Generation and Functional Characterization of PLAP CAR-T Cells against Cervical Cancer Cells

Yekehfallah, Vahid; Pahlavanneshan, Saghar; Sayadmanesh, Ali; Momtahan, Zahra; Ma, Bin; Basiri, Mohsen

doi:10.3390/biom12091296

Cited by 7 publications

(5 citation statements)

References 55 publications

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“…Any minute alteration to a CAR sequence may potentially have functional consequences. The strategy was used by many in the meantime [ 45 – 47 ]. However, a systematic comparison on the CAR performance has not been performed to date.…”

Section: Discussionmentioning

confidence: 99%

Comparative performance of scFv-based anti-BCMA CAR formats for improved T cell therapy in multiple myeloma

Stock,

Fertig,

Gottschlich

et al. 2024

Cancer Immunol Immunother

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In multiple myeloma (MM), B cell maturation antigen (BCMA)-directed CAR T cells have emerged as a novel therapy with potential for long-term disease control. Anti-BCMA CAR T cells with a CD8-based transmembrane (TM) and CD137 (41BB) as intracellular costimulatory domain are in routine clinical use. As the CAR construct architecture can differentially impact performance and efficacy, the optimal construction of a BCMA-targeting CAR remains to be elucidated. Here, we hypothesized that varying the constituents of the CAR structure known to impact performance could shed light on how to improve established anti-BCMA CAR constructs. CD8TM.41BBIC-based anti-BCMA CAR vectors with either a long linker or a short linker between the light and heavy scFv chain, CD28TM.41BBIC-based and CD28TM.CD28IC-based anti-BCMA CAR vector systems were used in primary human T cells. MM cell lines were used as target cells. The short linker anti-BCMA CAR demonstrated higher cytokine production, whereas in vitro cytotoxicity, T cell differentiation upon activation and proliferation were superior for the CD28TM.CD28IC-based CAR. While CD28TM.CD28IC-based CAR T cells killed MM cells faster, the persistence of 41BBIC-based constructs was superior in vivo. While CD28 and 41BB costimulation come with different in vitro and in vivo advantages, this did not translate into a superior outcome for either tested model. In conclusion, this study showcases the need to study the influence of different CAR architectures based on an identical scFv individually. It indicates that current scFv-based anti-BCMA CAR with clinical utility may already be at their functional optimum regarding the known structural variations of the scFv linker.

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Section: Discussionmentioning

confidence: 99%

Comparative performance of scFv-based anti-BCMA CAR formats for improved T cell therapy in multiple myeloma

Stock,

Fertig,

Gottschlich

et al. 2024

Cancer Immunol Immunother

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“…ALPP and ALPPL2 are closely related and regulated GPI anchored proteins that are known to be expressed on the cell surface in some cancers, whereas normal tissue expression is largely limited to the placenta [3, 6]. ALPP and ALPPL2 are currently being explored as cancer therapy targets [5, 7, 8, 9]. However, limited expression levels of ALPP/ALPPL2 in most cancer types may restrict its broader therapeutic potential.…”

Section: Discussionmentioning

confidence: 99%

“…ALPP-CAR-T cells mediated potent cytotoxicity towards cancer cells, while the combination of ALPP-CAR-T cells with anti-PD-1, PD-L1, or LAG-3 checkpoint inhibitors further increased the therapeutic efficacy of CAR T-cells [5]. Second-generation CAR T-cells with a fully human scFv against ALPP antigen effectively killed ALPP-expressing HeLa cells [8]. A clinical trial using α-ALPP CAR T cells for ovarian and endometrial cancer has been initiated, while another clinical study evaluating the efficacy of ALPP/ALPPL2 antibody-drug conjugate in advanced solid tumors is ongoing [9].…”

Section: Introductionmentioning

confidence: 99%

EGFR inhibition in lung adenocarcinoma upregulates cell surface expression of the placental antigen ALPP and enhances efficacy of ALPP-ADC therapy

Chen

Hong

et al. 2023

Preprint

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Alkaline phosphatase placental type (ALPP) and ALPPL2 are closely related and regulated GPI anchored proteins that are known to be expressed on the cell surface in some cancers, whereas normal tissue expression is largely limited to the placenta. Clinical utility of ALPP is potentially limited by heterogenous expression in tumors. Here, we assessed ALPP and ALPPL2 surfaceome protein levels in 158 cancer cell lines and mRNA expression levels in 10,967 tumors representing 32 cancer types from The Cancer Genome Atlas (TCGA), which revealed ALPP, and to a lesser extent ALPPL2, to be variably expressed in several cancer types including lung adenocarcinoma (LUAD). Surface expression of ALPP was confirmed by tissue microarray analysis of 204 lung tumors. Using LUAD as a model system, we demonstrated that treatment with EGFR inhibitors, or induction of cancer cell quiescence via nutrient deprivation greatly enhanced ALPP surface expression. Mechanistic studies revealed that enhancement of surface ALPP expression in LUAD following gefitinib treatment was mediated through repression of EGFR signaling and activation of the transcription factor FoxO3a, which was identified as an upstream transcriptional regulator of ALPP. Using xenograft models of LUAD, we further demonstrated that gefitinib treatment upregulates surface expression of ALPP in LUAD cells but not in normal tissues. Combination therapy with gefitinib and an ALPP antibody conjugated with Monomethylauristatin F (ALPP-ADC-MAF) resulted in superior anti-cancer efficacy compared with gefitinib or ALPP-ADC-MAF alone. Our findings support a novel combination treatment modality that boosts the efficacy of ALPP-ADC directed therapy.

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“…The researchers also observed increased secretion of IL-2, granzyme A, and IFN-γ after PLAP CAR-T cells were exposed to target cells. Therefore, it was concluded that PLAP CAR-T cells are potential candidates for further study of cervical cancer and other solid tumors ( 75 ).…”

Section: Studies Of Engineered T Cells In Cervical Cancermentioning

confidence: 99%

T cell immunotherapy for cervical cancer: challenges and opportunities

Lanqing

Huang

et al. 2023

Front. Immunol.

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Cancer cellular immunotherapy has made inspiring therapeutic effects in clinical practices, which brings new hope for the cure of cervical cancer. CD8+T cells are the effective cytotoxic effector cells against cancer in antitumor immunity, and T cells-based immunotherapy plays a crucial role in cellular immunotherapy. Tumor infiltrated Lymphocytes (TIL), the natural T cells, is approved for cervical cancer immunotherapy, and Engineered T cells therapy also has impressive progress. T cells with natural or engineered tumor antigen binding sites (CAR-T, TCR-T) are expanded in vitro, and re-infused back into the patients to eradicate tumor cells. This review summarizes the preclinical research and clinical applications of T cell-based immunotherapy for cervical cancer, and the challenges for cervical cancer immunotherapy.

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Generation and Functional Characterization of PLAP CAR-T Cells against Cervical Cancer Cells

Cited by 7 publications

References 55 publications

Comparative performance of scFv-based anti-BCMA CAR formats for improved T cell therapy in multiple myeloma

Comparative performance of scFv-based anti-BCMA CAR formats for improved T cell therapy in multiple myeloma

EGFR inhibition in lung adenocarcinoma upregulates cell surface expression of the placental antigen ALPP and enhances efficacy of ALPP-ADC therapy

T cell immunotherapy for cervical cancer: challenges and opportunities

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