Combination strategies to optimize the efficacy of chimeric antigen receptor T cell therapy in haematological malignancies

Xiao, Xinyi; Wang, Yazhuo; Zou, Zhengbang; Yang, Yufei; Wang, Xinyu; Xin, Xin; Tu, Sanfang; Li, Yuhua

doi:10.3389/fimmu.2022.954235

Cited by 20 publications

(22 citation statements)

References 198 publications

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“…Aside from large scale screens, individual combinatorial drug plus CAR T cell approaches have been evaluated, and some translated into clinical trials. [15][16][17]25 We identified I3A as a drug to increase B7-H3 expression in metastatic osteosarcoma cells. While this demonstrated utility of our screen, I3A is a topical medication and not readily applicable for patients with osteosarcoma.…”

Section: Discussionmentioning

confidence: 99%

A high-content screen identified ingenol-3-angelate as an enhancer of B7-H3-CAR T cell activity by increasing B7-H3 protein expression on the target cell surface via PKCα activation

Lee

O’Reilly

Beckett

et al. 2023

Preprint

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CAR T cell therapy is a promising approach to improve outcomes and decrease toxicities for patients with cancer. While extraordinary success has been achieved using CAR T cells to treat patients with CD19-positive malignancies, multiple obstacles have so far limited the benefit of CAR T cell therapy for patients with solid tumors. Novel manufacturing and engineering approaches show great promise to enhance CAR T cell function against solid tumors. However, similar to single agent chemotherapy approaches, CAR T cell monotherapy may be unable to achieve high cure rates for patients with difficult to treat solid tumors. Thus, combinatorial drug plus CAR T cell approaches may ultimately be required to achieve widespread clinical success. In this regard, we developed a novel high-content and high-throughput screen to evaluate 1114 FDA approved drugs to increase expression of the solid tumor antigen B7-H3 in metastatic osteosarcoma cells. In this proof-of-principle screen, we demonstrate that ingenol-3-angelate increased B7-H3 (CD276) mRNA, total protein, and cell surface expression. Mechanistically, ingenol-3-angelate increased B7-H3 expression via protein kinase C alpha activation. Functionally, ingenol-3-angelate induced B7-H3 expression enhanced B7-H3-CAR T cell function, highlighting utility of the approach, and paving the way for expanding this high-throughput and high-content technique to study other tumor and CAR T cell combinations.

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Section: Discussionmentioning

confidence: 99%

A high-content screen identified ingenol-3-angelate as an enhancer of B7-H3-CAR T cell activity by increasing B7-H3 protein expression on the target cell surface via PKCα activation

Lee

O’Reilly

Beckett

et al. 2023

Preprint

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“…Combining CAR T-cells with other therapies, including chemotherapy, radiotherapy, hematopoietic stem cell transplantation, and other immunotherapies, is regarded as a promising strategy to overcome challenges and enhance the effectiveness of CAR T-cell therapy [ 118 , 119 ]. In a study, cyclophosphamide (Cy) and oxaliplatin (Ox) were used innovatively to replace the conventional chemotherapy regimen Cy and fludarabine (Flu) prior to CAR T-cell infusion [ 120 ], which has been shown to promote T cell infiltration into tumors [ 121 ].…”

Section: Deciphering and Advancing Strategies For Car T-cell Therapymentioning

confidence: 99%

Deciphering and advancing CAR T-cell therapy with single-cell sequencing technologies

Huang

Wang

et al. 2023

Mol Cancer

Self Cite

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Chimeric antigen receptor (CAR) T-cell therapy has made remarkable progress in cancer immunotherapy, but several challenges with unclear mechanisms hinder its wide clinical application. Single-cell sequencing technologies, with the powerful unbiased analysis of cellular heterogeneity and molecular patterns at unprecedented resolution, have greatly advanced our understanding of immunology and oncology. In this review, we summarize the recent applications of single-cell sequencing technologies in CAR T-cell therapy, including the biological characteristics, the latest mechanisms of clinical response and adverse events, promising strategies that contribute to the development of CAR T-cell therapy and CAR target selection. Generally, we propose a multi-omics research mode to guide potential future research on CAR T-cell therapy.

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“…CAR‐T cell therapy as part of a combination treatment strategy is currently being investigated in preclinical and early clinical trials. A detailed review of all explored combinations is beyond the scope of this paper but has been the focus of a different paper 88 . No combination strategy is currently approved by a regulatory agency and further studies will have to be performed before the first combined treatment protocol will become available.…”

Section: Clinical Practicementioning

confidence: 99%

Model‐informed drug development of autologous CAR‐T cell therapy: Strategies to optimize CAR‐T cell exposure leveraging cell kinetic/dynamic modeling

Laughlin¹,

Milligan²,

Yee

et al. 2023

CPT Pharmacom & Syst Pharma

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Autologous Chimeric antigen receptor (CAR‐T) cell therapy has been highly successful in the treatment of aggressive hematological malignancies and is also being evaluated for the treatment of solid tumors as well as other therapeutic areas. A challenge, however, is that up to 60% of patients do not sustain a long‐term response. Low CAR‐T cell exposure has been suggested as an underlying factor for a poor prognosis. CAR‐T cell therapy is a novel therapeutic modality with unique kinetic and dynamic properties. Importantly, “clear” dose‐exposure relationships do not seem to exist for any of the currently approved CAR‐T cell products. In other words, dose increases have not led to a commensurate increase in the measurable in vivo frequency of transferred CAR‐T cells. Therefore, alternative approaches beyond dose titration are needed to optimize CAR‐T cell exposure. In this paper, we provide examples of actionable variables – design elements in CAR‐T cell discovery, development, and clinical practice, which can be modified to optimize autologous CAR‐T cell exposure. Most of these actionable variables can be assessed throughout the various stages of discovery and development as part of a well‐informed research and development program. Model‐informed drug development approaches can enable such study and program design choices from discovery through to clinical practice and can be an important contributor to cell therapy effectiveness and efficiency.

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Combination strategies to optimize the efficacy of chimeric antigen receptor T cell therapy in haematological malignancies

Cited by 20 publications

References 198 publications

A high-content screen identified ingenol-3-angelate as an enhancer of B7-H3-CAR T cell activity by increasing B7-H3 protein expression on the target cell surface via PKCα activation

A high-content screen identified ingenol-3-angelate as an enhancer of B7-H3-CAR T cell activity by increasing B7-H3 protein expression on the target cell surface via PKCα activation

Deciphering and advancing CAR T-cell therapy with single-cell sequencing technologies

Model‐informed drug development of autologous CAR‐T cell therapy: Strategies to optimize CAR‐T cell exposure leveraging cell kinetic/dynamic modeling

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