Challenges and Prospects of Chimeric Antigen Receptor T-cell Therapy for Metastatic Prostate Cancer

Gorchakov, Andrey A.; Kulemzin, Sergey V.; Кочнева, Г. В.; Taranin, Alexander V.

doi:10.1016/j.eururo.2019.08.014

Cited by 43 publications

(30 citation statements)

References 96 publications

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“…5 In recent years, chimeric antigen receptor-T-cell (CAR-T) therapy has been rapidly developed for the treatment of cancer. [6][7][8][9][10] Because of its success in the treatment of CD19 + hematological malignancies, 11 CAR-T therapy has also been used to treat solid tumors, including HCC. 12 However, clinical trials of CAR-T therapy for solid tumors have been disappointing.…”

Section: Introductionmentioning

confidence: 99%

<p>DNAM1 and 2B4 Costimulatory Domains Enhance the Cytotoxicity of Anti-GPC3 Chimeric Antigen Receptor-Modified Natural Killer Cells Against Hepatocellular Cancer Cells in vitro</p>

Huang

Zeng

et al. 2020

CMAR

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Purpose: Hepatocellular cancer (HCC) is the sixth most prevalent cancer and the third leading cause of cancer-related death worldwide. Cellular immunotherapy against glypican 3 (GPC3) has recently been used in the treatment of HCC, following the success of chimeric antigen receptor (CAR)-T therapy in treatment of B cell malignancy. However, CART cells are not "off-the-shelf" and always cause cytokine release syndrome, which can be eliminated by using natural killer (NK) cells as effector cells. Since a costimulatory signal is necessary for the activation, persistence, or cytotoxicity of CART cells, we speculated that the costimulatory signal is also required for CAR-NK cells in HCC treatment. Methods: Five anti-GPC3 CAR plasmids containing different costimulatory domains were constructed. They included Z (only the CD3ζ domain, no costimulatory domain), CD28.Z (T-cell costimulatory domain CD28), DNAM1/2B4.Z (NK-cell-associated costimulatory domain DNAM1 or 2B4), and DNAM1.2B4.Z (both NK-cell-associated costimulatory domains). Respective CAR-NK-92 cells were generated. The MTT viability assay was performed to evaluate the effect of the different costimulatory domains on CAR-NK-cell proliferation. The effect on persistence was analyzed using an apoptosis assay and flow cytometry. Special cytotoxicity against normal hepatocellular cells and GPC3 + malignant cells was investigated in vitro. The concentration of cytokines (TNF-α and IFN-γ) released by CAR-NK-92 cells was also measured by ELISA. Results: NK-cell-associated costimulatory signal was necessary for CAR-NK-92 cells. CAR-NK-92 cells with DNAM1 and/or 2B4 expanded more quickly and persisted with a lower apoptotic ratio, compared to the presence of CD28 or no costimulatory signal. All CAR-NK-92 cells showed special cellular cytotoxicity in vitro. CAR-NK-92 cells with NK-cell-associated costimulatory domains exhibited higher cytotoxic ability compared with those without any costimulatory domain or with T-cell costimulatory domain. CAR-NK-92 cells with both DNAM1 and 2B4 displayed the highest cytotoxicity. The cytokine release assay results were consistent with those of the cytotoxicity assay. Conclusion: We provided the first evidence supporting a strategy using DNAM1 and 2B4 costimulatory domains to generate anti-GPC3 CAR-NK-92 cells, which exhibits enhanced cytotoxicity against hepatocellular cancer cells in vitro.

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Section: Introductionmentioning

confidence: 99%

<p>DNAM1 and 2B4 Costimulatory Domains Enhance the Cytotoxicity of Anti-GPC3 Chimeric Antigen Receptor-Modified Natural Killer Cells Against Hepatocellular Cancer Cells in vitro</p>

Huang

Zeng

et al. 2020

CMAR

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“…CAR T-cell therapy enhances and localizes apoptotic activity in cancer cells by redirecting T-cell killing to malignant cells expressing specific antigens [52]. CAR antigen targeting is mediated by extracellular light and heavy chain immunoglobulins which attach to T-cell receptors, enhancing the activation and persistence of CAR T cells [55,56]. Numerous target antigens have been elucidated for CAR T-cell therapy for malignant tumors, including glypican-3, aberrantly glycosylated proteins, mesothelin, epithelial cell adhesion molecule and prostate stem cell antigens, each of which displays varying degrees of expression in healthy tissue [57].…”

Section: Genetic Modification Of T Cellsmentioning

confidence: 99%

“…Immunological approaches to cervical cancer therapy can radically change the landscape of cancer treatment, as evidenced by recent clinical results where patients achieved remission for more than 10 years [56,81]. The success rate of immunotherapy in cancer patients is limited.…”

Section: Nanomedicine-mediated Cancer Immunotherapymentioning

confidence: 99%

Nanomedicine-Mediated Optimization of Immunotherapeutic Approaches in Cervical Cancer

Venkatas

Singh

2021

Nanomedicine (Lond.)

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Cervical cancer shows immense complexity at the epigenetic, genetic and cellular levels, limiting conventional treatment. Immunotherapy has revolutionized nanomedicine and rejuvenated the field of tumor immunology. Although several immunotherapeutic approaches have shown favorable clinical responses, their efficacies vary, with subsets of patients benefitting. The success of cancer immunotherapy requires the enhancement of cytokines and antitumor effector cell production and activation. Recently, the feasibility of nanoparticle-based cytokine approaches in tumor immunotherapy has been highlighted. Immunotherapeutic nanoparticle-based platforms form a novel strategy enabling researchers to co-deliver immunomodulatory agents, target tumors, improve pharmacokinetics and minimize collateral toxicity to healthy cells. This review looks at the potential of immunotherapy and nanotechnologically enhanced immunotherapeutic approaches for cervical cancer.

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“…Currently, three tumor-associated antigens have been targeted in clinical trials of CAR T-cell therapy for patients with metastatic prostate cancer. In general, patients in these trials have not responded beneficially to any significant degree to CAR T-cell therapy against the prostatespecific membrane antigen (PSMA) and prostate stem cell antigen (PSCA) (19). Clinical trials targeting the third TA, the epithelial cell adhesion molecule (EPCaM), with CAR T cells are currently being conducted and evaluated for several cancers, including prostate cancer (19).…”

Section: Introductionmentioning

confidence: 99%

“…In general, patients in these trials have not responded beneficially to any significant degree to CAR T-cell therapy against the prostatespecific membrane antigen (PSMA) and prostate stem cell antigen (PSCA) (19). Clinical trials targeting the third TA, the epithelial cell adhesion molecule (EPCaM), with CAR T cells are currently being conducted and evaluated for several cancers, including prostate cancer (19). However, as noted above, one challenge in making a CAR T-cell therapy effective for prostate cancer is the choice of the targeted TA.…”

Section: Introductionmentioning

confidence: 99%

Targeting Radiation-Resistant Prostate Cancer Stem Cells by B7-H3 CAR T Cells

Zhang

Sadagopan

et al. 2021

Molecular Cancer Therapeutics

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Radiotherapy (RT) is a key treatment for prostate cancer. However, RT resistance can contribute to treatment failure. Prostate cancer stem cells (PCSCs) are radioresistant. We recently found that fractionated irradiation (FIR) upregulates expression of the immune checkpoint B7-H3 (CD276) on PCSCs and bulk cells in each prostate cancer cell line tested. These findings prompted us to investigate whether B7-H3 targeting chimeric antigen receptor (CAR) T cells, which may abrogate function of an immune checkpoint and mediate lysis of targeted cells, can target RT-resistant PCSCs in vitro and in vivo. B7-H3 expression is naturally higher on PCSCs than bulk prostate cancer cells and cytotoxicity of B7-H3 CAR T cells to PCSCs is more potent than to bulk prostate cancer cells. Furthermore, FIR significantly upregulates B7-H3 expression on PCSCs and bulk prostate cancer cells. The duration of FIR or single-dose irradiation-induced further upregulation of B7-H3 on bulk prostate cancer cells and PCSCs lasts for up to 3 days. B7-H3 CAR T-cell cytotoxicity against FIR-resistant PCSCs at a low effector to target ratio of 1:1 was assessed by flow cytometry and sphere formation assays. Further upregulation of B7-H3 expression by FIR made PCSCs even more sensitive to B7-H3 CAR T-cellmediated killing. Consequently, the FIR and B7-H3 CAR T-cell therapy combination is much more effective than FIR or CAR T cells alone in growth inhibition of hormone-insensitive prostate cancer xenografts in immunodeficient mice. Our work provides a sound basis for further development of this unique combinatorial model of RT and B7-H3 CAR T-cell therapy for prostate cancer.Significance: We demonstrate that FIR significantly upregulates B7-H3 expression by RT-resistant PCSCs and bulk cells; cytotoxicity of B7-H3 CAR T cells to FIR-treated PCSCs is potent and results in significantly improved antitumor efficacy in mice.

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Challenges and Prospects of Chimeric Antigen Receptor T-cell Therapy for Metastatic Prostate Cancer

Cited by 43 publications

References 96 publications

<p>DNAM1 and 2B4 Costimulatory Domains Enhance the Cytotoxicity of Anti-GPC3 Chimeric Antigen Receptor-Modified Natural Killer Cells Against Hepatocellular Cancer Cells in vitro</p>

<p>DNAM1 and 2B4 Costimulatory Domains Enhance the Cytotoxicity of Anti-GPC3 Chimeric Antigen Receptor-Modified Natural Killer Cells Against Hepatocellular Cancer Cells in vitro</p>

Nanomedicine-Mediated Optimization of Immunotherapeutic Approaches in Cervical Cancer

Targeting Radiation-Resistant Prostate Cancer Stem Cells by B7-H3 CAR T Cells

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