A rational approach to assess off-target reactivity of a dual-signal integrator for T cell therapy

Wang, Xueyin; Wong, Lu Min; McElvain, Michele; Matarazzo, Sara; Lee, Wen-Hua; Li, Chuck Z.; Fisher, Fernando; Maheshwari, Ruchika L.; Wu, Mei; Imun, Maria Chun; Murad, Rabi; Warshaviak, Dora Toledo; Yin, Jun; Kamb, Alexander; Han, Xu

doi:10.1016/j.taap.2022.115894

Cited by 6 publications

(3 citation statements)

References 68 publications

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“…Although this type of promising therapy is changing the paradigm of cancer treatment, especially for MM, CAR-T cells still have some limitations that have significantly compromised their safety and efficacy. An example is that CAR-T cells can cause on-target or off-target tumor toxicity [ 60 ] due to the induction of an autoimmune response caused by their antigen reactivity. In addition, CAR-T cells have a certain probability of losing antigen-specific reactivity in vivo due to antigen escape and may also lack in vivo persistence.…”

Section: Monovalent Car T Strategymentioning

confidence: 99%

From spear to trident: Upgrading arsenal of CAR-T cells in the treatment of multiple myeloma

Zhao,

Zheng,

et al. 2024

Heliyon

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Section: Monovalent Car T Strategymentioning

confidence: 99%

From spear to trident: Upgrading arsenal of CAR-T cells in the treatment of multiple myeloma

Zhao,

Zheng,

et al. 2024

Heliyon

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“…Therefore, when selecting a suitable target antigen, the primary consideration must be target antigens that are highly expressed in tumors but have low expression or are not expressed in normal tissues. Garcia et al 77 developed an alternative strategy to isolate TCR mutants that exhibited high activation signals coupled with low-affinity pMHC binding. Additionally, their model exhibited enhanced target killing potency and undetectable cross-reactivity as well as reduced potential for adverse cross-reactivity.…”

Section: Tcr-t Immunotherapymentioning

confidence: 99%

Current Situation and Prospect of Adoptive Cellular Immunotherapy for Malignancies

Zhao,

Zhu,

Cai

et al. 2023

Technol Cancer Res Treat

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Adoptive cell immunotherapy (ACT) is an innovative promising treatment for tumors. ACT is characterized by the infusion of active anti-tumor immune cells (specific and non-specific) into patients to kill tumor cells either directly or indirectly by stimulating the body's immune system. The patient's (autologous) or a donor's (allogeneic) immune cells are used to improve immune function. Chimeric antigen receptor (CAR) T cells (CAR-T) is a type of ACT that has gained attention. T cells from the peripheral blood are genetically engineered to express CARs that rapidly proliferate and specifically recognize target antigens to exert its anti-tumor effects. Clinical application of CAR-T therapy for hematological tumors has shown good results, but adverse reactions and recurrence limit its applicability. Tumor infiltrating lymphocyte (TIL) therapy is effective for solid tumors. TIL therapy exhibits T cell receptor (TCR) clonality, superior tumor homing ability, and low targeted toxicity, but its successful application is limited to a number of tumors. Regardless, TIL and CAR-T therapies are effective for treating cancer. Additionally, CAR-natural killer (NK), CAR-macrophages (M), and TCR-T therapies are currently being researched. In this review, we highlight the current developments and limitations of several types of ACT.

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“…[16][17][18][19] The over-expressed receptors in tumor cells could provide targets for nanoparticles, but off-target effects frequently occur due to the expression on the normal cells. [20][21][22][23] The heat shock protein 70 (Hsp70) serves as a molecular chaperone to support the correct folding of peptides, repair damaged protein, and protect cells from apoptosis. [24][25][26] Hsp70 is usually located in the cytoplasm of normal cells, but it would be highly expressed on the membrane of malignantly transformed cells under stress such as hypoxia, glucose deprivation, and cytotoxicity pressure.…”

Section: Introductionmentioning

confidence: 99%

Hsp70‐Targeting and Size‐Tunable Nanoparticles Combine with PD‐1 Checkpoint Blockade to Treat Glioma

Xie

Wang

Tong

et al. 2023

Small

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Invasive glioma usually disrupts the integrity of the blood‐brain barrier (BBB), making the delivery of nanodrugs across the BBB possible, but sufficient targeting ability is still avidly needed to improve drug accumulation in glioma. Membrane‐bound heat shock protein 70 (Hsp70) is expressed on the membrane of glioma cells rather than adjacent normal cells, therefore it can serve as a specific glioma target. Meanwhile, prolonging the retention in tumors is important for active‐targeting nanoparticles to overcome receptor‐binding barriers. Herein, the Hsp70‐targeting and acid‐triggered self‐assembled gold nanoparticles (D‐A‐DA/TPP) are proposed to realize selective delivery of doxorubicin (DOX) to glioma. In the weakly acidic glioma matrix, D‐A‐DA/TPP formed aggregates to prolong retention, improve receptor‐binding efficiency and facilitate acid‐responsive DOX release. DOX accumulation in glioma induced immunogenic cell death (ICD) to promote antigen presentation. Meanwhile, combination with the PD‐1 checkpoint blockade further activate T cells and provokes robust anti‐tumor immunity. The results showed that D‐A‐DA/TPP can induce more glioma apoptosis. Furthermore, in vivo studies indicated D‐A‐DA/TPP plus PD‐1 checkpoint blockade significantly improved median survival time. This study offeres a potential nanocarrier combining size‐tunable strategy with active targeting ability to increase drug enrichment in glioma and synergizes with PD‐1 checkpoint blockade to achieve chemo‐immunotherapy.

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A rational approach to assess off-target reactivity of a dual-signal integrator for T cell therapy

Cited by 6 publications

References 68 publications

From spear to trident: Upgrading arsenal of CAR-T cells in the treatment of multiple myeloma

From spear to trident: Upgrading arsenal of CAR-T cells in the treatment of multiple myeloma

Current Situation and Prospect of Adoptive Cellular Immunotherapy for Malignancies

Hsp70‐Targeting and Size‐Tunable Nanoparticles Combine with PD‐1 Checkpoint Blockade to Treat Glioma

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