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

Zhao, Sumei; Wang, Chunhua; Lu, Ping; Lou, Yalin; Liu, Huimin; Wang, Ting; Yang, Shanshan; Bao, Ziyou; Han, Lin; Liang, Xiaohong; Ma, Chao; Gao, Lifen

doi:10.1136/jitc-2021-003176

Cited by 21 publications

(25 citation statements)

References 60 publications

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“…CD28) (Blaeschke et al, 2021; Liu et al, 2021a; Liu et al, 2016). An array of synthetic surface receptors including CD200R/CD28 and TIM-3/CD28 have been developed (Oda et al, 2017; Zhao et al, 2021b), but systematic analysis is required to learn rules about which extracellular and intracellular domain pairings are most effective. More broadly, a modular screening approach is required to discover specific combinations of TFs or surface receptors (SRs) that can be coupled with specific TCRs or CARs to improve functional performance.…”

Section: Introductionmentioning

confidence: 99%

Modular Pooled Discovery of Synthetic Knockin Sequences to Program Durable Cell Therapies

Blaeschke

Chen

Apathy

et al. 2022

Preprint

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Chronic stimulation can cause T cell dysfunction and limit efficacy of cellular immunotherapies. CRISPR screens have nominated gene targets for engineered T cells, but improved methods are required to compare large numbers of synthetic knockin sequences to reprogram cell functions. Here, we developed Modular Pooled Knockin Screening (ModPoKI), an adaptable platform for modular construction of DNA knockin libraries using barcoded multicistronic adaptors. We built two ModPoKI libraries of 100 transcription factors (TFs) and 129 natural and synthetic surface receptors. Over 20 ModPoKI screens across human TCR and CAR T cells in diverse conditions identified a transcription factor AP4 (TFAP4) construct to enhance long-term T cell fitness and anti-cancer function in vitro and in vivo. ModPoKI's modularity allowed us to generate a ~10,000-member library of TF combinations. Non-viral knockin of a combined BATF-TFAP4 polycistronic construct further enhanced function in vivo. ModPoKI facilitates discovery of complex gene constructs to program cellular functions.

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Section: Introductionmentioning

confidence: 99%

Modular Pooled Discovery of Synthetic Knockin Sequences to Program Durable Cell Therapies

Blaeschke

Chen

Apathy

et al. 2022

Preprint

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“…The rationale is that CAR T cells with a fusion receptor can persist after a single infusion and will not have side effects beyond the known CAR-related complications as shown in recent CAR T-cell trials with PD-1-CD28 fusion proteins ( 31 ). Last year, Zhao et al ( 26 ) published a TIM-3-CD28 fusion protein that uses the transmembrane and intracellular domain of CD28 and the extracellular domain of TIM-3 and is thus similar to TIM-3/CD28-4 from our study. Their design mediated increased persistence and antitumor efficacy when combined with a second-generation anti-CD19 CAR.…”

Section: Discussionmentioning

confidence: 72%

“…These fusion proteins usually consist of the extracellular domains of the inhibitory molecule (e.g., PD-1) fused to stimulatory intracellular domains (e.g., CD28) to redirect inhibitory signals toward T-cell stimulation. In the last couple of years, PD-1-CD28, TIM-3-CD28, and CD200R-CD28 fusion receptors were described ( 21 – 26 ). Here, we describe a systematic evaluation of TIM-3-CD28 fusion protein designs to specifically overcome inhibitory signals with the potential to increase CAR T-cell functionality and persistence.…”

Section: Introductionmentioning

confidence: 99%

Design and Evaluation of TIM-3-CD28 Checkpoint Fusion Proteins to Improve Anti-CD19 CAR T-Cell Function

et al. 2022

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Therapeutic targeting of inhibitory checkpoint molecules in combination with chimeric antigen receptor (CAR) T cells is currently investigated in a variety of clinical studies for treatment of hematologic and solid malignancies. However, the impact of co-inhibitory axes and their therapeutic implication remains understudied for the majority of acute leukemias due to their low immunogenicity/mutational load. The inhibitory exhaustion molecule TIM-3 is an important marker for the interaction of T cells with leukemic cells. Moreover, inhibitory signals from malignant cells could be transformed into stimulatory signals by synthetic fusion molecules with extracellular inhibitory receptors fused to an intracellular stimulatory domain. Here, we designed a variety of different TIM-3-CD28 fusion proteins to turn inhibitory signals derived by TIM-3 engagement into T-cell activation through CD28. In the absence of anti-CD19 CAR, two TIM-3-CD28 fusion receptors with large parts of CD28 showed strongest responses in terms of cytokine secretion and proliferation upon stimulation with anti-CD3 antibodies compared to controls. We then combined these two novel TIM-3-CD28 fusion proteins with first- and second-generation anti-CD19 CAR T cells and found that the fusion receptor can increase proliferation, activation, and cytotoxic capacity of conventional anti-CD19 CAR T cells. These additionally armed CAR T cells showed excellent effector function. In terms of safety considerations, the fusion receptors showed exclusively increased cytokine release, when the CAR target CD19 was present. We conclude that combining checkpoint fusion proteins with anti-CD19 CARs has the potential to increase T-cell proliferation capacity with the intention to overcome inhibitory signals during the response against malignant cells.

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“…Similar approaches are used for another immune checkpoint T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) by generating TIM-3-CD28 fusion proteins in CD19- or CD138-CAR-T cells. It converts the immunosuppressive TIM-3 signaling to CAR-T cells immunostimulation ( 48 , 49 ).…”

Section: Approaches To Mitigate the Immunosuppressive Tumor Microenvi...mentioning

confidence: 99%

CAR-T cell therapy for hematological malignancies: Limitations and optimization strategies

Huang

2022

Front. Immunol.

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In the past decade, the emergence of chimeric antigen receptor (CAR) T-cell therapy has led to a cellular immunotherapy revolution against various cancers. Although CAR-T cell therapies have demonstrated remarkable efficacy for patients with certain B cell driven hematological malignancies, further studies are required to broaden the use of CAR-T cell therapy against other hematological malignancies. Moreover, treatment failure still occurs for a significant proportion of patients. CAR antigen loss on cancer cells is one of the most common reasons for cancer relapse. Additionally, immune evasion can arise due to the hostile immunosuppressive tumor microenvironment and the impaired CAR-T cells in vivo persistence. Other than direct antitumor activity, the adverse effects associated with CAR-T cell therapy are another major concern during treatment. As a newly emerged treatment approach, numerous novel preclinical studies have proposed different strategies to enhance the efficacy and attenuate CAR-T cell associated toxicity in recent years. The major obstacles that impede promising outcomes for patients with hematological malignancies during CAR-T cell therapy have been reviewed herein, along with recent advancements being made to surmount them.

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

Cited by 21 publications

References 60 publications

Modular Pooled Discovery of Synthetic Knockin Sequences to Program Durable Cell Therapies

Modular Pooled Discovery of Synthetic Knockin Sequences to Program Durable Cell Therapies

Design and Evaluation of TIM-3-CD28 Checkpoint Fusion Proteins to Improve Anti-CD19 CAR T-Cell Function

CAR-T cell therapy for hematological malignancies: Limitations and optimization strategies

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