PSMA-Specific CAR-Engineered T Cells Eradicate Disseminated Prostate Cancer in Preclinical Models

Zuccolotto, Gaia; Fracasso, Giulio; Merlo, Anna; Montagner, Isabella Monia; Rondina, Maria; Bobisse, Sara; Figini, Mariangela; Cingarlini, Sara; Colombatti, Marco; Zanovello, Paola; Rosato, Antonio

doi:10.1371/journal.pone.0109427

Cited by 65 publications

(68 citation statements)

References 44 publications

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“…Several prostate tumor models, both human and murine origins, have been described and used to study the targeting of hPSMA-CAR T cells, but some limitations have been identified 21, 24, 48, 49. We focused on murine cell lines, with prospective to utilize them in a syngeneic mouse model using immunocompetent mice.…”

Section: Resultsmentioning

confidence: 99%

“…Oncol., abstract). It has been shown that adoptive transfer of T cells modified with the anti-hPSMA CAR could specifically mediate regression of pulmonary experimental lung metastasis in SCID mice 21, 24, 49. However, this approach was ineffective against established subcutaneous tumors, 49 unless the CAR T cells were injected locally 49 …”

Section: Discussionmentioning

confidence: 99%

“…Our initial efforts to evaluate the effectiveness of second-generation anti-hPSMA CAR T cells24, 53 were comparable to that of others (Figure S2). 49 Namely, anti-hPSMA CAR T cell therapy alone was not effective against established subcutaneous Myc-Cap hPSMA(+) tumors. Nevertheless, a Winn assay 55 demonstrated that anti-hPSMA CAR T cells can inhibit Myc-CaP:hPSMA(+) tumor growth in a scarce nutrient microenvironment, and that this inhibition is hPSMA dependent.…”

Section: Discussionmentioning

confidence: 99%

“…administered CAR T cells is well known 49, 67. Nevertheless, the persistence of CAR T cells is well documented in the treatment of many “liquid” tumors,68, 69, 70 whereas the persistence of CAR T cells is not a common finding in the treatment of solid tumors 71 .…”

Section: Discussionmentioning

confidence: 99%

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Enhancement of PSMA-Directed CAR Adoptive Immunotherapy by PD-1/PD-L1 Blockade

Serganova

Мороз

Cohen

et al. 2017

Molecular Therapy - Oncolytics

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Chimeric antigen receptor (CAR) T cell therapy in hematologic malignancies has shown remarkable responses, but the same level of success has not been observed in solid tumors. A new prostate cancer model (Myc-CaP:PSMA(+)) and a second-generation anti-hPSMA human CAR T cells expressing a Click Beetle Red luciferase reporter) were used to study hPSMA targeting and assess CAR T cell trafficking and persistence by bioluminescence imaging (BLI). We investigated the antitumor efficacy of human CAR T cells targeting human prostate-specific membrane antigen (hPSMA), in the presence and absence of the target antigen; first alone and then combined with a monoclonal antibody targeting the human programmed death receptor 1 (anti-hPD1 mAb). PDL-1 expression was detected in Myc-CaP murine prostate tumors growing in immune competent FVB/N and immune-deficient SCID mice. Endogenous CD3+ T cells were restricted from the centers of Myc-CaP tumor nodules growing in FVB/N mice. Following anti-programmed cell death protein 1 (PD-1) treatment, the restriction of CD3+ T cells was reversed, and a tumor-treatment response was observed. Adoptive hPSMA-CAR T cell immunotherapy was enhanced when combined with PD-1 blockade, but the treatment response was of comparatively short duration, suggesting other immune modulation mechanisms exist and restrict CAR T cell targeting, function, and persistence in hPSMA expressing Myc-CaP tumors. Interestingly, an “inverse pattern” of CAR T cell BLI intensity was observed in control and test tumors, which suggests CAR T cells undergo changes leading to a loss of signal and/or number following hPSMA-specific activation. The lower BLI signal intensity in the hPSMA test tumors (compared with controls) is due in part to a decrease in T cell mitochondrial function following T cell activation, which may limit the intensity of the ATP-dependent Luciferin-luciferase bioluminescence signal.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Enhancement of PSMA-Directed CAR Adoptive Immunotherapy by PD-1/PD-L1 Blockade

Serganova

Мороз

Cohen

et al. 2017

Molecular Therapy - Oncolytics

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show abstract

“…The TM domain is usually derived from CD3ζ [74], CD4 [75,76], CD8 [47,60,68], or CD28 [70,75,77] molecules and is inserted between the hinge region and the signaling endodomains. It has significant effects on the cell surface expression of CARs.…”

Section: Car Hinge and Transmembranementioning

confidence: 99%

CARTs for Solid Tumors: Feasible or Infeasible?

Song²,

Jin

et al. 2017

Oncol Res Treat

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Adoptive transfer of chimeric antigen receptor-engineered T cells (CARTs) is a novel approach to cancer therapy as CARTs combine with the antigen specificity of an antibody and the activating functions of T lymphocytes. Recent results from preclinical and clinical trials with CARTs for B-cell malignancies are exciting, although different groups selected different tumor-associated antigens, binding domains, and signal domains, which make up the chimeric antigen receptor (CAR) configuration. However, there are few clinical trials with CARTs for solid tumors compared to hematologic malignancies. In this brief review, we discuss the basic principles of CAR design and clinical studies of CARTs for solid tumors.

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Combined treatment with anti‐PSMA CAR NK‐92 cell and anti‐PD‐L1 monoclonal antibody enhances the antitumour efficacy against castration‐resistant prostate cancer

Wang

Yin³

et al. 2022

Clinical & Translational Med

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Background The chimeric antigen receptor NK‐92 (CAR NK‐92) cell targeting the prostate‐specific membrane antigen (PSMA) has shown antitumour effects in castration‐resistant prostate cancer (CRPC). However, the expression changes of programmed death ligand 1 (PD‐L1) and its mechanisms on CAR NK‐92 and CRPC cells and the effect of the anti‐PD‐L1 monoclonal antibody (mAb) on PD‐L1 expressed on CAR NK‐92 cells remain unknown. Methods Human dendritic cells and CD8 + T cells were acquired from blood samples of healthy donors and cocultured with C4‐2 cells. Changes in PD‐L1 expression were detected by flow cytometry. Differential gene expressions were investigated by RNA sequence analysis, while the regulation of PD‐L1 molecular signaling was explored using western blotting. In vitro cytotoxicity was evaluated using the Cell Counting Kit‐8 assay and the bioluminescent intensity (BLI) of green fluorescent protein‐labelled C4‐2 cells. CRPC growth in vivo was monitored using callipers and BLI in male NOD/SCID mice subcutaneously injected with C4‐2 cells and treated intravenously with anti‐PD‐L1/PD‐1 mAb, CAR NK‐92 or cocultured CD8 + T cells. Results Significantly upregulated expression of PD‐L1k was observed in cocultured C4‐2 and CAR NK‐92 cells. In addition, upregulation of PD‐L1 expression was dependent on interferon‐γ in C4‐2 cells, while it was dependent on direct cell‐to‐cell interaction via the NK group 2 member D/ phosphatidylinositol 3‐kinase/AKT pathway in CAR NK‐92 cells. The anti‐PD‐L1 mAb directly acted on PD‐L1 expressed on CAR NK‐92 cells and augmented the cytotoxicity of CAR NK‐92 cells against C4‐2 and CRPC cells from one patient in vitro. Anti‐PD‐L1 mAb significantly enhanced the antitumour effect of CAR NK‐92 cells against CRPC cells in vivo when compared to treatment with CAR NK‐92 cells or combined with anti‐PD‐1 mAb in the absence or presence of cocultured CD8 + T cells. Conclusion Combined treatment with CAR NK‐92 and anti‐PD‐L1 mAb improved the antitumour efficacy against CRPC, which is of extraordinary translational value in the clinical treatment of CRPC.

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PSMA-Specific CAR-Engineered T Cells Eradicate Disseminated Prostate Cancer in Preclinical Models

Cited by 65 publications

References 44 publications

Enhancement of PSMA-Directed CAR Adoptive Immunotherapy by PD-1/PD-L1 Blockade

Enhancement of PSMA-Directed CAR Adoptive Immunotherapy by PD-1/PD-L1 Blockade

CARTs for Solid Tumors: Feasible or Infeasible?

Combined treatment with anti‐PSMA CAR NK‐92 cell and anti‐PD‐L1 monoclonal antibody enhances the antitumour efficacy against castration‐resistant prostate cancer

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