Modified CAR T cells targeting membrane-proximal epitope of mesothelin enhances the antitumor function against large solid tumor

Zhang, Zhiwei; Jiang, Duqing; Yang, Huan; He, Zhiwei; Liu, Xiangzhen; Qin, Wenxia; Li, Linfang; Wang, Chao; Li, Yang; Li, He; Xu, Hai; Jin, Haixia; Qian, Qijun

doi:10.1038/s41419-019-1711-1

Cited by 78 publications

(68 citation statements)

References 47 publications

(54 reference statements)

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“…In TICS, live cell imaging reveals that cancer cell lysis by primary human lymphocytes in response to PD-1/L1 blocking antibodies initiates after 3 days. This is in contrast to genetic-engineered or cytokine-activated T cells [11][12][13] or NK cells [24], which readily mediate cancer cell killing within hours in vitro, and which therefore may not be as sensitive to inhibition through immune checkpoint molecules. Moreover, the functional and mechanistic involvement of additional lymphocyte subsets upon PD-1/L1 blockade, such as B cells, gamma-delta T cells, and invariant NK cells, can be dissected in TICS.…”

Section: Discussionmentioning

confidence: 93%

“…Nonetheless, it is costly and time-consuming to construct these models, which could reduce their broad application. Using in vitro co-culture assays, we and others have utilised chimeric antigen receptors (CARs)-engineered human CD8+ T cells to study their killing mechanisms of human OC cells [11][12][13]. Although the engineered CD8+ T cells are highly potent in killing tumour cells, the requirement of pre-treatment with highdose immune stimulating cytokines may alter the endogenous sensitivity to PD-1/L1-mediated immune suppression.…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

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Human ovarian cancer intrinsic mechanisms regulate lymphocyte activation in response to immune checkpoint blockade

Natoli

Bonito

Robinson

et al. 2020

Cancer Immunol Immunother

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Immune checkpoint blocking antibodies are currently being tested in ovarian cancer (OC) patients and have shown some responses in early clinical trials. However, it remains unclear how human OC cancer cells regulate lymphocyte activation in response to therapy. In this study, we have established and optimised an in vitro tumour-immune co-culture system (TICS), which is specifically designed to quantify the activation of multiple primary human lymphocyte subsets and human cancer cell killing in response to PD-1/L1 blockade. Human OC cell lines and treatment naïve patient ascites show differential effects on lymphocyte activation and respond differently to PD-1 blocking antibody nivolumab in TICS. Using paired OC cell lines established prior to and after chemotherapy relapse, our data reveal that the resistant cells express low levels of HLA and respond poorly to nivolumab, relative to the treatment naïve cells. In accordance, knockdown of IFNγ receptor expression compromises response to nivolumab in the treatment naïve OC cell line, while enhanced HLA expression induced by a DNA methyltransferase inhibitor promotes lymphocyte activation in TICS. Altogether, our results suggest a 'cross resistance' model, where the acquired chemotherapy resistance in cancer cells may confer resistance to immune checkpoint blockade therapy through down-regulation of antigen presentation machinery. As such, agents that can restore HLA expression may be a suitable combination partner for immunotherapy in chemotherapy-relapsed human ovarian cancer patients.Keywords Human ovarian cancer · PD-1/PD-L1 blockade · Immune resistance · Human cancer/immune co-culture AbbreviationsDNMTi DNA methyltransferase inhibitor GFP Green fluorescent protein MSI Microsatellite instability OC Ovarian cancer PBMCs Peripheral blood mononuclear cells PD-1 Programmed cell death protein 1 PD-L1Programmed death-ligand 1 TICS Tumour-immune co-culture system TMB Tumour mutational burden * Sadaf Ghaem-Maghami

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Section: Discussionmentioning

confidence: 93%

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

Human ovarian cancer intrinsic mechanisms regulate lymphocyte activation in response to immune checkpoint blockade

Natoli

Bonito

Robinson

et al. 2020

Cancer Immunol Immunother

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“…At present, efficacy and safety of adoptive T-cell therapies, in particular chimeric antigen receptor-transduced T-cells (CAR-T), in MPM and other solid tumors are under investigation [49,50]. CAR-T-cells directed against mesothelin (MSLN), a glycoprotein expressed on MPM and other solid tumor cells, with a limited presence on normal tissues [51], represent a promising therapeutic option and many efforts have been made to improve their clinical efficacy and safety profile [52,53]. Recently, Adusumilli and colleagues reported the outcome of a phase I clinical trial, NCT02414269, [54,55] on patients with MPM and pleural metastases from lung or breast cancer treated with anti-MSLN CAR-T-cells.…”

Section: Immunotherapy In Mpmmentioning

confidence: 99%

Fully Human Antibodies for Malignant Pleural Mesothelioma Targeting

Nicolini

Bocchini

Angeli

et al. 2020

Cancers

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Immunotherapy is the most promising therapeutic approach against malignant pleural mesothelioma (MPM). Despite technological progress, the number of targetable antigens or specific antibodies is limited, thus hindering the full potential of recent therapeutic interventions. All possibilities of finding new targeting molecules must be exploited. The specificity of targeting is guaranteed by the use of monoclonal antibodies, while fully human antibodies are preferred, as they are functional and generate no neutralizing antibodies. The aim of this review is to appraise the latest advances in screening methods dedicated to the identification and harnessing of fully human antibodies. The scope of identifying useful molecules proceeds along two avenues, i.e., through the antigen-first or binding-first approaches. The first relies on screening human antibody libraries or plasma from immunized transgenic mice or humans to isolate binders to specific antigens. The latter takes advantage of specific binding to tumor cells of antibodies present in phage display libraries or in responders’ plasma samples without prior knowledge of the antigens. Additionally, next-generation sequencing analysis of B-cell receptor repertoire pre- and post-therapy in memory B-cells from responders allows for the identification of clones expanded and matured upon treatment. Human antibodies identified can be subsequently reformatted to generate a plethora of therapeutics like antibody-drug conjugates, immunotoxins, and advanced cell-therapeutics such as chimeric antigen receptor-transduced T-cells.

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“…The SKOV-3 cell line was obtained from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China), and SKOV-3-luc was established in our laboratory as described previously [11]. Human peripheral blood mononuclear cells (PBMC) from healthy donors were purchased from AllCells (Shanghai, China) and cryopreserved in our laboratory.…”

Section: Cellsmentioning

confidence: 99%

“…Our previous study demonstrated that modi ed CAR-T cells targeting membrane proximal (region III) epitope of mesothelin exhibited strong antitumor activity against various solid tumors [11,12]. Given this, CAR-T cells were generated with the ability to secrete the anti-CD40 antibody that target region III of the mesothelin to potentially achieve a more powerful e cacy.…”

Section: Introductionmentioning

confidence: 99%

Chimeric Antigen Receptor T Cells Engineered to Secrete CD40 Agonist Antibodies Enhance Antitumor Efficacy

Zhang

Wang

wang

et al. 2020

Preprint

Self Cite

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BackgroundAlthough chimeric antigen receptor (CAR) T-cell therapy has made remarkable achievements against hematological malignancies, the efficacy of it against solid tumors has been limited. By being combined with immune checkpoint inhibitors, such as PD-1, PD-L1, or CTLA-4 antibodies, this therapy has been shown to be a promising strategy to enhance the antitumor efficacy of CAR-T cells. However, due to the fact that acquired resistance to checkpoint inhibitors will occur in most patients, it is vital to investigate other strategies to further improve the antitumor efficacy of CAR-T cell therapy in solid tumors. Recently, CD40 agonist antibodies have been shown to possess potential antitumor efficacy by activating the CD40 pathway.ResultsBased on the piggyBac transposon system, rather than the widely used viral vector, we constructed a meso3-CD40 CAR-T targeting region III of mesothelin (MSLN) that possesses the ability to secrete anti-CD40 antibodies. The results show that compared with meso3 CAR-T, which does not secrete the anti-CD40 antibody, meso3-CD40 CAR-T secreted more cytokines and had a relatively higher proportion of central memory T (TCM) cells after being stimulated by the target antigen. In addition, compared with meso3 CAR-T, we found that meso3-CD40 CAR-T had a more powerful cytotoxicity effect on target cells at a relatively low effector to target ratio. More importantly, we demonstrated that meso3-CD40 CAR-T also had enhanced antitumor activity in a human ovarian cancer xenograft in vivo.ConclusionsIn conclusion, these results showed that anti-CD40-secreting CAR-T cells generated by non-viral vectors could be a potential clinical strategy for improving the efficacy of CAR-T cell therapies.

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Modified CAR T cells targeting membrane-proximal epitope of mesothelin enhances the antitumor function against large solid tumor

Cited by 78 publications

References 47 publications

Human ovarian cancer intrinsic mechanisms regulate lymphocyte activation in response to immune checkpoint blockade

Human ovarian cancer intrinsic mechanisms regulate lymphocyte activation in response to immune checkpoint blockade

Fully Human Antibodies for Malignant Pleural Mesothelioma Targeting

Chimeric Antigen Receptor T Cells Engineered to Secrete CD40 Agonist Antibodies Enhance Antitumor Efficacy

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