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Target Overview
Glypican-3 (GPC3) is a heparan sulfate proteoglycan, which is expressed in the majority (>70%) of hepatocellular carcinoma (HCC) cases1 and expression is associated with poor prognosis.2,3 GPC3 is virtually absent in normal adult tissues,4 making it an ideal target for CAR T-cell therapy.
Transforming growth factor-beta (TGFβ) is also a key molecular player in HCC, with elevated levels found in tumor and blood.5,6 In HCC tumors, TGFβ1 promotes epithelial mesenchymal transition, triggers cell migration and invasion, and induces an aggressive phenotype.7 TGFβ is also a potent immunosuppressive cytokine, which inhibits T cell-mediated immune responses.8 TGFβ signaling can be blocked by using a dominant negative transforming growth factor, beta receptor II (dnTGFβRII), which is truncated and lacks the intracellular domain necessary for downstream signaling.9
Early clinical data with C-CAR031 (AZD7003) showed promising tolerability and antitumor activity in patients with HCC.10
Compound Overview
AZD7003 is autologous T-lymphocytes, expressing a chimeric antigen receptor (CAR) specific for GPC3 and a dnTGFβRII as an armoring strategy. Expression of the GPC3 CAR allows T cells to recognize and kill GPC3-expressing tumor cells.11 Expression of dnTGFβRII can block TGFβ signaling, protecting CAR T-cells from the immunosuppressive effects of this cytokine.12
AZD7003 is manufactured at AstraZeneca collaborator’s manufacturing facility using lentiviral vector and autologous CAR-T manufacturing process designed to limit ex vivo expansion time and retain stemness of T cells with the potential to enhance CAR-T fitness, persistence, and anti-tumor efficacy.
Mechanism of Action
References
1. Moek KL, Fehrmann RSN, van der Vegt B, et al. Am J Pathol. 2018;188(9):1973-1981. 2. Yan B, Wei JJ, Qian YM, et al. Ann Diagn Pathol. 2011;15(3):162-169. 3. Zhang J, Zhang M, Ma H, et al. Medicine (Baltimore). 2018;97(24):e11130. 4. Suzuki M, Sugimoto K, Tanaka J, et al. Anticancer Res. 2010;30(12):5055-5061. 5. An Y, Gao S, Zhao WC, et al. World J Gastroenterol. 2018;24(25):2733-2740. 6. Shen Y, Wei Y, Wang Z, et al. Cell Physiol Biochem. 2015;35(4):1623-1632. 7. Fabregat I, Moreno-Càceres J, Sánchez A, et al. FEBS J. 2016;283(12):2219-2232. 8. Dahmani A, Delisle JS. Cancers (Basel). 2018;10(6):194. 9. Wieser R, Attisano L, Wrana JL, et al. Mol Cell Biol. 1993;13(12):7239-7247. 10. Zhang Q, Fu Q, Cao W, et al. Cancer Res. 2023;83(8_Supplement):CT097. 11. Giardino Torchia ML, Gilbreth R, Merlino A, et al. Cytotherapy. 2022;24(7):720-732. 12. De Folmont A, Bourhis J-H, Chouaib S, et al. Immuno. 2021;1(3):160-173.
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Abbreviations
CAR-T
chimeric antigen receptor T cell (therapy)
GPC3
glypican-3
HCC
hepatocellular carcinoma
TGFβ
transforming growth factor beta
TGFβRII
transforming growth factor, beta receptor II
Target Overview
Glypican-3 (GPC3) is a heparan sulfate proteoglycan, which is expressed in the majority (>70%) of hepatocellular carcinoma (HCC) cases1 and expression is associated with poor prognosis.2,3 GPC3 is virtually absent in normal adult tissues,4 making it an ideal target for CAR T-cell therapy.
Transforming growth factor-beta (TGFβ) is also a key molecular player in HCC, with elevated levels found in tumor and blood.5,6 In HCC tumors, TGFβ1 promotes epithelial mesenchymal transition, triggers cell migration and invasion, and induces an aggressive phenotype.7 TGFβ is also a potent immunosuppressive cytokine, which inhibits T cell-mediated immune responses.8 TGFβ signaling can be blocked by using a dominant negative transforming growth factor, beta receptor II (dnTGFβRII), which is truncated and lacks the intracellular domain necessary for downstream signaling.9
Early clinical data with C-CAR031 (AZD7003) showed promising tolerability and antitumor activity in patients with HCC.10
Compound Overview
AZD7003 is autologous T-lymphocytes, expressing a chimeric antigen receptor (CAR) specific for GPC3 and a dnTGFβRII as an armoring strategy. Expression of the GPC3 CAR allows T cells to recognize and kill GPC3-expressing tumor cells.11 Expression of dnTGFβRII can block TGFβ signaling, protecting CAR T-cells from the immunosuppressive effects of this cytokine.12
AZD7003 is manufactured at AstraZeneca collaborator’s manufacturing facility using lentiviral vector and autologous CAR-T manufacturing process designed to limit ex vivo expansion time and retain stemness of T cells with the potential to enhance CAR-T fitness, persistence, and anti-tumor efficacy.
Mechanism of Action
References
1. Moek KL, Fehrmann RSN, van der Vegt B, et al. Am J Pathol. 2018;188(9):1973-1981. 2. Yan B, Wei JJ, Qian YM, et al. Ann Diagn Pathol. 2011;15(3):162-169. 3. Zhang J, Zhang M, Ma H, et al. Medicine (Baltimore). 2018;97(24):e11130. 4. Suzuki M, Sugimoto K, Tanaka J, et al. Anticancer Res. 2010;30(12):5055-5061. 5. An Y, Gao S, Zhao WC, et al. World J Gastroenterol. 2018;24(25):2733-2740. 6. Shen Y, Wei Y, Wang Z, et al. Cell Physiol Biochem. 2015;35(4):1623-1632. 7. Fabregat I, Moreno-Càceres J, Sánchez A, et al. FEBS J. 2016;283(12):2219-2232. 8. Dahmani A, Delisle JS. Cancers (Basel). 2018;10(6):194. 9. Wieser R, Attisano L, Wrana JL, et al. Mol Cell Biol. 1993;13(12):7239-7247. 10. Zhang Q, Fu Q, Cao W, et al. Cancer Res. 2023;83(8_Supplement):CT097. 11. Giardino Torchia ML, Gilbreth R, Merlino A, et al. Cytotherapy. 2022;24(7):720-732. 12. De Folmont A, Bourhis J-H, Chouaib S, et al. Immuno. 2021;1(3):160-173.
Clinical trial information
Select trial for more information
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Abbreviations
CAR-T
chimeric antigen receptor T cell (therapy)
GPC3
glypican-3
HCC
hepatocellular carcinoma
TGFβ
transforming growth factor beta
TGFβRII
transforming growth factor, beta receptor II