UNASSIGNED: The development of CAR-T-cell immunotherapy has notably elevated the efficacy of treating multiple myeloma. Currently, a variety of targets, including BCMA, CS1, CD38, FcRH5, and GPRC5D, are being investigated. Despite these significant advancements, challenges such as antigen escape, limited persistence of CAR-T cells, and the intricate nature of the tumor microenvironment persist, leading to relapses following treatment.
UNASSIGNED: We report the case of a patient with recurrent and refractory multiple myeloma (RRMM) who developed a substantial extramedullary plasmacytoma in the muscles of the lower limb following multiple rounds of radiotherapy and chemotherapy. The patient underwent CAR-T-cell immunotherapy targeting BCMA and CS1; however, the tumor progressed despite treatment. Surgical resection of the extramedullary plasmacytoma was subsequently performed. Upon comparison of the tumor tissue with the adjacent tissue, increased expression of MYBL2 was noted in the tumor tissue, potentially contributing to the lack of improvement in extramedullary relapse after dual-targeted CAR-T cell therapy.
UNASSIGNED: In patients with recurrent and refractory multiple myeloma who underwent multiple cycles of chemotherapy and radiotherapy, dual-targeted CAR-T cell therapy aimed at BCMA and CS1 failed to effectively manage extramedullary relapse. Elevated expression of MYBL2 in multiple myeloma correlates with a poorer prognosis.

Liver cancer, which most commonly manifests as hepatocellular carcinoma (HCC), is the sixth most common cancer in the world. In HCC, the immune system plays a crucial role in the growth and proliferation of tumor cells. HCC achieve immune escape through the tumor microenvironment, which significantly promotes the development of this cancer. Here, this article introduces and summarizes the functions and effects of regulatory T cells (Tregs) in the tumor microenvironment, highlighting how Tregs inhibit and regulate the functions of immune and tumor cells, cytokines, ligands and receptors, etc, thereby promoting tumor immune escape. In addition, it discusses the mechanism of CAR-T therapy for HCC and elaborate on the relationship between CAR-T and Tregs.

In the past decade, chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising immunotherapeutic approach for combating cancers, demonstrating remarkable efficacy in relapsed/refractory hematological malignancies in both pediatric and adult patients. CAR-natural killer (CAR-NK) cell complements CAR-T cell therapy by offering several distinct advantages. CAR-NK cells do not require HLA compatibility and exhibit low safety concerns. Moreover, CAR-NK cells are conducive to \"off-the-shelf\" therapeutics, providing significant logistic advantages over CAR-T cells. Both CAR-T and CAR-NK cells have shown consistent and promising results in hematological malignancies. However, their efficacy against solid tumors remains limited due to various obstacles including limited tumor trafficking and infiltration, as well as an immuno-suppressive tumor microenvironment. In this review, we discuss the recent advances and current challenges of CAR-T and CAR-NK cell immunotherapies, with a specific focus on the obstacles to their application in solid tumors. We also analyze in depth the advantages and drawbacks of CAR-NK cells compared to CAR-T cells and highlight CAR-NK CAR optimization. Finally, we explore future perspectives of these adoptive immunotherapies, highlighting the increasing contribution of cutting-edge biotechnological tools in shaping the next generation of cellular immunotherapy.

UNASSIGNED: This is a summary of a phase 3 clinical trial called CARTITUDE-4. This trial compared the anti-cancer therapy ciltacabtagene autoleucel (or cilta-cel) with standard therapies in people who have multiple myeloma, a cancer that affects specific kinds of blood cells called plasma cells. The people in the study had been treated with 1 to 3 previous treatments for multiple myeloma, including a common anti-myeloma treatment called lenalidomide, but their multiple myeloma did not get better.
UNASSIGNED: About half of the 419 participants in this study received cilta-cel, while the other half received standard therapies, or therapies that are commonly used to treat multiple myeloma. Participants who received cilta-cel had a type of immune cell called T cells collected from their blood and genetically modified to recognize a specific protein found on myeloma cells. These modified T cells, which comprise cilta-cel, were then infused back into the bloodstream.
UNASSIGNED: After approximately 1 year in the study, more participants were alive without their cancer getting worse in the cilta-cel group (76%) than in the standard therapies group (49%). The most common side effects in both groups were infections and low blood cell counts. Cytokine release syndrome (a potentially serious side effect caused by overactivation of the immune system) was common but mostly mild. Neurotoxicities (including immune effector cell-associated neurotoxicity syndrome, which can cause symptoms such as headaches, changes in consciousness, and difficulty with memory, attention, speaking, or understanding others) were less common and were reported in 20.5% of participants treated with cilta-cel.
UNASSIGNED: In CARTITUDE-4, more participants treated with cilta-cel showed improvements and were alive with control of their disease 12 months after receiving cilta-cel compared with participants who received standard therapies.Clinical Trial Registration: NCT04181827 (CARTITUDE-4) (ClinicalTrials.gov).

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CAR-T cell therapy has established itself as a highly effective treatment for hematological malignancies. There are currently six commercial CAR-T products that have been FDA approved for diseases such as B-ALL, LBCL, MCL, FL, MM, and CLL/SLL. \"Real-world\" studies allow us to evaluate outcomes from the general population to determine their efficacy and safety compared to those who were included in the original trials. Based on several well conducted \"Real-world\" studies that represent diverse populations, we report that outcomes from the original trials that led to the approval of these therapies are comparable to those in practice.

T cell malignancies pose several unique issues for CAR-T cell therapy that were not significant concerns with CAR-T cells for B-cell malignancies. A general problem to consider in the production of CAR-T cells is \"on target-off tumor toxicity.\" This occurs when the antigen targeted by the CAR-T cells is also expressed on normal cells, not just tumor cells, which causes CAR-T cells to damage these normal cells. In CAR-T cell therapy for T cell tumors, antigens expressed on T cells (such as CD5, CD7, etc.) are the targets, which leads to a problem known as \"fratricide,\" where CAR-T cells kill each other. Other issues include T cell aplasia and contamination of CAR-T cell products with tumor cells. However, several recent clinical trials have shown excellent outcomes for CAR-T cell therapy when genome editing technology is used to overcome these issues by knocking out target antigens or T cell receptors. This review article outlines these challenges and their solutions and discusses the results of recent clinical trials.

Immunotherapy has made significant strides in cancer treatment with strategies like checkpoint blockade antibodies and adoptive T cell transfer. Chimeric antigen receptor T cells (CAR-T) have emerged as a promising approach to combine these strategies and overcome their limitations. This review explores CAR-T cells as a living drug for cancer treatment. CAR-T cells are genetically engineered immune cells designed to target and eliminate tumor cells by recognizing specific antigens. The study involves a comprehensive literature review on CAR-T cell technology, covering structure optimization, generations, manufacturing processes, and gene therapy strategies. It examines CAR-T therapy in haematologic cancers and solid tumors, highlighting challenges and proposing a suicide gene-based mechanism to enhance safety. The results show significant advancements in CAR-T technology, particularly in structure optimization and generation. The manufacturing process has improved for broader clinical application. However, a series of inherent challenges and side effects still need to be addressed. In conclusion, CAR-T cells hold great promise for cancer treatment, but ongoing research is crucial to improve efficacy and safety for oncology patients. The proposed suicide gene-based mechanism offers a potential solution to mitigate side effects including cytokine release syndrome (the most common toxic side effect of CAR-T therapy) and the associated neurotoxicity.

Although CRISPR-Cas9 technology is poised to revolutionize the treatment of diseases with underlying genetic mutations, it faces some significant issues limiting clinical entry. They include low-efficiency in vivo systemic delivery and undesired off-target effects. Here, we demonstrate, by modifying Cas9 with phosphorothioate-DNA oligos (PSs), that one can efficiently deliver single and bi-specific CRISPR-Cas9/guide RNA (gRNA) dimers in vitro and in vivo with reduced off-target effects. We show that PS-Cas9/gRNA-mediated gene knockout preserves chimeric antigen receptor T cell viability and expansion in vitro and in vivo. PS-Cas9/gRNA mediates gene perturbation in patient-derived tumor organoids and mouse xenograft tumors, leading to potent tumor antitumor effects. Further, HER2 antibody-PS-Cas9/gRNA conjugate selectively perturbs targeted genes in HER2+ ovarian cancer xenografts in vivo. Moreover, we created bi-specific PS-Cas9 with two gRNAs to target two adjacent sequences of the same gene, leading to efficient targeted gene disruption ex vivo and in vivo with markedly reduced unintended gene perturbation. Thus, the cell-penetrating PS-Cas9/gRNA can achieve efficient systemic delivery and precision in gene disruption.

Chimeric antigen receptor (CAR) T cells have shown significant efficacy in hematological diseases. However, CAR T therapy has demonstrated limited efficacy in solid tumors, including glioblastoma (GBM). One of the most important reasons is the immunosuppressive tumor microenvironment (TME), which promotes tumor growth and suppresses immune cells used to eliminate tumor cells. The human transforming growth factor β (TGF-β) plays a crucial role in forming the suppressive GBM TME and driving the suppression of the anti-GBM response. To mitigate TGF-β-mediated suppressive activity, we combined a dominant-negative TGF-β receptor II (dnTGFβRII) with our previous bicistronic CART-EGFR-IL13Rα2 construct, currently being evaluated in a clinical trial, to generate CART-EGFR-IL13Rα2-dnTGFβRII, a tri-modular construct we are developing for clinical application. We hypothesized that this approach would more effectively subvert resistance mechanisms observed with GBM. Our data suggest that CART-EGFR-IL13Rα2-dnTGFβRII significantly augments T cell proliferation, enhances functional responses, and improves the fitness of bystander cells, particularly by decreasing the TGF-β concentration in a TGF-β-rich TME. In addition, in vivo studies validate the safety and efficacy of the dnTGFβRII cooperating with CARs in targeting and eradicating GBM in an NSG mouse model.