Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape

Hegde, Meenakshi; Mukherjee, Malini; Grada, Zakaria; Pignata, Antonella; Landi, Daniel; Navai, Shoba A.; Wakefield, Amanda; Fousek, Kristen; Bielamowicz, Kevin; Chow, Kevin; Brawley, Vita S.; Byrd, Tiara; Krebs, Simone; Wels, Winfried S.; Baker, Matthew L.; Dotti, Gianpietro; Mamonkin, Maksim; Brenner, Malcolm K.; Orange, Jordan S.; Ahmed, Nabil

doi:10.1172/jci152477

Cited by 13 publications

(14 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…23,25 Potential approaches to overcome this challenge include engineering CAR-T cells to achieve bispecificity, to produce a response to lower levels of target antigen, and to more efficiently induce the of natural antitumor immune response of CAR-T cells. 26,27 However, the bispecific CAR-T cells generally caused the unexpected adverse effects, such as off-target toxicity or cytokine release syndrome. To overcome this challenge, we further designed and developed a novel bispecific sCAR-T cell approach to target breast cancers expressing Her2 and IGF1R (Figure 4A).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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

Cao

Wang

et al. 2021

ACS Synth. Biol.

View full text Add to dashboard Cite

Various antibody-redirected immunotherapeutic approaches, including antibody-drug conjugates (ADCs), bispecific antibodies (bsAbs), and chimeric antigen receptor-T (CAR-T) cells, have been devised to produce specific activity against various cancer types. Using genetically encoded unnatural amino acids, we generated a homogeneous Her2-targeted ADC, a T cellredirected bsAb, and a FITC-modified antibody capable of redirecting anti-FITC CAR-T (switchable CAR-T; sCAR-T) cells to target different Her2-expressing breast cancers. sCAR-T cells showed activity against Her2-expressing tumor cells comparable to that of conventional anti-Her2 CAR-T cells and superior to that of ADC-and bsAb-based approaches. To prevent antigen escape, we designed bispecific sCAR-T cells targeting both the Her2 receptor and IGF1R, which showed an overall improved activity against cancer cells with low Her2 expression. This study increases our understanding of various explored cancer therapeutics and underscores the efficient application of sCAR-T cells as a promising therapeutic option for breast cancer patients with low or heterogeneous antigen expression.

show abstract

Section: ■ Results and Discussionmentioning

confidence: 99%

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

Cao

Wang

et al. 2021

ACS Synth. Biol.

View full text Add to dashboard Cite

show abstract

“…Therefore, the use of dual-or multi-target CAR-T cells for the treatment of hematological malignant disease will improve the CR rate in lymphoma and reduce the recurrence rate of B-ALL. This provides a theoretical and practical basis for the exploration of this treatment in solid tumors [63] (Figure 3).…”

Section: Antigen Escape: Dual/three-target Modified Car-t Cellsmentioning

confidence: 99%

“…Downregulation of antigens participates in the resistance to CAR-T cell therapy [77] . To overcome antigen escape, dual-or multiple-target CAR-T cells have been explored in several cancer types [63] .…”

Section: Tumor Heterogeneity and Antigen Escapementioning

confidence: 99%

Gene-modified T cell therapy for cancer: Current challenges and potential solutions

Chen¹,

Li²,

Zhang³

et al. 2022

Gene Protein Dis

View full text Add to dashboard Cite

Immunotherapy has achieved significant breakthroughs in patients with hematological diseases and various cancers. The adoptive transfer of T cells, especially gene-modified T cells such as chimeric antigen receptor T (CAR-T) cells and T cell receptor-engineered T (TCR-T) cells, is developing rapidly. Since 2017, eight CAR-T cell products have been approved for the treatment of hematological diseases, such as refractory or relapsed acute B lymphoblastic leukemia, specific subtypes of B cell lymphoma, and multiple myeloma. The first TCR-T cell product, Kimmtrak, was approved for the treatment of unresectable or metastatic uveal melanoma in March 2022. However, there are still many problems, including side effects, relapse, high demand for individualization, and expensive cost in hematological diseases, tumor heterogeneity, antigen escape, poor immune cell infiltration ability, immunosuppressive microenvironment, and low response in solid tumors. With the in-depth exploration of tumor immunology and the development of genetic engineering technology, many novel strategies for improving the anti-tumor effect and safety of gene-modified T cell immunotherapy have been attempted. This paper presents a systematic review of the literature on CAR-T cell and TCR-T cell therapy, focusing on applications, clinical trials, problems, and potential solutions.

show abstract

“…When all scFvs bind to the corresponding tumor antigens, they may have synergistic effects, enhancing the anti-tumor ability of CAR-T cells ( 7 – 9 ). Moreover, certain designs, such as trivalent-tandem CARs, can effectively cope with tumor antigen heterogeneity and immune escape ( 11 , 17 – 19 ).…”

Section: Optimize the Recognition Ability Of Carsmentioning

confidence: 99%

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

et al. 2022

View full text Add to dashboard Cite

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.

show abstract

Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape

Cited by 13 publications

References 1 publication

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

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

Gene-modified T cell therapy for cancer: Current challenges and potential solutions

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

Contact Info

Product

Resources

About