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IL-23 and PSMA-targeted duo-CAR T cells in Prostate Cancer Eradication in a preclinical model.

ABSTRACT: BACKGROUND:Prostate cancer is one of the most common adult malignancies in men, and nearly all patients with metastatic prostate cancer can develop and receive resistance to primary androgen deprivation therapy (ADT), a state known as metastatic castration-resistant prostate cancer (mCRPC). Recent reports demonstrated the great breakthroughs made by the chimeric antigen receptor T (CAR-T) cell therapy, which is significantly different from traditional T cells therapies. In spite of the progress of CAR-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. METHODS:In this report, we designed a panel of IL23mAb-PSMA-CARs, including PSMA-CAR, IL23mAb-T2A-PSMA-CAR, IL23mAb-PSMA-CAR, and PSMA-CAR (soluble IL23mAb). And we studied the function of these CARs in mice model. RESULTS:Co-culture experiments with different CAR T cells have normal lysis function in vitro. The duo-CAR T cells co-expressing the IL-23mAb and PSMA-mAb had a significant higher population than the rest three different CAR T cells in co-culturing experiments at day 28, 35 and 42. A panel of cytokines were differentially secreted at higher amounts in IL23mAb-T2A-PSMA-CAR T cells than CAR T cells in other groups. In NOD/SCID IL-2 gamma (NSG) mice model, IL23mAb-T2A-PSMA-CAR T cells functioned significantly better than CAR T cells from the other groups and eradicated the tumor from these mice starting at day 14 post T cells injection and regained the body weight immediately. In IL23mAb-T2A-PSMA-CAR mice, CD45RO+ CD8+ T cells and CD127+ CD4+ CAR T cells were significantly increased. RNA sequencing revealed a difference expression pattern of genes in IL23mAb-T2A-PSMA-CAR mice. A reverse infusion experiment under the same model further proved the tumor eradication function of IL23mAb-T2A-PSMA-CAR T cells. CONCLUSIONS:We found that IL-23mAb combined PSMA CARs worked better than PSMA CAR only in Prostate Cancer Eradication, and we further discussed the mechanisms among different IL-23mAb combined PSMA CARs in Prostate Cancer Eradication.

SUBMITTER: Wang D

PROVIDER: S-EPMC6961333 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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IL-23 and PSMA-targeted duo-CAR T cells in Prostate Cancer Eradication in a preclinical model.

Wang Dawei D Shao Yuan Y Zhang Xiang X Lu Guoliang G Liu Boke B

Journal of translational medicine 20200114 1

<h4>Background</h4>Prostate cancer is one of the most common adult malignancies in men, and nearly all patients with metastatic prostate cancer can develop and receive resistance to primary androgen deprivation therapy (ADT), a state known as metastatic castration-resistant prostate cancer (mCRPC). Recent reports demonstrated the great breakthroughs made by the chimeric antigen receptor T (CAR-T) cell therapy, which is significantly different from traditional T cells therapies. In spite of the p ...[more]

PMID: 31937346

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Project description:The prostate-specific membrane antigen (PSMA)-targeted radiotracers 68Ga/177Lu-PSMA-I&T and 99mTc-PSMA-I&S (for i maging and s urgery) are currently successfully used for clinical PET imaging, radionuclide therapy, and radioguided surgery of metastatic prostate cancer. To additionally exploit the high sensitivity and spatial resolution of fluorescence imaging for improved surgical guidance, a PSMA-I&T-based hybrid tracer, PSMA-I&F (DOTAGA-k(Sulfo-Cy5)-y-nal-k-Sub-KuE), has been developed and evaluated. Methods: The in vitro PSMA-targeting efficiency of PSMA-I&F, the reference PSMA-I&T, and their corresponding natGa-/68Ga- and natLu/177Lu counterparts was determined in LNCaP cells via competitive binding assays (IC50) and dual-tracer radioligand and fluorescence internalization studies. Biodistribution and small-animal PET imaging studies were performed in CB17 SCID and LNCaP xenograft-bearing SHO mice, respectively, and complemented by intraoperative far-red fluorescence imaging using a clinical laparoscope. Additionally, fully automated serial cryosectioning and fluorescence imaging of 1 tumor-bearing animal as well as PSMA immunohistochemistry and fluorescence microscopy of organ cryosections (tumor, kidney, spleen) were also performed. Results: Compared with the parent PSMA-I&T analogs, the PSMA affinities of PSMA-I&F and its natGa-/natLu-complexes remained high and unaffected by dye conjugation (7.9 < IC50 < 10.5 nM for all ligands). The same was observed for the internalization of 68Ga- and 177Lu-PSMA-I&F. In vivo, blood clearance of 68Ga- and 177Lu-PSMA-I&F was only slightly delayed by high plasma protein binding (94%-95%), and very low accumulation in nontarget organs was observed already at 1 h after injection. Dynamic PET imaging confirmed PSMA-specific (as demonstrated by coinjection of 2-PMPA) uptake into the LNCaP xenograft (4.5% ± 1.8 percentage injected dose per gram) and the kidneys (106% ± 23 percentage injected dose per gram). Tumor-to-background ratios of 2.1, 5.2, 9.6, and 9.6 for blood, liver, intestines, and muscle, respectively, at 1 h after injection led to excellent imaging contrast in 68Ga-PSMA-I&F PET and in intraoperative fluorescence imaging. Furthermore, fluorescence imaging of tissue cryosections allowed high-resolution visualization of intraorgan PSMA-I&F distribution in vivo and its correlation with PSMA expression as determined by immunohistochemistry. Conclusion: Thus, with its high PSMA-targeting efficiency and favorable pharmacokinetic profile, 68Ga/177Lu-PSMA-I&F serves as an excellent proof-of-concept compound for the general feasibility of PSMA-I&T-based hybrid imaging. The PSMA-I&T scaffold represents a versatile PSMA-targeted lead structure, allowing relatively straightforward adaptation to the different structural requirements of dedicated nuclear or hybrid imaging agents.

Project description:Prostate cancer is the most common cancer among men and the second leading cause of cancer-related deaths in men in the United States. The treatment paradigm for prostate cancer has evolved with the emergence of a variety of novel therapies which have improved survival; however, treatment-related toxicities are abundant and durable responses remain rare. Immune checkpoint inhibitors have shown modest activity in a small subset of patients with prostate cancer and have not had an impact on most men with advanced disease. The discovery of prostate-specific membrane antigen (PSMA) and the understanding of its specificity to prostate cancer has identified it as an ideal tumor-associated antigen and has revived the enthusiasm for immunotherapeutics in prostate cancer. T-cell immunotherapy in the form of bispecific T-cell engagers (BiTEs) and chimeric antigen receptor (CAR) T-cell therapy have shown exceptional success in treating various hematologic malignancies, and are now being tested in patients with prostate cancer with drug design centered on various target ligands including not just PSMA, but others as well including six-transmembrane epithelial antigen of the prostate 1 (STEAP1) and prostate stem cell antigen (PSCA). This summative review will focus on the data surrounding PSMA-targeting T-cell therapies. Early clinical studies with both classes of T-cell redirecting therapies have demonstrated antitumor activity; however, there are multiple challenges with this class of agents, including dose-limiting toxicity, 'on-target, off-tumor' immune-related toxicity, and difficulty in maintaining sustained immune responses within a complex and overtly immunosuppressive tumor microenvironment. Reflecting on experiences from recent trials has been key toward understanding mechanisms of immune escape and limitations in developing these drugs in prostate cancer. Newer generation BiTE and CAR T-cell constructs, either alone or as part of combination therapy, are currently under investigation with modifications in drug design to overcome these barriers. Ongoing innovation in drug development will likely foster successful implementation of T-cell immunotherapy bringing transformational change to the treatment of prostate cancer.

Dataset Information

IL-23 and PSMA-targeted duo-CAR T cells in Prostate Cancer Eradication in a preclinical model.

Publications

IL-23 and PSMA-targeted duo-CAR T cells in Prostate Cancer Eradication in a preclinical model.

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