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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

References

1. Wang, Fujin, et al. "Advances in PSMA-targeted therapy for prostate cancer." Prostate Cancer and Prostatic Diseases 25.1 (2022): 11-26.
2. 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.
3. Kinoshita, Yoshihisa, et al. "Expression of prostate-specific membrane antigen in normal and malignant human tissues." World journal of surgery 30 (2006): 628-636.
4. 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.
5. Heitmann, Jonas S., et al. "Bispecific antibodies in prostate cancer therapy: current status and perspectives." Cancers 13.3 (2021): 549.
6. Rahbar, Kambiz, et al. "PSMA theranostics: current status and future directions." Molecular imaging 17 (2018): 1536012118776068.
7. 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.
8. Sartor, Oliver, et al. "Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer." New England Journal of Medicine 385.12 (2021): 1091-1103.
9. 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.