Abstract: In recent years, the, chimeric antigen receptor T (CAR-T) cell therapy as an adoptive immunotherapy has received great attention and made great breakthroughs. CAR-T cells show great specificity, targeting, and less major histocompatibility complex restriction in tumor immunotherapy, significantly different from traditional T cells. In spite of the progress of CART-T technology in the treatment of lymphoma, leukemia, and other blood system tumor, there are still many difficulties in the treatment of solid tumors by CAR-T technology. In this review, we will make a brief summary of the present situation of CAR-T cells in the treatment of prostate cancer, and discuss the promise of the application of this technology to prostate cancer therapy.
Keywords: prostate cancer, CAR-T cells, adoptive immunotherapy, review
With the improvement of human living standard and the increase of life expectancy, the incidence of prostate cancer in the middle-aged and elderly males is increasing. Prostate cancer has become the most common tumor among males in Europe and the USA.1 Due to the lack of full understanding of the pathogenesis of prostate cancer, most patients are in the middle and late stage when the tumor is diagnosed and miss the best time for surgical therapy. Consequently, prostate cancer has high mortality. Androgen deprivation therapy is effective for the treatment of early stage prostate cancer because of the characteristics of androgen dependence in early development of prostate cancer. However, after androgen deprivation therapy, most of the patients develop castration-resistant prostate cancer (CRPC), which will finally develop into the metastatic castration-resistant prostate cancer (mCRPC).2 The development of mCRPC may be related to androgen receptor gene amplification, and regulatory factors of androgen receptors are abnormally expressed in prostate cancer.3 There is still no effective treatment for patients with CRPC.4
The chimeric antigen receptor T cell (CAR-T) therapy has gained great attention due to the advantages of CAR-T cells in the treatment of malignant tumors of the blood system and has achieved great breakthroughs.5,6 CAR-T technology provides a new way for the treatment of malignant solid tumors including prostate cancer. Up to now, there are only two ongoing clinical trials for prostate cancer CAR-T therapy. One is a Phase I trial of prostate-specific membrane antigen (PSMA)-targeted CAR-T in mCRPC patients (NCT01140373). Another (NCT03089203) is a Phase I trial of “CART-PSMA-TGFβRDN Cells for CRPC” to evaluate the safety and feasibility of intravenously administered, lentivirally transduced, dual PSMA-specific/TGFβ-resistant, CAR-modified autologous T cells (CART-PSMA-TGFβRDN cells) in mCRPC patients.7 However, there are still many difficulties in the treatment of solid tumors by CAR-T technology. In this review, we make a systematic summary of the present situation of CAR-T cells in the treatment of prostate cancer and discuss the promise of the application of this technology to prostate cancer therapy.
The molecular structure of CAR-T
The CARs are fusion proteins constructed by modern molecular biotechnology. CARs are generally composed of three parts: extracellular antigen identification zone, transmembrane zone, and intracellular signal transduction zone.5 The extracellular antigen identification zone is the basis of specific recognition of tumor antigens by CARs.6 Single-chain fragment variable (scFv) of CAR-T cells can recognize tumor-associated antigen (TAA) specifically. The transmembrane zone usually consists of the transmembrane region of CD3, CD8, CD28, or FcεRI and can fix scFv on the surface of T cells and transduce the signal into the cells. The intracellular signal transduction zone is composed of CD8, CD28, or CD137 intracellular area and CD3ζ, which contain the immune-receptor tyrosine-based activation motif (ITAM). ITAM plays a crucial role in the transduction of signal to active T cells.