Overview of PSMA-Targeted CAR Cell Therapies

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Background of PSMA

Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCP2), is a type II transmembrane glycoprotein belonging to the M28 peptidase family, expressed by the folate hydrolase 1 (FOLH1) gene in humans. It possesses both folate hydrolase and N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) activity. The structure of PSMA is a homodimer with a cofactor binding site for two Zn2+ ions per subunit (Fig 1). The cofactor is required for NAALADase activity.

Fig.1 Structure of PSMA

PSMA is highly expressed in prostate epithelium and is also detected in the urinary bladder, kidney, testis, small intestine, colon, and brain. Additionally, its expression in prostate cancer (PCa) tissues increases 100-1000 times compared to that in normal tissues, particularly in poorly differentiated, metastatic, and castration-resistant PCa tissues. PSMA is used as a diagnostic and therapeutic biomarker of prostate cancer and as a possible indicator for various neurological disorders, such as schizophrenia, Alzheimer's disease, and Huntington's disease.

PSMA Signaling Pathways

PSMA is involved in one-carbon metabolism as folate hydrolase. PSMA promotes the uptake and synthesis of folate in the prostate. Intracellular folate is a double-edged sword because a low concentration of folate can increase the susceptibility of chromosomal damage, while a high concentration induces abnormal cell proliferation. This suggests that the high expression of PSMA promotes tumorigenesis and tumor growth in PCa.

Clinical Status of PSMA-Targeted CAR Cell Therapies

Metastatic castration-resistant prostate cancer (mCRPC) is considered to be an immune "cold" tumor, characterized by low lymphocyte infiltration and the predominance of immunosuppressive factors. In the past decade, new therapies for mCRPC have emerged, but all have resulted in drug resistance. The disease is still progressing, and immunotherapy may be the new way out due to the fundamental correction of the immunosuppressed state. At present, 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.

In recent years, chimeric antigen receptor (CAR) cells have demonstrated promising efficacy, and investigators are also exploring more CAR therapies in advanced solid malignancies. Based on the fact that PSMA is highly expressed in PCa, PSMA-targeted CAR cells can target PCa and deliver beta-particle radiation to cancer cells and the tumor microenvironment (TME). Nature Medicine reported results from an in-human phase 1 trial of CAR T cells armored with a dominant-negative TGF-β receptor directed to PSMA (NCT03089203) for metastatic castration-resistant prostate cancer (mCRPC).

Five of the 13 patients developed grade ≥ 2 cytokine release syndrome (CRS), including one patient who experienced a marked clonal CAR T cell expansion, > 98% reduction in prostate-specific antigen (PSA) before death with concurrent sepsis. Three additional patients achieved a PSA reduction of ≥ 30%, with CAR T cell failure accompanied by upregulation of multiple TME-localized inhibitory molecules following adoptive cell transfer. Researchers suggest that future studies should use superior multipronged approaches against the TME to improve outcomes.

By far, PSMA-targeted CAR cell therapies have not entered the stage of approval, still with 17 pre-market clinical trials (Table 1, seen in the appendix). But PSMA has already been proven to be an ideal antigen target in prostate cancer in many other therapies, particularly the prominent success in PSMA-targeted radioligand therapy.

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

NCT Number

Title

Status

Conditions

Sponsor/Collaborators

Phases

NCT03198052	GPC3/Mesothelin/Claudin18.2/GUCY2C/B7-H3/PSCA/PSMA/MUC1/TGFβ/HER2/Lewis-Y/AXL/EGFR-CAR-T Cells Against Cancers	Recruiting	Lung Cancer\|Cancer\|Immunotherapy\|CAR-T Cell	Second Affiliated Hospital of Guangzhou Medical University\|Hunan Zhaotai Yongren Medical Innovation Co. Ltd.\|Guangdong Zhaotai InVivo Biomedicine Co. Ltd.	Phase 1
NCT05354375	Clinical Study of PSMA-targeted CAR-T Cells in the Treatment of Castration-resistant Prostate Cancer	Recruiting	Immunotherapy	The Affiliated Hospital of Xuzhou Medical University\|Xuzhou Medical University	Phase 1
NCT04249947	P-PSMA-101 CAR-T Cells in the Treatment of Subjects With Metastatic Castration-Resistant Prostate Cancer (mCRPC) and Advanced Salivary Gland Cancers (SGC)	Active, not recruiting	Prostatic Neoplasms, Castration-Resistant\|Neoplasms by Histologic Type\|Neoplasms, Prostate\|Prostate Cancer\|Metastatic Castration-resistant Prostate Cancer\|Neoplasms\|Prostatic Neoplasms\|Genital Neoplasms, Male\|Urogenital Neoplasms\|Neoplasms by Site\|Prostatic Disease\|Salivary Gland Cancer\|Salivary Gland Tumor\|Adenoid Cystic Carcinoma\|Salivary Duct Carcinoma\|Mucoepidermoid Carcinoma\|Acinic Cell Tumor	Poseida Therapeutics, Inc.	Phase 1
NCT05437341	PSMA/CD70 Bi-specific CAR-T Cell Therapy	Recruiting	Cancer Disease	Shenzhen Geno-Immune Medical Institute	Phase 1\|Phase 2
NCT04429438	Multi-CAR-T Cells Targeting B Cell Lymphomas	Recruiting	B Cell Lymphoma (BCL)	Shenzhen Geno-Immune Medical Institute\|The Seventh Affiliated Hospital of Sun Yat-sen University\|Shenzhen Children's Hospital	Phase 1\|Phase 2
NCT05437315	GD2/PSMA Bi-specific CAR-T Cell Therapy	Recruiting	Solid Tumor	Shenzhen Geno-Immune Medical Institute	Phase 1\|Phase 2
NCT04637503	4SCAR-T Therapy Targeting GD2, PSMA and CD276 for Treating Neuroblastoma	Recruiting	Neuroblastoma	Shenzhen Geno-Immune Medical Institute\|Shenzhen Children's Hospital	Phase 1\|Phase 2
NCT04429451	PSMA-specific CAR-T Cell Therapy	Recruiting	PSMA Positive Tumors or Tumor Tissues	Shenzhen Geno-Immune Medical Institute\|Shenzhen Children's Hospital\|The Seventh Affiliated Hospital of Sun Yat-sen University\|Shenzhen Hospital of Southern Medical University	Phase 1\|Phase 2
NCT04768608	PD1 Integrated Anti-PSMA CAR-T in Treating Patients With Castrate-Resistant Prostate Cancer	Recruiting	Castrate-Resistant Prostate Cancer	Zhejiang University\|Bioray Laboratories	Phase 1
NCT04227275	A Study of CART-PSMA-TGFβRDN in Patients With Metastatic Castration Resistant Prostate Cancer	Active, not recruiting	Metastatic Castration-resistant Prostate Cancer	Tmunity Therapeutics	Phase 1
NCT03692663	Study of Anti-PSMA CAR NK Cell (TABP EIC) in Metastatic Castration-Resistant Prostate Cancer	Recruiting	Metastatic Castration-resistant Prostate Cancer	Allife Medical Science and Technology Co., Ltd.\|Tianjin People's Hospital	Early Phase 1
NCT05489991	A Study of TmPSMA-02 Chimeric Antigen Receptor (CAR) T-cells in Patients With Metastatic Castration Resistant Prostate Cancer (mCRPC)	Active, not recruiting	Metastatic Castration-resistant Prostate Cancer	Tmunity Therapeutics	Phase 1\|Phase 2
NCT04053062	LIGHT-PSMA-CART in Treating Patients With Castrate-Resistant Prostate Cancer	Suspended	Castrate-Resistant Prostate Cancer	Bioray Laboratories\|Changhai Hospital	Phase 1
NCT03089203	CART-PSMA-TGFβRDN Cells for Castrate-Resistant Prostate Cancer	Recruiting	Prostate Cancer	University of Pennsylvania	Phase 1
NCT05656573	CART-PSMA Cells for Advanced Prostate Cancer	Recruiting	Prostate Cancer	Nova Therapeutics LLC\|Chinese PLA General Hospital	Phase 1
NCT04633148	Dose-escalating Trial With UniCAR02-T Cells and PSMA Target Module (TMpPSMA) in Patients With Progressive Disease After Standard Systemic Therapy in Cancers With Positive PSMA Marker	Recruiting	Prostate Cancer	AvenCell Europe GmbH\|PHARMALOG Institut für klinische Forschung GmbH	Phase 1
NCT01140373	Adoptive Transfer of Autologous T Cells Targeted to Prostate Specific Membrane Antigen (PSMA) for the Treatment of Castrate Metastatic Prostate Cancer (CMPC)	Active, not recruiting	Prostate Cancer	Memorial Sloan Kettering Cancer Center\|United States Department of Defense	Phase 1

References

Wang, Fujin, et al. "Advances in PSMA-targeted therapy for prostate cancer." Prostate Cancer and Prostatic Diseases 25.1 (2022): 11-26.
Davis, Mindy I., et al. "Crystal structure of prostate-specific membrane antigen, a tumor marker and peptidase." Proceedings of the National Academy of Sciences 102.17 (2005): 5981-5986.
Kinoshita, Yoshihisa, et al. "Expression of prostate-specific membrane antigen in normal and malignant human tissues." World journal of surgery 30 (2006): 628-636.
Giraudet, Anne-Laure, et al. "PSMA targeting in metastatic castration-resistant prostate cancer: where are we and where are we going?." Therapeutic Advances in Medical Oncology 13 (2021): 17588359211053898.
Heitmann, Jonas S., et al. "Bispecific antibodies in prostate cancer therapy: current status and perspectives." Cancers 13.3 (2021): 549.
Rahbar, Kambiz, et al. "PSMA theranostics: current status and future directions." Molecular imaging 17 (2018): 1536012118776068.
O’Keefe, Denise S., et al. "A perspective on the evolving story of PSMA biology, PSMA-based imaging, and endoradiotherapeutic strategies." Journal of Nuclear Medicine 59.7 (2018): 1007-1013.
Sartor, Oliver, et al. "Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer." New England Journal of Medicine 385.12 (2021): 1091-1103.
de Bono, Johann S., et al. "Phase I Study of MEDI3726: A Prostate-Specific Membrane Antigen-Targeted Antibody–Drug Conjugate, in Patients with mCRPC after Failure of Abiraterone or Enzalutamide." Clinical Cancer Research 27.13 (2021): 3602-3609.