Knowns and Unknowns about CAR-T Cell Dysfunction

Titov, Aleksei; Kaminskiy, Yaroslav; Ganeeva, Irina; Zmievskaya, Ekaterina; Valiullina, Aygul; Rakhmatullina, Aygul; Petukhov, Alexey; Miftakhova, Regina; Rizvanov, Albert A.; Bulatov, Emil

doi:10.3390/cancers14041078

Cited by 33 publications

(24 citation statements)

References 203 publications

(262 reference statements)

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“…Thus, the risk of metastasis promotion by CSPG4 upregulation bears little relevance in patients harboring already multiple metastases. Moreover, CSPG4-mediated chemoresistance does even favor the use of immunotherapy, especially CAR-T cells, and no reports on CSPG4-mediated immune-evasion, which could potentially act on pathways known to impair the functionality of CAR-T-cells [ 34 ], have been published. In aggregate, the benefits of generating targetability for CSPG4-CAR-T cells via decitabine treatment clearly outweighs conceivable CSPG4-mediated tumor progress promoting actions.…”

Section: Discussionmentioning

confidence: 99%

Decitabine-Mediated Upregulation of CSPG4 in Ovarian Carcinoma Cells Enables Targeting by CSPG4-Specific CAR-T Cells

Harrer

Schenkel²,

Berking

et al. 2022

Cancers

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The addition of CAR-T cells to the armamentarium of immunotherapy revigorated the field of oncology by inducing long-lasting remissions in patients with relapsing/refractory hematological malignancies. Nevertheless, in the lion’s share of patients diagnosed with solid tumors, CAR-T-cell therapy so far failed to demonstrate satisfactory anti-tumor activity. A crucial cause of resistance against the antigen-specific attack of CAR-T cells is predicated on the primary or secondary absence of suitable target antigens. Thus, the necessity to create a broad repertoire of different target antigens is vital. We aimed to evaluate the potential of the well-established melanoma antigen chondroitin sulfate proteoglycan 4 (CSPG4) as an inducible antigen in ovarian cancer cells, using CSPG4-negative SKOV-3 ovarian cancer cells as a model. Based on the hypomethylating activity of the FDA-approved drug decitabine, we refined a protocol to upregulate CSPG4 in the majority of decitabine-treated SKOV-3 cells. CSPG4-specific CAR-T cells generated by mRNA-electroporation showed CSPG4-directed cytokine secretion and cytotoxicity towards decitabine-treated SKOV-3. Another ovarian cancer cell line (Caov-3) and the neoplastic cell line 293T behaved similar. In aggregate, we generated proof-of-concept data paving the way for the further exploration of CSPG4 as an inducible antigen for CAR-T cells in ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Decitabine-Mediated Upregulation of CSPG4 in Ovarian Carcinoma Cells Enables Targeting by CSPG4-Specific CAR-T Cells

Harrer

Schenkel²,

Berking

et al. 2022

Cancers

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“…This mechanism may open the possibility of using immunotherapies to treat LF patients developing SNHL. Dysregulation of T cells is an important topic in viral immunology as well as in oncology [ 43 ]. Previous research into the modulation of these T cells could provide insight for the eventual development of therapies to aid those suffering LF-associated SNHL.…”

Section: Discussionmentioning

confidence: 99%

Depletion of CD4 and CD8 T Cells Reduces Acute Disease and Is Not Associated with Hearing Loss in ML29-Infected STAT1-/- Mice

et al. 2022

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Lassa virus (LASV) is a zoonotic virus endemic to western Africa that can cause a potentially lethal and hemorrhagic disease, Lassa fever (LF). Survivors suffer a myriad of sequelae, most notably sudden onset sensorineural hearing loss (SNHL), the mechanism of which remains unclear. Unfortunately, studies aiming to identify the mechanism of these sequelae are limited due to the biosafety level 4 (BSL4) requirements of LASV itself. ML29, a reassortant virus proposed as an experimental vaccine candidate against LASV, is potentially an ideal surrogate model of LF in STAT1-/- mice due to similar phenotype in these animals. We intended to better characterize ML29 pathogenesis and potential sequelae in this animal model. Our results indicate that while both CD4 and CD8 T cells are responsible for acute disease in ML29 infection, ML29 induces significant hearing loss in a mechanism independent of either CD4 or CD8 T cells. We believe that this model could provide valuable information for viral-associated hearing loss in general.

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“…In our system, to improve in vivo persistence, in might be necessary to add CD137 STD to CAR, co-express anti-apoptotic molecules, or establish an expanded culture method that is less likely to end in CAR-T cell exhaustion. Additionally, it is important to modulate epigenetic and transcriptional regulators in complex with CAR signal to reduce exhaustion [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Binding and Efficacy of Anti-Robo4 CAR-T Cells against Solid Tumors

et al. 2022

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Chimeric antigen receptor expression T (CAR-T) cell therapy has been shown be efficacious against relapsed/refractory B-cell malignant lymphoma and has attracted attention as an innovative cancer treatment. However, cells of solid tumors are less accessible to CAR-T cells; moreover, CAR-T function is decreased in the immunosuppressive state of the tumor microenvironment. Since most tumors induce angiogenesis, we constructed CAR-T cells targeting roundabout homolog 4 (Robo4), which is expressed at high levels in tumor vascular endothelial cells, by incorporating three anti-Robo4 single-chain variable fragments (scFv) that were identified using phage display. We found that binding affinities of the three CARs to mouse and human Robo4 reflected their scFv affinities. More importantly, when each CAR-T cell was assayed in vitro, antigen-specific cytotoxicity, cytokine-producing ability, and proliferation were correlated with binding affinity for Robo4. In vivo, all three T-cells inhibited tumor growth in a B16BL6 murine model, which also correlated with Robo4 binding affinities. However, growth inhibition of mouse Robo4-expressing tumors was observed only in the model with CAR-T cells with the lowest Robo4 affinity. Therefore, at high Robo4 expression, CAR-T in vitro and in vivo were no longer correlated, suggesting that clinical tumors will require Robo4 expression assays.

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Knowns and Unknowns about CAR-T Cell Dysfunction

Cited by 33 publications

References 203 publications

Decitabine-Mediated Upregulation of CSPG4 in Ovarian Carcinoma Cells Enables Targeting by CSPG4-Specific CAR-T Cells

Decitabine-Mediated Upregulation of CSPG4 in Ovarian Carcinoma Cells Enables Targeting by CSPG4-Specific CAR-T Cells

Depletion of CD4 and CD8 T Cells Reduces Acute Disease and Is Not Associated with Hearing Loss in ML29-Infected STAT1-/- Mice

Binding and Efficacy of Anti-Robo4 CAR-T Cells against Solid Tumors

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