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Target Overview
STEAP2 is a metalloreductase that displays high, homogeneous expression across all stages of prostate tumors and is virtually absent in normal adult non-prostate tissues, making it an ideal target for a CAR-T therapy for patients with prostate cancer.1-4
Transforming growth factor-beta (TGFβ) is a potent immunosuppressive cytokine that is found across tumor sites in prostate cancer and is particularly highly expressed in the surrounding stroma and bone metastases.5,6 TGFβ is a negative prognostic factor for patients with prostate cancer and may be a factor that contributes to the inability of immunotherapies to function in these tumor types.7,8 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
Compound Overview
AZD0754 is an autologous patient-specific T cell therapy product designed to express a chimeric antigen receptor (CAR) encoding a single-chain variable fragment (scFv) targeting STEAP2 in conjunction with dnTGFβRII armoring. The armoring acts to reduce the immune suppressive effects of TGFβ on CAR-T cell activity in the tumor microenvironment. AZD0754 is currently undergoing Phase 1 clinical investigations in patients with metastatic castration-resistant prostate cancer (mCRPC) who have failed at least one androgen receptor pathway inhibitors (ARPI) and a taxane.
Mechanism of Action
References
1. Hubert RS, Vivanco I, Chen E, et al. Proc Natl Acad Sci U S A. 1999;96(25):14523-14528. 2. Porkka KP, Helenius MA, Visakorpi T. Lab Invest. 2002;82(11):1573-1582. 3. Lee JK, Bangayan NJ, Chai T. Proc Natl Acad Sci U S A. 2018;115(19):E4473-E4482. 4. Zanvit P, van Dyk D, Fazenbaker C, et al. J Clin Invest. 2023;133(22):e169655. 5. Robinson D, Van Allen EM, Wu YM. Cell. 2015;161(5):1215-1228. 6. Abida W, Cyrta J, Heller G, et al. Proc Natl Acad Sci U S A. 2019;116(23):11428-11436. 7. Jiao S, Subudhi SK, Aparicio A, et al. Cell. 2019;179(5):1177-1190.e13. 8. Wu T, Wang W, Shi G. Cell Death Dis. 2022;13(7):624. 9. Wieser R, Attisano L, Wrana JL, Massagué J. Mol Cell Biol. 1993;13(12):7239-7247.
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Abbreviations
ARPI
androgen receptor pathway inhibitor
CAR-T
chimeric antigen receptor T cell (therapy)
mCRPC
metastatic castration-resistant prostate cancer
scFv
single-chain variable fragment
STEAP2
six transmembrane epithelial antigen of prostate-2
TGFβ
transforming growth factor beta
TGFβRII
transforming growth factor, beta receptor II
Target Overview
STEAP2 is a metalloreductase that displays high, homogeneous expression across all stages of prostate tumors and is virtually absent in normal adult non-prostate tissues, making it an ideal target for a CAR-T therapy for patients with prostate cancer.1-4
Transforming growth factor-beta (TGFβ) is a potent immunosuppressive cytokine that is found across tumor sites in prostate cancer and is particularly highly expressed in the surrounding stroma and bone metastases.5,6 TGFβ is a negative prognostic factor for patients with prostate cancer and may be a factor that contributes to the inability of immunotherapies to function in these tumor types.7,8 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
Compound Overview
AZD0754 is an autologous patient-specific T cell therapy product designed to express a chimeric antigen receptor (CAR) encoding a single-chain variable fragment (scFv) targeting STEAP2 in conjunction with dnTGFβRII armoring. The armoring acts to reduce the immune suppressive effects of TGFβ on CAR-T cell activity in the tumor microenvironment. AZD0754 is currently undergoing Phase 1 clinical investigations in patients with metastatic castration-resistant prostate cancer (mCRPC) who have failed at least one androgen receptor pathway inhibitors (ARPI) and a taxane.
Mechanism of Action
References
1. Hubert RS, Vivanco I, Chen E, et al. Proc Natl Acad Sci U S A. 1999;96(25):14523-14528. 2. Porkka KP, Helenius MA, Visakorpi T. Lab Invest. 2002;82(11):1573-1582. 3. Lee JK, Bangayan NJ, Chai T. Proc Natl Acad Sci U S A. 2018;115(19):E4473-E4482. 4. Zanvit P, van Dyk D, Fazenbaker C, et al. J Clin Invest. 2023;133(22):e169655. 5. Robinson D, Van Allen EM, Wu YM. Cell. 2015;161(5):1215-1228. 6. Abida W, Cyrta J, Heller G, et al. Proc Natl Acad Sci U S A. 2019;116(23):11428-11436. 7. Jiao S, Subudhi SK, Aparicio A, et al. Cell. 2019;179(5):1177-1190.e13. 8. Wu T, Wang W, Shi G. Cell Death Dis. 2022;13(7):624. 9. Wieser R, Attisano L, Wrana JL, Massagué J. Mol Cell Biol. 1993;13(12):7239-7247.
Clinical trial information
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Abbreviations
ARPI
androgen receptor pathway inhibitor
CAR-T
chimeric antigen receptor T cell (therapy)
mCRPC
metastatic castration-resistant prostate cancer
scFv
single-chain variable fragment
STEAP2
six transmembrane epithelial antigen of prostate-2
TGFβ
transforming growth factor beta
TGFβRII
transforming growth factor, beta receptor II