Switchable CAR-T Cells Outperformed Traditional Antibody-Redirected Therapeutics Targeting Breast Cancers

Cao, Yu; Wang, Xuechun; Wang, Zhidong; Zhao, Lijun; Li, Shuhong; Zhang, Zhuxia; Wei, Xiaoyi; Yun, Hwayoung; Choi, Sei-hyun; Liu, Zhong; Zhao, Lili; Kazane, Stephanie A.

doi:10.1021/acssynbio.1c00007

Cited by 18 publications

(23 citation statements)

References 30 publications

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“…GPC3 and ERBB2, as common solid tumor target antigens, are frequently diffused in various tissues and organs; therefore, reducing the damage to important organs while targeting these antigens is a top priority. Other target antigens have also shown potential in CAR-T therapy, such as IGF1R ( 39 , 40 ), CD1A ( 41 , 42 ), CCR9, and CXCR4. Our results showed that IGF1R is widely expressed in various lineages from three germ layers, while the expression of CD1A, CCR9, and CXCR4 is relatively limited to immune cell types ( Supplementary Figure 10 ).…”

Section: Discussionmentioning

confidence: 99%

Single-Cell Analysis of Target Antigens of CAR-T Reveals a Potential Landscape of “On-Target, Off-Tumor Toxicity”

Zhang

Cao

et al. 2021

Front. Immunol.

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Cellular immunotherapy represented by CD19-directed chimeric antigen receptor T (CAR-T) cells has achieved great success in recent years. An increasing number of CAR-T therapies are being developed for cancer treatment, but the frequent and varied adverse events, such as “on-target, off-tumor toxicity”, limit CAR-T application. Here, we identify the target antigen expression patterns of CAR therapies in 18 tissues and organs (peripheral blood mononuclear cells, bone marrow, lymph nodes, spleen, heart, ascending aortic tissue, trachea, lung, skin, kidney, bladder, esophagus, stomach, small intestine, rectum, liver, common bile duct, and pancreas) from healthy human samples. The atlas determines target antigens expressed on some normal cell types, which facilitates elucidating the cause of “on-target, off-tumor toxicity” in special tissues and organs by targeting some antigens, but not others. Moreover, we describe the target antigen expression patterns of B-lineage-derived malignant cells, acute myeloid leukemia (AML), and solid tumors. Overall, the present study indicates the pathogenesis of “on-target, off-tumor toxicity” during CAR therapies and provides guidance on taking preventive measures during CAR treatment.

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Section: Discussionmentioning

confidence: 99%

Single-Cell Analysis of Target Antigens of CAR-T Reveals a Potential Landscape of “On-Target, Off-Tumor Toxicity”

Zhang

Cao

et al. 2021

Front. Immunol.

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“…T cells simultaneously engineered with CAR to recognize dual antigens have been successfully applied to redirect various hematological and solid malignancies [14,15]. Preclinical studies have shown that this approach results in increased antitumor function compared with that obtained with CAR-T cells specific for one TAA [16,17]. Although a few studies explored trispecific antibodies (tsAbs) with the feasibility of eliciting an anticancer response for dual-TAA targeting [18][19][20][21], researchers have not yet determined whether the constructs were well designed based on the molecular events relating to optimal bsAb configuration.…”

Section: Ivyspringmentioning

confidence: 99%

A Novel Her2/VEGFR2/CD3 trispecific antibody with an optimal structural design showed improved T-cell-redirecting antitumor efficacy

Liu¹,

Qi²,

Wei³

et al. 2022

Theranostics

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Rationale: T-cell-redirecting bispecific antibodies (bsAbs) and trispecific antibodies (tsAbs) designed to recognize different epitopes or antigens have emerged as promising cancer therapies. Current approaches are all designed to include another antibody specific to the site of the primary antibody, and the molecular structures are generally established. However, the dimensions of target molecule and epitope location play a key role in the efficiency of the immunological synapse (IS) formation and subsequent T-cell-redirecting activities, therefore the connection flexibility of these antibodies determines the geometries of different formats of these molecules and will have a major impact on the efficacy. Methods: We describe a novel recombination strategy using various linker designs to site-specifically fuse anti-Her2 (2Rs15) or anti-VEGFR2 (3VGR19) nanobodies to different positions of the anti-CD3 antibody fragment (Fab, SP34). Based on the comparison among the various antigen-specific bsAbs, we could determine the desired fusion site of each nanobody to SP34, and further ensure the optimal structure of tsAbs with synergistic dual-antigen enhanced T-cell-redirecting activities. Results: This approach allows precise control of the formation of IS between Her2- and/or VEGFR2-expressing cancer cells and T cells, to obtain the optimal structure of the Her2/VEGFR2/CD3 tsAb without the need to map antibody-binding epitopes. Optimization of Her2/VEGFR2/CD3 tsAb results in enhanced T-cell-redirecting in vitro and in vivo antitumor efficacy compared with the corresponding bsAbs alone or in combination, and the potency to overcome tumor relapse due to antigen escape or resistance to Herceptin and Cyramza therapy. Conclusion: The novel design strategy for developing tsAbs using a site-specific recombination approach represents a promising platform for immuno-oncology and in applications other than cancer therapy.

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“…There are many exciting areas of ongoing HER2-directed research, including novel ADCs (ARX788 and RC48), 65,66 bi-specific antibodies, 67,68 and chimeric antigen receptor T-cells. 69–72 A number of phase III trials exploring the role of new HER2-directed agents for advanced and earlier stage BC are also underway (Table 4). In the advanced setting, a number of novel agents are being assessed for patients with progressive disease on prior HER2-directed therapy, including tucatinib combined with T-DM1 (HER2CLIMB-02, NCT03975647), T-DXd (DESTINY-Breast02, NCT03523585), and the trastuzumab ADC BAT8001 (NCT04185649).…”

Section: Discussionmentioning

confidence: 99%

Current and future landscape of targeted therapy in HER2-positive advanced breast cancer: redrawing the lines

et al. 2022

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Background: Evidence to date supports continued human epidermal growth factor receptor 2 (HER2) suppression beyond progression on HER2-directed therapy for advanced HER2-positive breast cancer. Data from several phase II and III trials evaluating HER2-directed therapy following second-line T-DM1 have recently become available. Methods: We performed a systematic search of the published and presented literature to identify phase II and phase III trials assessing novel HER2-targeted agents as third-line therapy or beyond for HER2-positive advanced breast cancer using search terms ‘breast cancer’ AND ‘HER2’ AND ‘advanced’ AND (‘phase II’ OR ‘phase III’). Results: Eight clinical trials reporting efficacy outcomes on third-line or greater HER2-directed therapy for HER2-positive advanced breast cancer were identified. In phase III trials, margetuximab and neratinib combinations demonstrated significant 1.3-month (hazard ratio, HR = 0.71, p < 0.001) and 0.1-month (HR = 0.76, p = 0.006) net improvements in median progression-free survival (PFS), respectively, with no significant improvements in overall survival (OS). Tucatinib added to trastuzumab and capecitabine demonstrated a significant 2.7-month improvement in median PFS (HR = 0.57, p < 0.00001) and a 5.5-month improvement in median OS (HR = 0.73, p = 0.004) in a randomized phase II trial, including significant clinical benefit for patients with brain metastases. Finally, trastuzumab-deruxtecan, zenocutuzumab, and poziotinib demonstrated benefit in phase II trials with the most robust overall response rate (62.0%) and median duration of response (18.2 months) observed for trastuzumab-deruxtecan among heavily pretreated patients. Conclusion: Tucatinib plus trastuzumab and capecitabine significantly prolongs OS, and promising preliminary response outcomes for trastuzumab-deruxtecan suggest that sequencing of these regimens following second-line therapy is reasonable.

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Switchable CAR-T Cells Outperformed Traditional Antibody-Redirected Therapeutics Targeting Breast Cancers

Cited by 18 publications

References 30 publications

Single-Cell Analysis of Target Antigens of CAR-T Reveals a Potential Landscape of “On-Target, Off-Tumor Toxicity”

Single-Cell Analysis of Target Antigens of CAR-T Reveals a Potential Landscape of “On-Target, Off-Tumor Toxicity”

A Novel Her2/VEGFR2/CD3 trispecific antibody with an optimal structural design showed improved T-cell-redirecting antitumor efficacy

Current and future landscape of targeted therapy in HER2-positive advanced breast cancer: redrawing the lines

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