Novel therapeutic agents in clinical trials offer a paradigm shift in the approach to battling this prevalent and destructive disease, and the area of cancer therapy is on the precipice of a trans formative revolution. Despite the importance of tried-and-true cancer treatments like surgery, radiation, and chemotherapy, the disease continues to evolve and adapt, making new, more potent methods necessary. The field of cancer therapy is currently witnessing the emergence of a wide range of innovative approaches. Immunotherapy, including checkpoint inhibitors, CAR-T cell treatment, and cancer vaccines, utilizes the host\'s immune system to selectively target and eradicate malignant cells while minimizing harm to normal tissue. The development of targeted medicines like kinase inhibitors and monoclonal antibodies has allowed for more targeted and less harmful approaches to treating cancer. With the help of genomics and molecular profiling, \"precision medicine\" customizes therapies to each patient\'s unique genetic makeup to maximize therapeutic efficacy while minimizing unwanted side effects. Epigenetic therapies, metabolic interventions, radio-pharmaceuticals, and an increasing emphasis on combination therapy with synergistic effects further broaden the therapeutic landscape. Multiple-stage clinical trials are essential for determining the safety and efficacy of these novel drugs, allowing patients to gain access to novel treatments while also furthering scientific understanding. The future of cancer therapy is rife with promise, as the integration of artificial intelligence and big data has the potential to revolutionize early detection and prevention. Collaboration among researchers, and healthcare providers, and the active involvement of patients remain the bedrock of the ongoing battle against cancer. In conclusion, the dynamic and evolving landscape of cancer therapy provides hope for improved treatment outcomes, emphasizing a patient-centered, data-driven, and ethically grounded approach as we collectively strive towards a cancer-free world.

The emergence of chimeric antigen receptor T cell (CAR-T cell) therapy has revolutionized cancer treatment, particularly for hematologic malignancies. This commentary discusses developments in CAR-T cell therapy, focusing on the molecular mechanisms governing T cell fate and differentiation. Transcriptional and epigenetic factors play a pivotal role in determining the specificity, effectiveness, and durability of CAR-T cell therapy. Understanding these mechanisms is crucial to improve the efficacy and decrease the adverse events associated with CAR-T cell therapies, unlocking the full potential of these approaches. T cell differentiation in CAR-T cell product manufacturing plays an important role in clinical outcomes. A positive correlation exists between the clinical efficacy of CAR-T cell therapy and signatures of memory, whereas a negative correlation has been observed with signatures of effector function or exhaustion. The effectiveness of CAR-T cell products is likely influenced by T-cell frequency and by their ability to proliferate, which is closely linked to early T cell differentiation. The differentiation process involving distinct T memory cell subsets is initiated upon antigen elimination, indicating infection resolution. In chronic infections or cancer, T cells may undergo exhaustion, marked by continuous inhibitory receptor expression, decreased cytokine production, and diminished proliferative capacity. Other cell subsets, such as CD4+ T cells, innate-like T lymphocytes, NKT cells, and cord blood-derived hematopoietic stem cells, offer unique advantages in developing the next-generation CAR-T cell-based therapies. Future research should focus on optimizing T-cell-enhancing approaches and developing strategies to potentially cure patients with hematological diseases and solid tumors.

UNASSIGNED: Acute lymphoblastic leukemia (ALL) represents the predominant cancer in pediatric populations, though its occurrence in adults is relatively rare. Pre-treatment risk stratification is crucial for predicting prognosis. Important factors for assessment include patient age, white blood cell (WBC) count at diagnosis, extramedullary involvement, immunophenotype, and cytogenetic aberrations. Minimal residual disease (MRD), primarily assessed by flow cytometry following remission, plays a substantial role in guiding management plans. Over the past decade, significant advancements in ALL outcomes have been witnessed. Conventional chemotherapy has remarkably reduced mortality rates; however, its intensive nature raises safety concerns and has led to the emergence of treatment-resistant cases with recurrence of relapses. Consequently, The U.S. Food and Drug Administration (FDA) has approved several novel treatments for relapsed/refractory ALL due to their demonstrated efficacy, as indicated by improved complete remission and survival rates. These treatments include tyrosine kinase inhibitors (TKIs), the anti-CD19 monoclonal antibody blinatumomab, anti-CD22 inotuzumab ozogamicin, anti-CD20 rituximab, and chimeric antigen receptor (CAR) T-cell therapy. Identifying the variables that influence treatment decisions is a pressing necessity for tailoring therapy based on heterogeneous patient characteristics. Key predictive factors identified in various observational studies and clinical trials include prelymphodepletion disease burden, complex genetic abnormalities, and MRD. Furthermore, the development of serious adverse events following treatment could be anticipated through predictive models, allowing for appropriate prophylactic measures to be considered. The ultimate aim is to incorporate the concept of precision medicine in the field of ALL through valid prediction platform to facilitate the selection of the most suitable treatment approach.

UNASSIGNED: Inconsistent results observed in recent phase III trials assessing chimeric antigenic receptor T (CAR-T) cell therapy as a second-line treatment compared to standard of care (SOC) in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) prompted a meta-analysis to assess the effectiveness of CAR-T cell therapy in this setting.
UNASSIGNED: Random-effects meta-analysis was conducted to pool effect estimates for comparison between CAR-T cell therapy and SOC. Mixed treatment comparisons were made using a frequentist network meta-analysis approach.
UNASSIGNED: Meta-analysis of three trials with 865 patients showed significant improvement in event-free survival (EFS: HR: 0.51; 95% CI: 0.27-0.97; I2: 92%), progression-free survival (PFS: HR: 0.47; 95% CI: 0.37-0.60; I2: 0%) with CAR-T cell therapy compared to SOC. Although there was a signal of potential overall survival (OS) improvement with CAR-T cell therapy, the difference was not statistically significant between the two groups (HR 0.76; 95% CI: 0.56 to 1.03; I2: 29%). Mixed treatment comparisons showed significant EFS benefit with liso-cel (HR: 0.37; 95% CI: 0.22-0.61) and axi-cel (HR: 0.42; 95% CI: 0.29-0.61) compared to tisa-cel.
UNASSIGNED: CAR-T cell therapy, as a second-line treatment, appears to be effective in achieving higher response rates and delaying the disease progression compared to SOC in R/R DLBCL.

Chimeric antigen receptor (CAR)-T cell therapy represents one of the most innovative immunotherapy approaches. The encouraging results achieved by CAR-T cell therapy in hematological disorders paved the way for the employment of CAR engineered T cells in different types of solid tumors. This adoptive cell therapy represents a selective and efficacious approach to eradicate tumors through the recognition of tumor-associated antigens (TAAs). Binding of engineered CAR-T cells to TAAs provokes the release of several cytokines, granzyme, and perforin that ultimately lead to cancer cells elimination and patient\'s immune system boosting. Within the tumor mass a subpopulation of cancer cells, known as cancer stem cells (CSCs), plays a crucial role in drug resistance, tumor progression, and metastasis. CAR-T cell therapy has indeed been exploited to target CSCs specific antigens as an effective strategy for tumor heterogeneity disruption. Nevertheless, a barrier to the efficacy of CAR-T cell-based therapy is represented by the poor persistence of CAR-T cells into the hostile milieu of the CSCs niche, the development of resistance to single targeting antigen, changes in tumor and T cell metabolism, and the onset of severe adverse effects. CSCs resistance is corroborated by the presence of an immunosuppressive tumor microenvironment (TME), which includes stromal cells, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and immune cells. The relationship between TME components and CSCs dampens the efficacy of CAR-T cell therapy. To overcome this challenge, the double strategy based on the use of CAR-T cell therapy in combination with chemotherapy could be crucial to evade immunosuppressive TME. Here, we summarize challenges and limitations of CAR-T cell therapy targeting CSCs, with particular emphasis on the role of TME and T cell metabolic demands.

Cancer stem cells (CSCs) represent the most aggressive subpopulation present in the tumor bulk retaining invasive capabilities, metastatic potential and high expression levels of drug efflux pumps responsible for therapy resistance. Cancer is still an incurable disease due to the inefficacy of standard regimens that spare this subpopulation. Selective targeting of CSCs is still an unmet need in cancer research field. Aberrant epigenetic reprogramming promotes the initiation and maintenance of CSCs, which are able to escape the immune system defense. Promising therapeutic approaches able to induce the selective inhibition of this stem-like small subset include immunotherapy alone or in combination with epigenetic compounds. These strategies are based on the specific expression of epitopes and/or epigenetic alterations present only in the CSC and not in the other cancer cells or normal cells. Thus, the combined approach utilizing CAR-T immunotherapy along with epigenetic probes may overcome the barriers of treatment ineffectiveness towards a more precision medicine approach in patients with known specific alterations of CSCs. In this perspective article we will shed new lights on the future applications of epi-immunotherapy in tumors enriched in CSCs, along with its potential side-effects, limitations and the development of therapy resistance.

BACKGROUND: CAR-T cell therapy is approved for the treatment of relapsed/refractory (R/R) large B cell lymphoma (LBCL). However, elderly patients might not be candidates for this therapy due to its toxicity, and criteria for candidate selection are lacking. Our aim was to analyze efficacy and toxicity results of CAR-T cell therapy in the population of 70 years and older as compared to those obtained in younger patients in the real-world setting.
METHODS: A multicentric retrospective study was performed including patients with R/R aggressive LBCL who received commercial CAR-T cell therapy with either tisagenlecleucel or axicabtagene ciloleucel within Spanish GETH-TC/GELTAMO centers between 2019 and 2023.
RESULTS: As of August 2023, 442 adult patients with aggressive LBCL underwent apheresis for CAR-T cell therapy as third or subsequent line and had follow-up data. Of 412 infused patients, 71 (17%) were 70 years or older. Baseline characteristics, product selection and characteristics at apheresis (including disease status, Ann Arbor stage, R-IPI, bulky disease, LDH and ECOG) were comparable between groups. Median time from both approval to infusion and apheresis to infusion did not differ. No differences were found between groups in overall and complete response rates at one and three months. With a median follow-up of 12.2 months (range 1-44), 12-month progression-free survival (PFS) and overall survival (OS) were comparable between groups (35.2% in <70y vs. 35.9% in ≥70y (p= p=0.938) and 51.1% and 52.1% (p= p=0.885), respectively). Age ≥70 years did not affect PFS (HR 0.98, p=0.941) and OS (HR 0.97, p=0.890) in the univariate and multivariate analysis. Cytokine release syndrome (CRS) was observed in 82% patients in <70y and 84.5% in ≥70y (p=0.408). Grade ≥3 CRS was more frequent in the older group (5% vs. 15%, p=0.002). In the multivariate analysis, age ≥70y was associated with an increased risk of grade ≥3 CRS (OR 3.7, p=0.013). No differences were observed in terms of overall neurotoxicity (35% vs. 42%, p=0.281) or grade ≥3 (12% vs. 17%, p=0.33). The proportion of patients with infections, admission to intensive care unit within the first month and non-relapse mortality were similar between both groups.
CONCLUSIONS: CAR-T cell therapy in patients older than 70 years showed similar efficacy than that observed in younger patients in the real-world setting. However, age ≥70 years was an independent risk factor for grade 3-4 CRS. Need of additional strategies to reduce toxicity in this population should be addressed in future studies.

The leading cause of cancer deaths worldwide is attributed to non-small cell lung cancer (NSCLC), necessitating a continual focus on improving the diagnosis and treatment of this disease. In this review, the latest breakthroughs and emerging trends in managing NSCLC are highlighted. Major advancements in diagnostic methods, including better imaging technologies and the utilization of molecular biomarkers, are discussed. These advancements have greatly enhanced early detection and personalized treatment plans. Significant improvements in patient outcomes have been achieved by new targeted therapies and immunotherapies, providing new hope for individuals with advanced NSCLC. This review discusses the persistent challenges in accessing advanced treatments and their associated costs despite recent progress. Promising research into new therapies, such as CAR-T cell therapy and oncolytic viruses, which could further revolutionize NSCLC treatment, is also highlighted. This review aims to inform and inspire continued efforts to improve outcomes for NSCLC patients globally, by offering a comprehensive overview of the current state of NSCLC treatment and future possibilities.

Chimeric antigen receptor (CAR)-T-cell therapy is one of the most effective immunotherapies. CAR-T-cell therapy has achieved great success in the treatment of hematological malignancies. However, due to the characteristics of solid malignant tumors, such as on-target effects, off-tumor toxicity, an immunosuppressive tumor microenvironment (TME), and insufficient trafficking, CAR-T-cell therapy for solid tumors is still in the exploration stage. Mesothelin (MSLN) is a molecule expressed on the surface of various solid malignant tumor cells that is suitable as a target of tumor cells with high MSLN expression for CAR-T-cell therapy. This paper briefly described the development of CAR-T cell therapy and the structural features of MSLN, and especially summarized the strategies of structure optimization of MSLN-targeting CAR-T-cells and the enhancement methods of MSLN-targeting CAR-T cell anti-tumor efficacy by summarizing some preclinical experiment and clinical trials. When considering MSLN-targeting CAR-T-cell therapy as an example, this paper summarizes the efforts made by researchers in CAR-T-cell therapy for solid tumors and summarizes feasible treatment plans by integrating the existing research results.

BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapies targeting glioblastoma (GBM)-associated antigens such as interleukin-13 receptor subunit alpha-2 (IL-13Rα2) have achieved limited clinical efficacy to date, in part due to an immunosuppressive tumor microenvironment (TME) characterized by inhibitory molecules such as transforming growth factor-beta (TGF-β). The aim of this study was to engineer more potent GBM-targeting CAR-T cells by countering TGF-β-mediated immune suppression in the TME.
METHODS: We engineered a single-chain, bispecific CAR targeting IL-13Rα2 and TGF-β, which programs tumor-specific T cells to convert TGF-β from an immunosuppressant to an immunostimulant. Bispecific IL-13Rα2/TGF-β CAR-T cells were evaluated for efficacy and safety against both patient-derived GBM xenografts and syngeneic models of murine glioma.
RESULTS: Treatment with IL-13Rα2/TGF-β CAR-T cells leads to greater T-cell infiltration and reduced suppressive myeloid cell presence in the tumor-bearing brain compared to treatment with conventional IL-13Rα2 CAR-T cells, resulting in improved survival in both patient-derived GBM xenografts and syngeneic models of murine glioma.
CONCLUSIONS: Our findings demonstrate that by reprogramming tumor-specific T-cell responses to TGF-β, bispecific IL-13Rα2/TGF-β CAR-T cells resist and remodel the immunosuppressive TME to drive potent anti-tumor responses in GBM.