Targeting GPC-3 in Hepatocellular Carcinoma Treatment

T-cell engager (TCE)-based immunotherapy is clinically validated in hematological cancers. However, application in solid tumors faces hurdles including T cell penetration, the immunosuppressive tumor microenvironment, and toxicity. We develop an mRNA-encoded TCE (MTS105) targeting Glypican-3, the hepatocellular carcinoma antigen, delivered via lipid nanoparticles directly to liver tissue. In mice, rats, and cynomolgus monkeys, MTS105 exhibits higher liver exposure versus plasma. Liver-orthotopic tumor-bearing mice achieve complete, dose-dependent regression, with fast intratumoral T cell activation owing to sustained higher liver and tumor functional TCE exposure versus conventional antibody-based TCE. In vivo, MTS105 induces intratumoral CD8 cell precursor and terminally differentiated memory subsets with high activation scores. In cynomolgus monkeys, MTS105 displays favorable, linear plasma pharmacokinetics including mRNA, ionizable lipid, and translated TCE following single and repeated-four-weekly dosing (up to 45 μg/kg). No severe adverse effects or gross pathology were observed. Our results thus support the advancement of MTS105 into clinical trials, with a first-in-human study currently underway. Paper and research by @Yan Huang,  Wei Xu and larger team

Interleukin-15-armoured GPC3 CAR T cells for patients with solid cancers Interleukin-15 (IL-15) promotes the survival of T lymphocytes and enhances the antitumour properties of chimeric antigen receptor (CAR) T cells in preclinical models of solid neoplasms in which CAR T cells have limited efficacy1,2,3,4. Glypican-3 (GPC3) is expressed in a group of solid cancers5,6,7,8,9,10, and here we report the evaluation in humans of the effects of IL-15 co-expression on GPC3-expressing CAR T cells (hereafter GPC3 CAR T cells). Cohort 1 patients (NCT02905188 and NCT02932956) received GPC3 CAR T cells, which were safe but produced no objective antitumour responses and reached peak expansion at 2 weeks. Cohort 2 patients (NCT05103631 and NCT04377932) received GPC3 CAR T cells that co-expressed IL-15 (15.CAR), which mediated significantly increased cell expansion and induced a disease control rate of 66% and antitumour response rate of 33%. Infusion of 15.CAR T cells was associated with increased incidence of cytokine release syndrome, which was controlled with IL-1/IL-6 blockade or rapidly ameliorated by activation of the inducible caspase 9 safety switch. Compared with non-responders, tumour-infiltrating 15.CAR T cells from responders showed repression of SWI/SNF epigenetic regulators and upregulation of FOS and JUN family members, as well as of genes related to type I interferon signalling. Collectively, these results demonstrate that IL-15 increases the expansion, intratumoural survival and antitumour activity of GPC3 CAR T cells in patients. https://lnkd.in/eNtaGQ-T

LNPs + mRNA = In vivo CAR-T? Not always. When we talk about LNP-mediated in vivo delivery, the conversation usually turns straight to in vivo CAR-T programs (like those from Capstan Therapeutics or CREATE Medicines). But a recent study corroborates a powerful alternative: mRNA-encoded T-cell Engagers (TCEs). Instead of re-engineering the T-cell itself, this approach turns the liver into a local "bio-factory" to produce bispecific antibodies in situ. The Breakdown (MTS105 for Hepatocellular Carcinoma): 🔹 The Cargo: mRNA encoding a bispecific T-cell engager (CD3 x GPC3) 🔹 The Vehicle: Liver-tropic Lipid Nanoparticles (LNPs).  🔹 The Mechanism: After IV infusion, hepatocytes uptake the LNPs and begin secreting the TCE protein directly into the tumor microenvironment. Why this matters: This creates high local concentrations in the liver and tumor while maintaining low systemic exposure, reducing cytokine release syndrome (CRS) and off-target toxicity. The Results: 🟢 Efficacy: Complete tumor regression in orthotopic HCC models (using humanized CD3EDG mice). 🟢 Safety: Favorable PK and toxicology profiles in Non-Human Primates (NHP).  🟢 Clinical: First-in-human trials are already underway (NCT06689540). The link to the full study is in the comments. 

🧬 INTERCEPT Study: IL-15/IL-21 Armored GPC3-CAR T Cells with iCasp9 Safety Switch in Solid Tumors 🧠 CAR T-cell therapy has shown remarkable success in hematologic cancers, but translating this into solid tumors has remained a major scientific and clinical hurdle. The INTERCEPT study (NCT07224568), led by Seattle Children's Hospital, represents a cutting-edge approach to tackle this challenge using cytokine-armored CAR T cells in adults with relapsed or refractory GPC3-positive solid tumors. 🔬 This first-in-human, Phase 1 trial investigates the safety, feasibility, and preliminary efficacy of a next-generation CAR T cell product: 🔗 GPC3-targeting CAR — for antigen-specific tumor recognition 💡 IL-15 and IL-21 cytokine transgenes — to enhance T cell survival, expansion, and persistence in the hostile tumor microenvironment 🛑 iCasp9 suicide gene — a built-in safety switch allowing rapid CAR T cell elimination via rimiducid (AP1903)in case of severe toxicity 🧪 Preclinical studies demonstrated that this multi-armored CAR construct (SC-CAR.GPC3xIL15.21) showed superior antitumor activity compared to conventional CAR T cells, particularly in GPC3-expressing malignancies such as: 🏥 Hepatocellular carcinoma 🧬 Yolk sac tumor 🧫 Rhabdomyosarcoma 🧱 Liposarcoma 📍 All treatments will be administered at Fred Hutch Cancer Center (Seattle) following lymphodepleting chemotherapy. The study will enroll 21 adult patients, with each participant undergoing close monitoring post-infusion and long-term follow-up for up to 15 years. 📈 If successful, this trial could mark a pivotal advancement in designing durable, safe, and tumor-specific cellular immunotherapies for solid tumors — a domain where CAR T success has been elusive. 📄 More info: NCT07224568 on ClinicalTrials.gov #INTERCEPTStudy #CARTCells #GPC3 #IL15 #IL21 #iCasp9 #SolidTumors #CellTherapy #Immunotherapy #HepatocellularCarcinoma #Rhabdomyosarcoma #YolkSacTumor #Liposarcoma #SeattleChildrens #FredHutch #OncologyResearch #CancerImmunotherapy #ClinicalTrials #PrecisionMedicine

AstraZeneca’s CAR-T Buyout: A Quiet but Powerful Signal for Cell Therapy AstraZeneca’s decision to acquire the remaining China rights to AbelZeta’s armored CAR-T therapy (C-CAR031) may look like a routine regional consolidation. It isn’t. This deal — valued at up to $630M — gives AstraZeneca full global control of a GPC3-targeting armored CAR-T for hepatocellular carcinoma, one of the hardest solid tumors to treat. More importantly, it signals where capital, confidence, and commitment in cell therapy are heading. For financing: Big pharma is no longer just partnering — it is buying out risk once early clinical rationale is clear. That’s a critical validation for startups building differentiated cell therapy assets: progress plus platform innovation can unlock real exits, even in a cautious funding environment. For the cell therapy sector: This reinforces a renewed belief that solid tumor CAR-T is investable, particularly when designs address the tumor microenvironment. Armored approaches are moving from theory to strategic priority. For patients: Global rights matter. They accelerate development, simplify manufacturing strategy, and increase the likelihood that complex therapies actually reach patients — especially in diseases like liver cancer where options remain limited. This is not just a licensing clean-up. It’s a signal that cell therapy’s next chapter will be driven by focused assets, global scale, and disciplined capital — with patients at the center. #celltherapy #financing #advancedtherapies #globalimpact #BigPharma https://lnkd.in/etAPy-Pf

🚀 FDA #Fast #Track for #BGB-B2033: BeOne Medicines Advances a New Bispecific Strategy in Liver Cancer A meaningful regulatory milestone in oncology: BeOne Medicines has received U.S. FDA Fast Track Designation for BGB-B2033, its GPC3 × 4-1BB bispecific antibody, for adults with hepatocellular carcinoma (HCC) who progressed on or after prior systemic therapy. Here’s why this matters 👇 ⭐ 1️⃣ Fast Track Signals Urgent Unmet Need HCC is the 6th most common cancer globally and a leading cause of cancer mortality. With ~80% diagnosed at advanced stages and <20% five-year survival, Fast Track underscores the FDA’s recognition that new mechanisms are needed beyond current systemic options. 🧬 2️⃣ Tumor-Selective Immune Activation by Design BGB-B2033 targets: • GPC3, a tumor-specific antigen highly expressed in HCC • 4-1BB, a powerful T-cell costimulatory receptor By coupling these targets, the therapy aims to activate T cells preferentially at the tumor site, reducing systemic toxicity that has challenged prior 4-1BB approaches. 🛡️ 3️⃣ Engineered for Safety Without Losing Potency The molecule is designed with reduced ADCC, helping avoid off-tumor immune activation while maintaining anti-tumor activity—a key differentiator in this class. 🌍 4️⃣ Global Phase 1 Program Is Underway BeOne is running a global, multi-center Phase 1 trial (NCT06427941) evaluating BGB-B2033: • As monotherapy • In combination with @TEVIMBRA® (tislelizumab) This accelerates learning on safety, dosing, and early efficacy signals in advanced HCC. 🗣️ 5️⃣ Regulatory Momentum Matters Early As Julie Lepin, SVP & Chief Regulatory Affairs Officer at BeOne Medicines, noted, Fast Track reflects the encouraging profile of BGB-B2033 in a setting with limited options—unlocking more frequent FDA interaction and potential development efficiencies. 💡 My takeaway: BGB-B2033 represents the next wave of precision immuno-oncology—pairing tumor antigens with costimulatory signals to focus immune power where it’s needed most. If clinical data validate the concept, GPC3-directed bispecifics could meaningfully reshape the HCC treatment landscape. Fast Track doesn’t guarantee success—but it marks credible science with real clinical promise. #BeOneMedicines #BGBB2033 #HCC #LiverCancer #BispecificAntibodies #ImmunoOncology #FastTrack #FDA #OncologyPipeline https://lnkd.in/gdwDqebG