One article to understand: Prostate tumor-associated antigen T cell targeted therapy

‍‍Metastatic castration-resistant prostate cancer (mCRPC) is still a fatal disease
.

Although many new therapies have been developed in the past decade, all therapies will eventually become resistant and the disease will progress
.

mCRPC is considered a "cold" tumor, characterized by less lymphocyte infiltration and predominance of immunosuppressive factors (including myeloid-derived suppressor cells)
.

Autologous activated cell therapy Sipuleucel-T is currently the only immunotherapy that has shown survival benefits in mCRPC
.

Therefore, other immunotherapies are urgently needed
.

In recent years, the "redirect" T lymphocyte new immunotherapy has attracted great attention from researchers
.

In particular, both chimeric antigen receptor modified T cells (CAR-T) and bispecific antibodies (for example, bispecific T cell adaptor [BiTE]) have shown good application prospects in hematological malignancies
.

Figure BiTE antibody (A, B) and CAR-T therapy (C, D) mechanism of action.
Clinical studies have shown that BiTE and CAR-T cell therapy have shown long-lasting anti-tumor effects in various refractory hematological malignancies Clinically active, a variety of therapies have been approved by the FDA for clinical use
.

Based on this, researchers are also exploring more "T cell-directed" therapies with a view to the treatment of advanced solid malignant tumors
.

In recent years, based on the characteristics of mCRPC, CAR-T cell therapy and BiTE therapy have become hot research areas for mCRPC therapy
.

This article mainly introduces the prostate cancer-related antigens related to cellular immunotherapy and the current status of clinical research
.

Prostate Stem Cell Antigen (PSCA) PSCA is a glycoprotein anchored on the cell membrane surface through glycosyl phosphatidylinositol (GPI).
It belongs to the Thy-1/Ly-6 family and was identified as being high on the surface of prostate cells in 1998.
Express
.

PSCA is expressed in up to 94% of primary prostate cancer and 87.
5%~100% of prostate cancer metastases (Table 1)
.

Table 1 Tumor-associated antigens are expressed in prostate cancer and normal tissues.
PSCA expression in tumors is related to prostate cancer disease progression and prognosis
.

Currently, PSCA has been explored as a target for PET imaging (used for tumor detection, staging, and monitoring)
.

Based on the results of preclinical research, there have been two clinical studies of CAR-T therapy targeting PSCA
.

Other T-cell targeted immunotherapies targeting PSCA are also undergoing preclinical research
.

Currently, there is no relevant clinical research on BiTE therapy targeting PSCA
.

Table 2 Clinical studies related to CAR-T and BiTE therapy in prostate cancer.
Prostate-specific membrane antigen (PSMA) PSMA is a type II transmembrane protein.
In the past 30 years, it has been explored for disease biomarkers, in vivo imaging and Specific therapeutic target for prostate cancer disease
.

Under normal physiological conditions, PSMA is low-expressed to varying degrees in prostate, kidney, glial cells of the nervous system, salivary gland cells and small intestine
.

However, PSMA is highly expressed in malignant prostate tissue and is associated with prostate cancer disease progression and higher histological grade
.

The high expression of PSMA can be used as a biomarker of prostate cancer progression.
It is independently related to the recurrence of prostate specific antigen (PSA) after local treatment, and is related to the development of castration-resistant prostate cancer
.

Due to its high expression and membrane binding properties, PSMA is considered to be an ideal tumor-associated antigen for targeted therapy of prostate cancer
.

It is worth noting that PSMA is expressed in malignant tumors rich in tumor angiogenesis (such as renal cell carcinoma and adenoid cystic carcinoma), so PSMA targeted therapy is also promising for other solid tumors
.

The emergence of small molecule PSMA ligands represents the coming of the era of PSMA targeted PET imaging drug therapy
.

68Ga-labeled (for example: Ga-68 PSMA-11) and 18F-labeled (for example: DCFPyL) PSMA ligands have advantages in biochemically recurring prostate cancer, negative or ambiguous routine imaging, and even detection in patients with low PSA levels
.

PSMA imaging paves the way for the treatment strategy of mCRPC patients-confirming the expression of the target antigen by radiology and giving a therapeutic dose of radiopharmaceutical
.

The radiolabeled PSMA ligand (177Lu-PSMA-617) has shown significant anti-tumor activity in patients with refractory mCRPC
.

At the ASCO conference this year, a large phase III randomized trial proved that 177Lu-PSMA-617+ standard treatment compared with standard treatment significantly improved the progression-free survival (PFS) and overall survival (OS) of mCRPC patients with at least one PSMA PET-avid lesion
.

A phase I study evaluated BiTE therapy targeting PSMA, which was initially developed according to a standard formulation and required continuous intravenous infusion of AMG212 (pasotuxizumab)
.

The study showed that 47 patients had decreased PSA, and 2 of them had a long-term response
.

Subsequent researchers developed AMG160 with a prolonged half-life.
The phase I study showed that in 24 evaluable patients, AMG160 could reduce PSA50 in 6 patients, and in 18 measurable lesions, 1 patient experienced objective remission (radiation).
Scientifically confirmed), 2 patients had disease control for 1 year
.

Most toxic reactions are predictable
.

See Table 2 for other ongoing clinical studies
.

STEAP1STEAP1 is a member of the six-segment transmembrane epithelial antigen of prostate (STEAP) family.
STEAP acts as an ion channel at cell junctions and plays a role of metal reductase
.

STEAP-1 has been shown to be highly expressed in prostate cancer
.

Under normal physiological conditions, STEAP-1 is low expressed in bladder, ovary, bone marrow, heart and lung tissues
.

In terms of diagnostic value, 89Zr-DFO-MSTP2109A is a radiolabeled antibody targeting STEAP1, which is well tolerated and shows excellent visualization effects in bones and soft tissues of mCRPC patients, so it can be used as STEAP-1 targeted therapy Potential predictive biomarkers
.

STEAP1 is also immunogenic
.

Preclinical studies have shown that STEAP1-derived peptides can induce the generation of CD8+T toxic cells in specific cells
.

Studies have also shown that vaccines targeting STEAP1 also show anti-tumor activity
.

Since STEAP1 is mainly expressed on the cell surface, researchers are also exploring BiTE therapy targeting STEAP1.
The relevant clinical studies are shown in Table 2
.

Current immunotherapies have failed to show a durable response in patients with advanced prostate cancer, and more effective T cell-directed therapies may be needed to overcome immune rejection and suppressive immune microenvironment
.

PSCA, PSMA, STEAP-1, etc.
may be better "partners" for CAR-T therapy or bispecific antibody therapy
.

With the announcement of the research results, understanding the functions and properties of these targets and their different efficacy and toxicity results is the key to pushing these therapies into clinical practice
.

References Dorff TB, Narayan V, Forman SJ, et al.
Novel Redirected T-Cell Immunotherapies for Advanced Prostate Cancer.
Clin Cancer Res.
2021 Oct 21.
doi: 10.
1158/1078-0432.
CCR-21-1483.
Epub ahead of print.
PMID: 34675084.
‍‍