Overview of PSCA-targeted CAR Cell Therapies

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Background of PSCA

Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol-anchored cell membrane glycoprotein coded by the PSCA gene in humans, probably involved in the regulation of cell proliferation, and possessing a function as a modulator of nicotinic acetylcholine receptor (nAChR) activity.

The primary structure of PSCA is formed by 114 amino acids. The crystal structure has not been determined, and in AlphaFold, the spatial structure of the middle domain has been predicted with very high confidence (Fig. 1). In SWISS-MODEL, the whole structure is predicted with an average model confidence of 0.55 (Fig. 2). From both models, it can be concluded that PSCA has just one subunit and lots of beta-alpha-beta units.

Fig.1 Prediction of AlphaFold model of PSCA

Fig.2 Prediction of SWISS-MODEL model of PSCA

PSMA is a specific biomarker of advancing prostate cancer and a possible indicator for Alzheimer's disease. In normal tissue, PSCA is expressed at a low level in the cell membrane of neuroendocrine cells or epithelium of the stomach, prostate, bladder, placenta, colon, and kidney. Overexpression in prostate cancer (PCa) is associated with tumor stages, grade, and androgen-independence. Additionally, PSCA is highly expressed in PCa bone metastases. In the brain cortex, PSCA is also found at the protein level, and expression is significantly increased in the front cortex of Alzheimer's disease patients.

PSCA Signaling Pathways

In normal tissue, PSCA is involved in post-translational modification: the synthesis of GPI-anchored proteins and plays a critical role in cell proliferation. In tumorigenesis, PSCA promotes prostate cancer proliferation and cell-cycle progression by up-regulating c-Myc. Additionally, PSCA regulates IL-6 expression through p38/NF-κB signaling in prostate cancer.

Clinical Status of PSCA-Targeted CAR Cell Therapies

Despite the development of many new therapies in the last decade, metastatic castration resistant prostate cancer (mCRPC) remains a fatal disease due to the drug-resistance of all therapies. It is considered an immune "cold" tumor, characterized by low lymphocyte infiltration and predominance of immunosuppressive factors. Therefore, immunotherapy may be a new hope for the eradication of mCRPC. The autologous activated DC vaccine Sipuleucel-T is currently the only immunotherapy that has shown a survival benefit in mCRPC, and other immunotherapies are urgently needed. Investigators are also exploring more CAR therapies in advanced solid malignancies.

There are two ongoing clinical trials for PSCA-targeted CAR T cell therapies, both aiming at metastatic castration-resistant prostate cancer (Table 1). The results are worth waiting for because the safety and therapeutic efficacy of PSCA-CAR T-cells were successfully proven in an animal experience with the observation of activated and enhanced long-term anti-tumor immunity and no toxicities.

Another animal study demonstrated the potency of a PSCA-targeted CAR natural killer (NK) cell to treat human pancreatic cancer (PC) in mice engrafted with human PC and showed significantly prolonged survival.

Table 1. Ongoing PSCA-Targeted CAR Cell Therapy Clinical Trials

References

1. Gu, Z., et al. "Prostate stem cell antigen (PSCA) expression increases with high gleason score, advanced stage and bone metastasis in prostate cancer." Oncogene 19.10 (2000): 1288-1296.
2. Jensen, Majbrit M., et al. "Prostate stem cell antigen interacts with nicotinic acetylcholine receptors and is affected in Alzheimer's disease." Neurobiology of aging 36.4 (2015): 1629-1638.
3. Li, Ermao, et al. "PSCA promotes prostate cancer proliferation and cell‐cycle progression by up‐regulating c‐Myc." The Prostate 77.16 (2017): 1563-1572.
4. Liu, Luhao, et al. "PSCA regulates IL‐6 expression through p38/NF‐κB signaling in prostate cancer." The Prostate 77.14 (2017): 1389-1400.
5. Murad, John P., et al. "Pre-conditioning modifies the TME to enhance solid tumor CAR-T cell efficacy and endogenous protective immunity." Molecular Therapy 29.7 (2021): 2335-2349.
6. Teng, Kun-Yu, et al. "Off-the-Shelf Prostate Stem Cell Antigen–Directed Chimeric Antigen Receptor Natural Killer Cell Therapy to Treat Pancreatic Cancer." Gastroenterology 162.4 (2022): 1319-1333.