CAR-T Cells and Oncolytic Viruses: Joining Forces to Overcome the Solid Tumor Challenge

AbstractMalignant mesothelioma (MM) is a treatment-resistant tumor originating in the mesothelial lining of the pleura or the abdominal cavity with very limited treatment options. More effective therapeutic approaches are urgently needed to improve the poor prognosis of MM patients. Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a novel potential treatment for this incurable solid tumor. The tumor-associated antigen mesothelin (MSLN) is an attractive target for cell therapy in MM, as this antigen is expressed at high levels in the diseased pleura or peritoneum in the majority of MM patients and not (or very modestly) present in healthy tissues. Clinical trials using anti-MSLN CAR T cells in MM have shown that this potential therapeutic is relatively safe. However, efficacy remains modest, likely due to the MM tumor microenvironment (TME), which creates strong immunosuppressive conditions and thus reduces anti-MSLN CAR T cell tumor infiltration, efficacy and persistence. Various approaches to overcome these challenges are reviewed here. They include local (intratumoral) delivery of anti-MSLN CAR T cells, improved CAR design and co-stimulation, and measures to avoid T cell exhaustion. Combination therapies with checkpoint inhibitors as well as oncolytic viruses are also discussed. Preclinical studies have confirmed that increased efficacy of anti-MSLN CAR T cells is within reach and offer hope that this form of cellular immunotherapy may soon improve the prognosis of MM patients.

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Combination therapy with CAR T cells and oncolytic viruses: a new era in cancer immunotherapy

Cancer Gene Therapy ◽

10.1038/s41417-021-00359-9 ◽

2021 ◽

Author(s):

Ramazan Rezaei ◽

Hadi Esmaeili Gouvarchin Ghaleh ◽

Mahdieh Farzanehpour ◽

Ruhollah Dorostkar ◽

Reza Ranjbar ◽

...

Keyword(s):

T Cells ◽

Combination Therapy ◽

Cancer Immunotherapy ◽

Oncolytic Viruses ◽

New Era ◽

Car T Cells ◽

Car T

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SynNotch CAR circuits enhance solid tumor recognition and promote persistent antitumor activity in mouse models

Science Translational Medicine ◽

10.1126/scitranslmed.abd8836 ◽

2021 ◽

Vol 13 (591) ◽

pp. eabd8836

Author(s):

Axel Hyrenius-Wittsten ◽

Yang Su ◽

Minhee Park ◽

Julie M. Garcia ◽

Josef Alavi ◽

...

Keyword(s):

Ovarian Cancer ◽

T Cells ◽

T Cell ◽

Antitumor Activity ◽

Solid Tumors ◽

Mouse Models ◽

Solid Tumor ◽

Car T Cells ◽

Therapeutic Benefits ◽

Car T

The first clinically approved engineered chimeric antigen receptor (CAR) T cell therapies are remarkably effective in a subset of hematological malignancies with few therapeutic options. Although these clinical successes have been exciting, CAR T cells have hit roadblocks in solid tumors that include the lack of highly tumor-specific antigens to target, opening up the possibility of life-threatening “on-target/off-tumor” toxicities, and problems with T cell entry into solid tumor and persistent activity in suppressive tumor microenvironments. Here, we improve the specificity and persistent antitumor activity of therapeutic T cells with synthetic Notch (synNotch) CAR circuits. We identify alkaline phosphatase placental-like 2 (ALPPL2) as a tumor-specific antigen expressed in a spectrum of solid tumors, including mesothelioma and ovarian cancer. ALPPL2 can act as a sole target for CAR therapy or be combined with tumor-associated antigens such as melanoma cell adhesion molecule (MCAM), mesothelin, or human epidermal growth factor receptor 2 (HER2) in synNotch CAR combinatorial antigen circuits. SynNotch CAR T cells display superior control of tumor burden when compared to T cells constitutively expressing a CAR targeting the same antigens in mouse models of human mesothelioma and ovarian cancer. This was achieved by preventing CAR-mediated tonic signaling through synNotch-controlled expression, allowing T cells to maintain a long-lived memory and non-exhausted phenotype. Collectively, we establish ALPPL2 as a clinically viable cell therapy target for multiple solid tumors and demonstrate the multifaceted therapeutic benefits of synNotch CAR T cells.

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Inducible Activation of MyD88 and CD40 in CAR T Cells Results in Controllable and Potent Antitumor Activity in Preclinical Solid Tumor Models

Cancer Discovery ◽

10.1158/2159-8290.cd-17-0263 ◽

2017 ◽

Vol 7 (11) ◽

pp. 1306-1319 ◽

Cited By ~ 43

Author(s):

Melinda Mata ◽

Claudia Gerken ◽

Phuong Nguyen ◽

Giedre Krenciute ◽

David M. Spencer ◽

...

Keyword(s):

T Cells ◽

Antitumor Activity ◽

Solid Tumor ◽

Tumor Models ◽

Car T Cells ◽

Car T ◽

Inducible Activation

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BOXR1030, an anti-GPC3 CAR with exogenous GOT2 expression, shows enhanced T cell metabolism and improved antitumor activity

10.1101/2021.11.17.469041 ◽

2021 ◽

Author(s):

Taylor L Hickman ◽

Eugene Choi ◽

Kathleen R Whiteman ◽

Sujatha Muralidharan ◽

Tapasya Pai ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Antitumor Activity ◽

Solid Tumor ◽

Cell Function ◽

Cell Metabolism ◽

Car T Cells ◽

Car T

Purpose: The solid tumor microenvironment (TME) drives T cell dysfunction and inhibits the effectiveness of immunotherapies such as chimeric antigen receptor-based T cell (CAR T) cells. Early data has shown that modulation of T cell metabolism can improve intratumoral T cell function in preclinical models. Experimental Design: We evaluated GPC3 expression in human normal and tumor tissue specimens. We developed and evaluated BOXR1030, a novel CAR T therapeutic co-expressing glypican-3 (GPC3)-targeted CAR and exogenous glutamic-oxaloacetic transaminase 2 (GOT2) in terms of CAR T cell function both in vitro and in vivo. Results: Expression of tumor antigen GPC3 was observed by immunohistochemical staining in tumor biopsies from hepatocellular carcinoma, liposarcoma, squamous lung cancer, and Merkel cell carcinoma patients. Compared to control GPC3 CAR alone, BOXR1030 (GPC3-targeted CAR T cell that co-expressed GOT2) demonstrated superior in vivo efficacy in aggressive solid tumor xenograft models, and showed favorable attributes in vitro including an enhanced cytokine production profile, a less-differentiated T cell phenotype with lower expression of stress and exhaustion markers, an enhanced metabolic profile and increased proliferation in TME-like conditions. Conclusions: Together, these results demonstrated that co-expression of GOT2 can substantially improve the overall antitumor activity of CAR T cells by inducing broad changes in cellular function and phenotype. These data show that BOXR1030 is an attractive approach to targeting select solid tumors. To this end, BOXR1030 will be explored in the clinic to assess safety, dose-finding, and preliminary efficacy (NCT05120271).

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The tumor vasculature an attractive CAR T cell target in solid tumors

Angiogenesis ◽

10.1007/s10456-019-09687-9 ◽

2019 ◽

Vol 22 (4) ◽

pp. 473-475 ◽

Cited By ~ 4

Author(s):

Parvin Akbari ◽

Elisabeth J. M. Huijbers ◽

Maria Themeli ◽

Arjan W. Griffioen ◽

Judy R. van Beijnum

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Microenvironment ◽

Solid Tumors ◽

Solid Tumor ◽

Hematological Malignancies ◽

Tumor Vasculature ◽

Car T Cells ◽

Car T Cell ◽

Car T

Abstract T cells armed with a chimeric antigen receptor, CAR T cells, have shown extraordinary activity against certain B lymphocyte malignancies, when targeted towards the CD19 B cell surface marker. These results have led to the regulatory approval of two CAR T cell approaches. Translation of this result to the solid tumor setting has been problematic until now. A number of differences between liquid and solid tumors are likely to cause this discrepancy. The main ones of these are undoubtedly the uncomplicated availability of the target cell within the blood compartment and the abundant expression of the target molecule on the cancerous cells in the case of hematological malignancies. Targets expressed by solid tumor cells are hard to engage due to the non-adhesive and abnormal vasculature, while conditions in the tumor microenvironment can be extremely immunosuppressive. Targets in the tumor vasculature are readily reachable by CAR T cells and reside outside the immunosuppressive tumor microenvironment. It is therefore hypothesized that targeting CAR T cells towards the tumor vasculature of solid tumors may share the excellent effects of CAR T cell therapy with that against hematological malignancies. A few reports have shown promising results. Suggestions are provided for further improvement.

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