HCW9218 protein localizes in tumors and significantly lowers TGF-β levels and increases proinflammatory cytokines. In the first-in-human clinical trial, there were no dose limiting toxicities. The most common adverse events are grade 1–2 injection site reactions and transient lymphopenia. Patients receiving ≥0.25 mg/kg HCW9218 exhibit robust NK cell and CD8⁺ T cell proliferation through day 15 and recurred with each treatment cycle, a biologic effect beyond what has been previously observed with other IL-15 agonists. At ≥0.5 mg/kg HCW9218, serum TGF-β1 levels decrease to baseline through day 8. Immunofluorescent staining of patients’ tumors show that HCW9218 increases CD8⁺ T cell infiltration with elevated tumor Tpex and/or fully differentiated memory CD8⁺ T cells correlating with disease stabilization. Single-cell RNA-seq tumor analysis demonstrates that HCW9218 reduces expression of genes associated with tumor invasion, immunosuppression, and inflammation and upregulates genes involved in differentiation of Tpex, TCR signaling, and inflammatory response, while downregulating proinflammatory response genes of tumor lymphocytes. HCW9218 has a serum half-life of ~25h in patients.

Conclusions

Repeated HCW9218 administration at ≥0.5 mg/kg in heavily pretreated advanced solid tumor patients resulted in immune cell activation, proliferation, and infiltration into the tumor microenvironment without causing unacceptable toxicity. HCW treatment presents a promising approach to enhancing the antitumor activity of immune checkpoint inhibitors in patients with solid tumors.

Trial Registration

NCT05322408

References

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. 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. Geller M, Patel M, Wong H, et al. A phase I study of HCW9218, a bifunctional TGF-β antagonist/IL-15 protein complex, in advanced solid tumors. J Immunother Cancer 2022;10. doi: 10.1136/jitc-2022-SITC2022.0724

Ethics Approval

This study was approved by the University of Minnesota’s Institutional Review Board; approval number: 00015102.

Consent

Written informed consent was obtained from the patients included in the clinical trial 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.