The rational development of CD5-targeting biepitopic CARs with fully human heavy-chain-only antigen recognition domains

Dai, Zhenyu; Mu, Wei; Zhao, Ya; Jia, Xiangyin; Liu, Jianwei; Wei, Qiaoe; Tan, Taochao; Zhou, Jianfeng

doi:10.1016/j.ymthe.2021.07.001

Cited by 39 publications

(35 citation statements)

References 48 publications

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“…In particular, engineered CAR T-cells with self-limiting persistence could target molecules (e.g., antigens with co-expression on healthy tissue) that would cause lasting toxicities once targeted by conventional CAR T-cells. Furthermore, promising target antigens, such as CD30 in Hodgkin´s lymphoma and colon cancer [ 33 , 39 ], or CD5 on T-cell lymphoma [ 40 ], are co-expressed by healthy T cells creating the risk of durable damage to endogenous healthy T-cells upon targeting by conventional CAR T-cells. Finally, CAR T-cells have gained attraction beyond the realm of oncology and are currently being evaluated as a promising therapy for autoimmune diseases, such as systemic lupus erythematosus [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

CAR Triggered Release of Type-1 Interferon Limits CAR T-Cell Activities by an Artificial Negative Autocrine Loop

Harrer

Schenkel

Bezler³

et al. 2022

Cells

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The advent of chimeric antigen receptor (CAR) T cells expedited the field of cancer immunotherapy enabling durable remissions in patients with refractory hematological malignancies. T cells redirected for universal cytokine-mediated killing (TRUCKs), commonly referred to as “fourth generation” CAR T-cells, are designed to release engineered payloads upon CAR-induced T-cell activation. Building on the TRUCK technology, we aimed to generate CAR T-cells with a CAR-inducible artificial, self-limiting autocrine loop. To this end, we engineered CAR T-cells with CAR triggered secretion of type-1 interferons (IFNs). At baseline, IFNα and IFNβ CAR T-cells showed similar capacities in cytotoxicity and cytokine secretion compared to conventional CAR T-cells. However, under “stress” conditions of repetitive rounds of antigen stimulation using BxPC-3 pancreas carcinoma cells as targets, anti-tumor activity faded in later rounds while being fully active in destructing carcinoma cells during first rounds of stimulation. Mechanistically, the decline in activity was primarily based on type-1 IFN augmented CAR T-cell apoptosis, which was far less the case for CAR T-cells without IFN release. Such autocrine self-limiting loops can be used for applications where transient CAR T-cell activity and persistence upon target recognition is desired to avoid lasting toxicities.

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Section: Discussionmentioning

confidence: 99%

CAR Triggered Release of Type-1 Interferon Limits CAR T-Cell Activities by an Artificial Negative Autocrine Loop

Harrer

Schenkel

Bezler³

et al. 2022

Cells

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“…Cell apoptosis was examined with an APC Annexin V Apoptosis Detection Kit (88-8007-72, Thermo Fisher) following the manufacturer’s instructions ( 29 ). Briefly, Capan-1 and PANC-1 cells from the groups transfected with B7H6-siRNA or scramble siRNA were harvested.…”

Section: Methodsmentioning

confidence: 99%

B7H6 Serves as a Negative Prognostic Marker and an Immune Modulator in Human Pancreatic Cancer

et al. 2022

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Pancreatic cancer (PC), the third leading cause of cancer-related death in the U.S., is frequently found too late to be cured by traditional chemotherapy. Expression of B7 homolog 6 (B7H6), a member of the B7 family of immunoreceptors, has been found in PC and several other cancers. B7H6 is a ligand for cytotoxicity triggering receptor 3 (NKp30), which is expressed on NK cells. Here, we demonstrate that B7H6 can be detected in PC tissues but not normal organs. Its expression in patients associated significantly with tumor differentiation grade and lymphatic metastasis. The soluble form of B7H6 was detected in the PC patients’ sera, and its concentration associated with tumor differentiation grade and tumor, node, metastasis (TNM) stages. Also, higher levels of B7H6 in PC patients’ malignant tissues or serum correlated with shorter overall survival. In vitro, downregulation of B7H6 by CRISPR/Cas9 or siRNA technology had no significant impact on the viability or mobility of PC cells. Instead, knocking out B7H6 sensitized PC cells to NK-mediated cytotoxicity and cytokine production. These results indicate that B7H6 not only serves as a negative prognostic marker but also acts as an immune modulator in PC.

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“…manufactured a new biepitopic CAR with fully human heavy-chain variables FHV H 3 and FHV H 1, which could bind different epitopes of CD5. As such, CD5KO FHV H 3/V H 1 CAR-T cells showed prolonged and sustained efficacy against CD5+ T-ALL cell lines, such as Jurkat, CCRF-CEM, MOLT4, SupT1 in vitro , and CCRF-CEM in vivo , with moderate cytokine production, proved that this new CD5 CAR deserved more exploration ( 66 ). Due to recurrence occurring in some patients after CAR-T therapy which targets single antigen CD5 or CD7 ( 63 , 67 ), in 2022, Dai et al.…”

Section: Car-t Therapy For Non-b-cell Acute Leukemiamentioning

confidence: 98%

Chimeric antigen receptor T-cell therapy for T-ALL and AML

et al. 2022

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Non-B-cell acute leukemia is a term that encompasses T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Currently, the therapeutic effectiveness of existing treatments for refractory or relapsed (R/R) non-B-cell acute leukemia is limited. In such situations, chimeric antigen receptor (CAR)-T cell therapy may be a promising approach to treat non-B-cell acute leukemia, given its promising results in B-cell acute lymphoblastic leukemia (B-ALL). Nevertheless, fratricide, malignant contamination, T cell aplasia for T-ALL, and specific antigen selection and complex microenvironment for AML remain significant challenges in the implementation of CAR-T therapy for T-ALL and AML patients in the clinic. Therefore, designs of CAR-T cells targeting CD5 and CD7 for T-ALL and CD123, CD33, and CLL1 for AML show promising efficacy and safety profiles in clinical trials. In this review, we summarize the characteristics of non-B-cell acute leukemia, the development of CARs, the CAR targets, and their efficacy for treating non-B-cell acute leukemia.

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The rational development of CD5-targeting biepitopic CARs with fully human heavy-chain-only antigen recognition domains

Cited by 39 publications

References 48 publications

CAR Triggered Release of Type-1 Interferon Limits CAR T-Cell Activities by an Artificial Negative Autocrine Loop

CAR Triggered Release of Type-1 Interferon Limits CAR T-Cell Activities by an Artificial Negative Autocrine Loop

B7H6 Serves as a Negative Prognostic Marker and an Immune Modulator in Human Pancreatic Cancer

Chimeric antigen receptor T-cell therapy for T-ALL and AML

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