Fourth-generation chimeric antigen receptor T Cells for hepatocellular carcinoma - Clinical Trials Arena
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Fourth-generation chimeric antigen receptor T Cells for hepatocellular carcinoma

By GlobalData Healthcare 01 Jul 2021 (Last Updated July 1st, 2021 16:44)

Results for multiple hepatocellular carcinoma (HCC) clinical trials were presented at the 2021 American Society of Clinical Oncology (ASCO) virtual annual meeting held June 4–8 June. CARsgen Therapeutics presented data from a Phase I trial (NCT03980288) of its fourth-generation chimeric antigen receptor T (CAR-T) cells targeting glypican-3 (GPC3).

Fourth-generation chimeric antigen receptor T Cells for hepatocellular carcinoma
Credit: Shutterstock

Results for multiple hepatocellular carcinoma (HCC) clinical trials were presented at the 2021 American Society of Clinical Oncology (ASCO) virtual annual meeting held June 4–8 June. CARsgen Therapeutics presented data from a Phase I trial (NCT03980288) of its fourth-generation chimeric antigen receptor T (CAR-T) cells targeting glypican-3 (GPC3). Fourth-generation CAR-T cells are additionally engineered to secrete a transgenic cytokine upon CAR signaling in the targeted tumor tissue. As a result, in addition to the direct antitumor attack, they can trigger T cells to eliminate antigen-negative cancer cells at the target site. GPC3 is a cell-surface glycoprotein that is highly expressed in HCC and is thus being evaluated as a target for HCC immunotherapy. CARsgen’s novel pipeline therapy for advanced HCC stands out for being a first-in-class approach with a unique mechanism of action that targets heavily pretreated advanced HCC patients.

In this study, CARSgen’s fourth-generation CAR-GPC3 T cells in combination with the tyrosine kinase inhibitors (TKIs) Nexavar (sorafenib) or Stivarga (regorafenib) demonstrated manageable safety and potential antitumor activity for hepatitis B virus (HBV)-related metastatic HCC patients who have been previously treated with systemic therapy. Safety results showed an absence of dose-limiting toxicity, treatment-related serious adverse events (AEs), AE-related death or study withdrawal, and neurotoxicity. Three out of the six patients in the study experienced grade 3 cytokine release syndrome (CRS), a common AE seen in response to CAR-T cell therapy. Preliminary efficacy results revealed the objective response rate and disease control rate were 16.7% and 50%, respectively. The median progression-free survival was 4.2 months. The median peak CAR-GPC3 copy number in patients’ peripheral blood on day 7 after treatment was 5,067 copies per μg genomic DNA and CAR-GPC3 copies were still detectable on day 28 at levels ranging between 113 and 2,071 copies per μg genomic DNA. Earlier Phase I trials for the second-generation version of this therapeutic agent (NCT02395250 and NCT03146234) also reported clinical benefit and tolerability.

KOLs interviewed by GlobalData noted that CAR-T cells or adoptive cellular therapy is an emerging area that may change HCC treatment practice in the future. The majority of late-stage pipeline drugs for advanced HCC are for use in the first-line setting, which has the highest number of treated cases. Therefore, subsequent lines of therapy are being overlooked by drug developers, despite high unmet need. However, CARsgen Therapeutics conducted the study of their CAR-T cell therapy on patients who progressed on two or more lines of systemic therapy, having tried at least one TKI combined with anti-programmed death-1 (PD-1)/ programmed death ligand 1 (PD-L1) immunotherapy or FOLFOX4 (5-fluorouracil, leucovorin, and oxaliplatin) chemotherapy. A similar strategy of focusing on subsequent lines of therapy was used by other companies studying adoptive cellular therapy for HCC in the early-stage development including Immunotech Biopharm, Immunicum AB, Eureka Therapeutics, Adaptimmune Therapeutics, Fate Therapeutics, and Origincell Therapeutics. Therefore, investigation of heavily pretreated advanced HCC patients seems to be a general trend with CAR-T cell developers in HCC.

The HCC clinical pipeline is crowded with me-too drugs targeting patients in the first-line setting. CARsgen’s CAR-GPC3 T cell therapy is a first-in-class targeted drug addressing advanced HCC patients who have progressed on or developed resistance to previous therapy—a patient population with little to no treatment options. GlobalData expects that if successful in later stage trials, CARsgen’s therapy will be beneficial to underserved patients in late-stage advanced HCC.

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