Key Players in the Mutant p53 Team: Small Molecules, Gene Editing, Immunotherapy

Chasov, Vitaly; Mirgayazova, Regina; Zmievskaya, Ekaterina; Khadiullina, Raniya; Valiullina, Aygul; Clarke, Joseph R. Stephenson; Rizvanov, Albert A.; Baud, Matthias G. J.; Bulatov, Emil

doi:10.3389/fonc.2020.01460

Cited by 34 publications

(39 citation statements)

References 75 publications

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“…It improves the efficacy of anti-CD19 CAR T-cell-targeted therapy suggesting that the TP53 mutation could be a potential target of CAR T-cell therapy. We speculate that anti-CD19 CAR T-cells could have a therapeutic effect on TP53 gene mutations ( Malekzadeh et al, 2019 ; Chasov et al, 2020 ; Titov et al, 2020 ).…”

Section: Discussionmentioning

confidence: 98%

Benefits of Chimeric Antigen Receptor T-Cell Therapy for B-Cell Lymphoma

et al. 2022

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Objective: The aim was to study the benefits and risks of anti-CD19 chimeric antigen receptor (CAR) T-cells in adults with B-cell lymphoma.Methods: From October 2015 to October 2021, we treated five patients with B-cell lymphoma, comprising two with mantle cell lymphoma, one case of Burkitt lymphoma, one case of diffuse large B-cell lymphoma, and one case of chronic lymphocytic leukemia/small lymphocytic lymphoma. The patients were given the FC regimen 5 days before the infusion of anti-CD19 CAR T-cells. The median total number of CAR T-cells infusions was 350*10^6 (88*10^6–585*10^6).Results: 1) Patients who received CAR T-cell induction therapy achieved complete remission (CR) in Case 1 and Case 3 and partial remission (PR) in Case 2. Case 3’s ATM and D13S25 gene deletions were negative 42 days after CAR T-cell therapy, and molecular biology CR (mCR) and minimal residual disease (MRD) were negative for 5 years and 6 months. The patient in Case 3 was cured. 2) Case 4 patient’s TP53 gene mutation became negative 1 month after CAR T-cell therapy. MRD was negative after CAR T-cell therapy at 41 and 42 months in Cases 4 and 5, respectively. 3) Case 1∼Case 3 patients developed cytokine release syndrome (CRS) without encephalopathy syndrome, accompanied with serious adverse events. CRS can be effectively managed with tocilizumab, etanercept, glucocorticoids, and plasmapheresis.Conclusion: Anti-CD19 CAR T-cell therapy is effective in treating relapsed/refractory B-cell lymphoma, and the side effects of CAR T-cell therapy can be properly managed. CAR T-cell therapy has high efficacy and presented no side effects in the treatment of MRD in B-cell lymphoma (NCT03685786, NCT02456350).

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Section: Discussionmentioning

confidence: 98%

Benefits of Chimeric Antigen Receptor T-Cell Therapy for B-Cell Lymphoma

et al. 2022

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“…The P53 protein encoded by the TP53 gene is an important tumor suppressor that mediates cell cycle arrest, DNA repair, apoptosis, aging and autophagy under cellular stress [ 15 ]. Nonsynonymous TP53 mutations alter the P53 protein sequence and structure, disrupt its function and are the most common mechanism that inactivates TP53 [ 29 , 30 ]. In this study, we tested 29 specific TP53 mutations, most of which resided within the DNA-binding domain and have been reported to be associated with a poor prognosis in various cancers, including NHL [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

TP53-Mutated Circulating Tumor DNA for Disease Monitoring in Lymphoma Patients after CAR T Cell Therapy

Chen

et al. 2021

Diagnostics

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Chimeric antigen receptor T (CAR T) cell immunotherapy has shown remarkable efficacy in non-Hodgkin’s lymphoma (NHL) patients. Minimal residual disease (MRD) monitoring in NHL is essential after CAR T cell therapy, which can be achieved by monitoring circulating tumor DNA (ctDNA). The mutation of TP53 in NHL has been suggested to be associated with a poor prognosis. However, whether TP53-mutated ctDNA can be used as a biomarker remains undetermined. In this study, a total of 40 patients with mutated TP53 who received CAR T cell treatment were analyzed, and specific probes targeting 29 different TP53 mutation sites in the 40 patients were designed and verified. Then, the presence of TP53-mutated ctDNA in longitudinal plasma samples was tracked by droplet digital PCR. Patients were stratified into two groups, favorable or unfavorable, based on their highest ctDNA level using a MAF cutoff of 3.15% according to the ROC curve. The unfavorable group had significantly worse PFS than the favorable group (p < 0.001). Our results suggest that patients with mutated TP53 with a favorable ctDNA profile in the first trimester have better prognostic outcomes than patients with an unfavorable profile, and ctDNA can be a reliable predictor of the subsequent clinical outcome.

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“…Human cancer is often accompanied by genetic mutations, especially in TP53 , with each patient carrying their own set of mutations resulting in neoantigen-specific T cell responses. This knowledge can be utilized to develop personalized therapies depending on the tumor genetic profile ( 20 ). One of the main treatment modalities within cancer immunotherapy is the adoptive cell therapy (ACT) approach based on autologous or allogeneic tumor-specific cytotoxic T cells.…”

Section: Adoptive T Cell-based Immunotherapymentioning

confidence: 99%

Promising New Tools for Targeting p53 Mutant Cancers: Humoral and Cell-Based Immunotherapies

et al. 2021

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Transcription factor and oncosuppressor protein p53 is considered as one of the most promising molecular targets that remains a high-hanging fruit in cancer therapy. TP53 gene encoding the p53 protein is known to be the most frequently mutated gene in human cancers. The loss of transcriptional functions caused by mutations in p53 protein leads to deactivation of intrinsic tumor suppressive responses associated with wild-type (WT) p53 and acquisition of new pro-oncogenic properties such as enhanced cell proliferation, metastasis and chemoresistance. Hotspot mutations of p53 are often immunogenic and elicit intratumoral T cell responses to mutant p53 neoantigens, thus suggesting this protein as an attractive candidate for targeted anti-cancer immunotherapies. In this review we discuss the possible use of p53 antigens as molecular targets in immunotherapy, including the application of T cell receptor mimic (TCRm) monoclonal antibodies (mAbs) as a novel powerful approach.

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Key Players in the Mutant p53 Team: Small Molecules, Gene Editing, Immunotherapy

Cited by 34 publications

References 75 publications

Benefits of Chimeric Antigen Receptor T-Cell Therapy for B-Cell Lymphoma

Benefits of Chimeric Antigen Receptor T-Cell Therapy for B-Cell Lymphoma

TP53-Mutated Circulating Tumor DNA for Disease Monitoring in Lymphoma Patients after CAR T Cell Therapy

Promising New Tools for Targeting p53 Mutant Cancers: Humoral and Cell-Based Immunotherapies

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