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P53 mutation (TP53m) is a common intrinsic factor involved in relapsed or refractory (R/R) B cell malignancies that associates with treatment resistance. As a novel immunotherapy, CAR‐T has been increasingly applied in TP53m B cell malignancies, yet whether it can overcome the poor outcome of the TP53m population is controversial. We searched MEDLINE and EMBASE to identify population‐based cohort studies that evaluated the CAR‐T treatment outcomes between wild type and TP53m patients in B cell malignancies. Meta‐analysis on their complete response (CR), partial response (PR), overall response rate (ORR), progression‐free survival (PFS) and overall survival (OS) was carried out and pooled risk ratios (RR) or hazard ratios (HR) were estimated. A total of 10 eligible studies reporting 848 patients with B cell malignancies from wild type and TP53m groups receiving CAR‐T therapy were selected. The CR and ORR were comparable in both wild type and TP53m patients either with B cell lymphoma or leukaemia (all p > 0.05). However, the TP53m group was associated with shorter PFS and OS in both diseases (all p < 0.05). In traditional single targeting CAR‐T therapy, the PFS and OS were shorter in the TP53m group than in the wild type group (all p < 0.05). In contrast, the former outcomes of the wild type and TP53m groups were comparable when receiving dual‐targeting CAR‐T treatment (all p > 0.05). Though the CR and ORR of wild type and TP53m groups were similar, the PFS and OS of B cell malignancy patients bearing TP53m were inferior to wild type patients receiving CAR‐T cell treatment. Notably, the CR, PFS and OS of wild type and TP53m groups exhibit the same therapeutic effect via CD19/22 CAR‐T cocktail therapy. In other words, the poor prognosis of TP53m patients may be overcome by double targeting CAR‐T mode.

Background The efficacy of CD22 or CD19 chimeric antigen receptor T (CAR‐T) cells in the management of acute lymphoblastic leukemia (ALL) and non‐Hodgkin lymphoma (NHL) was observed. Because antigen loss and lack of CAR‐T‐cell persistence are the leading causes of progressive disease following single‐antigen targeting, we evaluated CD22/CD19 dual‐targeting CAR‐T‐cell therapy efficacy and safety in relapsed/refractory B‐cell malignancies. Methods The Web of Science, PubMed, Cochrane, and Embase databases were searched until July 2022. Patients confirmed with any relapsed/refractory B‐cell hematological malignancies were included regardless of age, gender, or ethnicity, receiving CD22 and CD19‐dual‐targeting CAR‐T‐cell therapy. The studies conducted on patients with coexisting other cancer were excluded. We used random‐effect models to explore the outcome, and heterogeneity was investigated by subgroup analysis. Results Fourteen studies (405 patients) were included. The pooled overall response (OR) and complete remission (CR) were 97% and 93%, respectively, for ALL patients. The 1‐year proportions of overall survival (OS) and progression‐free survival (PFS) were 70% and 49%, respectively. For NHL, OR occurred in 85% of patients, and 57% experienced CR. The results illustrated that the 1‐year OS and 1‐year PFS were 77% and 65%, respectively. The subgroup analysis showed that the dual‐targeting modality achieved higher CR in the following cases: coadministration of CD22/CD19‐CAR‐T cells and third‐generation CAR‐T cells combined with ASCT and BEAM pretreatment. The ALL and NHL groups seemed similar in treatment‐related toxicity: all grade cytokine release syndrome (CRS), severe CRS, and neurotoxicity occurred in 86%, 7%, and 12% of patients, respectively. Conclusions Our meta‐analysis demonstrated that the CD22/CD19 dual‐targeting CAR‐T‐cell strategy has high efficiency with tolerable adverse effects in B‐cell malignancies. This meta‐analysis demonstrates very high responses by using dual‐targeting CAR‐T therapy with a tolerable safety profile in treating R/R B‐cell hematologic malignancies. Although further studies are warranted, these findings may help immunologists and clinicians design proper CAR structure and/or combine with important target therapies to improve clinical outcomes.

Epithelial ovarian cancer is the most lethal of gynecological cancers. The therapeutic efficacy of chimeric antigen receptor (CAR) T cell directed against single antigens is limited by the heterogeneous target antigen expression in epithelial ovarian tumors. To overcome this limitation, we describe an engineered cell with both dual targeting and orthogonal cytotoxic modalities directed against two tumor antigens that are highly expressed on ovarian cancer cells: cell surface Muc16 and intracellular WT1. Muc16-specific CAR T cells (4H11) were engineered to secrete a bispecific T cell engager (BiTE) constructed from a TCR mimic antibody (ESK1) reactive with the WT1-derived epitope RMFPNAPYL (RMF) presented by HLA-A2 molecules. The secreted ESK1 BiTE recruited and redirected other T cells to WT1 on the tumor cells. We show that ESK1 BiTE-secreting 4H11 CAR T cells exhibited enhanced anticancer activity against cancer cells with low Muc16 expression, compared to 4H11 CAR T cells alone, both in vitro and in mouse tumor models. Dual orthogonal cytotoxic modalities with different specificities targeting both surface and intracellular tumor-associated antigens present a promising strategy to overcome resistance to CAR T cell therapy in epithelial ovarian cancer and other cancers.

Single-targeted chimeric antigen receptor (CAR) T cells tremendously improve outcomes for patients with relapsed/refractory hematological malignancies and are considered a breakthrough therapy. However, over half of treated patients experience relapse or refractory disease, with antigen escape being one of the main contributing mechanisms. Dual-targeting CAR T-cell therapy is being developed to minimize the risk of relapse or refractory disease. Preclinical and clinical data on five categories of dual-targeting CAR T-cell therapies and approximately fifty studies were summarized to offer insights and support the development of dual-targeting CAR T-cell therapy for hematological malignancies. The clinical efficacy (durability and survival) is validated and the safety profiles of dual-targeting CAR T-cell therapy are acceptable, although there is still room for improvement in the bispecific CAR structure. It is one of the best approaches to optimize the bispecific CAR structure by boosting T-cell transduction efficiency and leveraging evidence from preclinical activity and clinical efficacy.

CD19-targeted chimeric receptor antigen (CAR)-T cell therapy has shown remarkable clinical efficacy in the treatment of relapsed or refractory (R/R) B-cell malignancies. However, 30%–60% of patients eventually relapsed, with the CD19-negative relapse being an important hurdle to sustained remission. CD22 expression is independent of CD19 expression in malignant B cells. Consequently, CD22 is a potential alternative target for CD19 CAR-T cell-resistant patients. CD22-targeted therapies, mainly including the antibody–drug conjugates (ADCs) and CAR-T cells, have come into wide clinical use with acceptable toxicities and promising efficacy. In this review, we explore the molecular and physiological characteristics of CD22, development of CD22 ADCs and CAR-T cells, and the available clinical data on CD22 ADCs and CAR-T cell therapies. Furthermore, we propose some perspectives for overcoming tumor escape and enhancing the efficacy of CD22-targeted therapies.

Leukemia is a prevalent pediatric cancer with significant challenges, particularly in relapsed or refractory cases. Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a personalized cancer treatment, modifying patients’ T cells to target and destroy resistant cancer cells. This study reviews the current therapeutic options of CAR-T therapy for leukemia, addressing the primary obstacles such as antigen escape and T-cell exhaustion. We explore dual-targeting strategies and their potential to improve treatment outcomes by preventing the loss of target antigens. Additionally, we examine the mechanisms of T-cell exhaustion and strategies to enhance CAR-T persistence and effectiveness. Despite remarkable clinical successes, CAR-T therapy poses risks such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Our findings highlight the need for ongoing research to optimize CAR-T applications, reduce toxicities, and extend this innovative therapy to a broader range of hematologic malignancies. This comprehensive review aims to provide valuable insights for improving leukemia treatment and advancing the field of cancer immunotherapy.

In the last decade, anti-CD19 CAR-T cell therapy has led to a treatment paradigm shift for B-cell non-Hodgkin lymphomas, first with the approval for relapsed/refractory (R/R) large B-cell lymphomas and subsequently for R/R mantle cell and follicular lymphoma. Many efforts are continuously being made to extend the therapeutic setting in the lymphoma field. Several reports are supporting the safety and efficacy of CAR-T cells in patients with central nervous system disease involvement. Anti-CD30 CAR-T cells for the treatment of Hodgkin lymphoma are in development and early studies looking for the optimal target for T-cell malignancies are ongoing. Anti-CD19/CD20 and CD19/CD22 dual targeting CAR-T cells are under investigation in order to increase anti-lymphoma activity and overcome tumor immune escape. Allogeneic CAR product engineering is on the way, representing a rapidly accessible ‘off-the-shelf’ and potentially more fit product. In the present manuscript, we will focus on recent advances in CAR-T cell therapy for lymphomas, including new settings and future perspectives in the field, reviewing data reported in literature in the last decade up to October 2023.

In the last few decades, chimeric antigen receptor (CAR) T-cell therapy has led to a paradigm shift in the treatment of hematological malignancies, including various subtypes of B-cell non-Hodgkin’s lymphoma, B-cell acute lymphoblastic leukemia, and multiple myeloma. However, most patients experience refractoriness to CAR T-cells or relapse after treatment. Many efforts are underway to understand the mechanisms behind CAR T-cell failure, which are mainly related to CAR T-cell dysfunction, tumor-intrinsic resistance, an immunosuppressive tumor microenvironment, manufacturing issues, or patient-related factors. Several strategies are being developed to overcome these resistance mechanisms, including the engineering of more functional allogeneic CAR T-cell products, the targeting of alternative tumor antigens, and combination therapies with other drugs such as checkpoint inhibitors or small molecules to enhance CAR T-cell efficacy. In this review, we will provide an updated overview of the mechanisms of CAR T-cell failure and the therapeutic advances currently under development to address them.

HIV cannot be cured by current antiretroviral therapy (ART) because it persists in a transcriptionally silent form in long-lived CD4+ cells. Leading efforts to develop a functional cure have prioritized latency reversal to expose infected cells to immune surveillance, coupled with enhancement of the natural cytolytic function of immune effectors, or \"kick and kill.\" The most clinically advanced approach to improving the kill is therapeutic immunization, which aims to augment or re-focus HIV-specific cytolytic T cell responses. However, no vaccine strategy has enabled sustained virological control after ART withdrawal. Novel approaches are needed to overcome the limitations of natural adaptive immune responses, which relate to their specificity, potency, durability, and access to tissue reservoirs. Adoptive T cell therapy to treat HIV infection was first attempted over two decades ago, without success. Since then, progress in the field of cancer immunotherapy, together with recognition of the similarities in tumor microenvironments and HIV reservoirs has reignited interest in the application of T cell therapies to HIV eradication. Advances in engineering of chimeric antigen receptor (CAR)-transduced T cells have led to improved potency, persistence and latterly, resistance to HIV infection. Immune retargeting platforms have incorporated non-neutralizing and broadly neutralizing antibodies to generate Bispecific T cell Engagers (BiTEs) and Dual-Affinity Re-Targeting proteins (DARTs). T cell receptor engineering has enabled the development of the first bispecific Immune-mobilizing monoclonal T Cell receptors Against Viruses (ImmTAV) molecules. Here, we review the potential for these agents to provide a better \"kill\" and the challenges ahead for clinical development.