CD19 CAR-T expressing PD-1/CD28 chimeric switch receptor as a salvage therapy for DLBCL patients treated with different CD19-directed CAR T-cell therapies

Liang, Yun; Liu, Hui; Lu, Zheming; Lei, Wen; Zhang, Chaoting; Li, Ping; Liang, Aibin; Young, Ken H.; Qian, W.

doi:10.1186/s13045-021-01044-y

Cited by 39 publications

(20 citation statements)

References 13 publications

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“…[8][9][10][11] Moreover, in clinical trials, the application of the PD1-28 chimera presented encouraging results. 48 The Carl June group verified that the co-stimulatory domain 41BB promotes memory T cells and CD28 promotes effector T cells. In this study, our data showed that T3-CD28 signaling combined with 41BB might benefit CAR-T cells to some extent.…”

Section: Discussionmentioning

confidence: 99%

Switch receptor T3/28 improves long-term persistence and antitumor efficacy of CAR-T cells

Zhao

Wang

et al. 2021

J Immunother Cancer

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BackgroundChimeric antigen receptor (CAR) T cells have been successfully used in tumor immunotherapy due to their strong antitumor responses, especially in hematological malignancies such as B cell acute lymphoid leukemia. However, on-target off-tumor toxicity and poor persistence severely limit the clinical application of CAR-T cell therapy.MethodsT-cell immunoglobulin mucin domain molecule 3 (TIM-3) was used to develop a second-generation 41BB CD19 CAR linked with a T3/28 chimera, in which truncated extracellular TIM-3 was fused with the CD28 transmembrane and cytoplasmic domains. The efficacy of T3/28 CAR-T cells was evaluated in vitro and in vivo.ResultsWe demonstrated that the switch receptor T3/28 preserved the TCM phenotype, improved proliferative capacity, and reduced exhaustion of CAR-T cells, resulting in superior in vitro and in vivo antitumor activity in B lymphoma. Importantly, the switch receptor T3/28 substantially prolonged the persistence of CAR-T cells, and the interleukin-21/Stat3 axis probably contributed to the enhanced cytotoxicity of T3/28 CAR-T cells.ConclusionOverall, the T3/28 chimera significantly prolonged the persistence of CAR-T cells, and T3/28 CAR-T cells possessed potent antitumor activity in mice, shedding new light on potential improvements in adoptive T cell therapies.

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Section: Discussionmentioning

confidence: 99%

Switch receptor T3/28 improves long-term persistence and antitumor efficacy of CAR-T cells

Zhao

Wang

et al. 2021

J Immunother Cancer

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“…To further verify the effects of 7 × 19 secretion on human CAR-T cells, we constructed three CAR vectors targeting GPC3, MSLN, and CD20 (Fig. 1a) [4][5][6], which all contained intracellular domains of CD28 and TLR2 [7][8][9]. As the cargo capacity of the lentiviral vector is limited, human IL-7 and CCL19 linked through the 2A peptide were inserted into a separate lentiviral vector (Fig.…”

Section: To the Editormentioning

confidence: 99%

“…8 Guangdong Zhaotai Cell Biology Technology Ltd., Guangzhou, China. 9 Guangdong Zhaotai InVivo Biomedicine Co. Ltd., Guangzhou, China. 10 The Second Xiangya Hospital, Central South University, Changsha, China.…”

Section: Abbreviationsmentioning

confidence: 99%

IL-7 and CCL19-secreting CAR-T cell therapy for tumors with positive glypican-3 or mesothelin

et al. 2021

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Although chimeric antigen receptor (CAR)-engineered T cells have shown great success in the treatment of B cell malignancies, this strategy has limited efficacy in patients with solid tumors. In mouse CAR-T cells, IL-7 and CCL19 expression have been demonstrated to improve T cell infiltration and CAR-T cell survival in mouse tumors. Therefore, in the current study, we engineered human CAR-T cells to secrete human IL-7 and CCL19 (7 × 19) and found that these 7 × 19 CAR-T cells showed enhanced capacities of expansion and migration in vitro. Furthermore, 7 × 19 CAR-T cells showed superior tumor suppression ability compared to conventional CAR-T cells in xenografts of hepatocellular carcinoma (HCC) cell lines, primary HCC tissue samples and pancreatic carcinoma (PC) cell lines. We then initiated a phase 1 clinical trial in advanced HCC/PC/ovarian carcinoma (OC) patients with glypican-3 (GPC3) or mesothelin (MSLN) expression. In a patient with advanced HCC, anti-GPC3-7 × 19 CAR-T treatment resulted in complete tumor disappearance 30 days post intratumor injection. In a patient with advanced PC, anti-MSLN-7 × 19 CAR-T treatment resulted in almost complete tumor disappearance 240 days post-intravenous infusion. Our results demonstrated that the incorporation of 7 × 19 into CAR-T cells significantly enhanced the antitumor activity against human solid tumor. Trial registration: NCT03198546. Registered 26 June 2017, https://clinicaltrials.gov/ct2/show/NCT03198546?term=NCT03198546&draw=2&rank=1

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“…Both the PD-1/CD28 CSR and the IL-4/7 ICR should be combined ( Figure 8C ). After being activated, CAR-T cells expressing these two receptors may be able to reverse the inhibitory signal transmitted by tumor cells as well as the inhibitory effect of IL-4 simultaneously ( 29 , 32 , 34 – 37 ).…”

Section: Improving the Killing Ability Of Carsmentioning

confidence: 99%

Special Chimeric Antigen Receptor (CAR) Modifications of T Cells: A Review

et al. 2022

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Chimeric antigen receptor (CAR) -T cell therapy has become one of the hot topics in tumor immunity research in recent years. Although CAR-T cell therapy is highly effective in treating hematological malignancies, there are numerous obstacles that prevent CAR-T cells from having anti-tumor effects. Traditional CARs, from the first to the fourth generation, are incapable of completely overcoming these challenges. Therefore, identifying ways to boost the efficacy of CAR-T cells by utilizing the limited tumor surface antigens has become an urgent area of research. Certain special CARs that have special structures, special systems, or are greatly improved on the basis of traditional CARs, such as tandem CAR, dual-signaling CARs, AND-gate CARs, inhibitory CAR, AND-NOT CARs, CARs with three scFvs, ON/OFF-switch CARs, and universal CARs have been introduced. This study aims to use these special CARs to improve the anti-tumor ability, accuracy, and safety of CAR-T cells. In addition to summarizing various special CARs of T cells, this paper also expounds some of our own conjectures, aiming to provide reference and inspiration for CARs researchers.

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CD19 CAR-T expressing PD-1/CD28 chimeric switch receptor as a salvage therapy for DLBCL patients treated with different CD19-directed CAR T-cell therapies

Cited by 39 publications

References 13 publications

Switch receptor T3/28 improves long-term persistence and antitumor efficacy of CAR-T cells

Switch receptor T3/28 improves long-term persistence and antitumor efficacy of CAR-T cells

IL-7 and CCL19-secreting CAR-T cell therapy for tumors with positive glypican-3 or mesothelin

Special Chimeric Antigen Receptor (CAR) Modifications of T Cells: A Review

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