Breaking the shield of solid tumors: a combined approach for enhanced efficacy of CAR-T cells.

The use of chimeric antigen receptor (CAR)-T cells has enhanced the range of available therapeutic modalities in the context of cancer treatment. CAR-T cells have demonstrated considerable efficacy in the targeted eradication of blood cancer cells, thereby stimulating substantial interest in the advancement of such therapeutic approaches. However, the efficacy of CAR-T cells against solid tumor cells has been limited due to the presence of various obstacles. Solid tumors exhibit antigenic diversity and an immunosuppressive microenvironment, which presents a challenge for immune cells attempting to penetrate the tumor. CAR-T cells also demonstrate decreased proliferative activity and cytotoxicity. Furthermore, concerns exist regarding tumor antigen loss and therapy-associated toxicity. Currently, scientists are working to enhance the structure of the CAR and improve the survival and efficiency of CAR-T cells in recognizing tumor antigens in solid tumors. Chemotherapy drugs are frequently employed in the treatment of malignant neoplasms and can also be used prior to cell therapy to enhance CAR-T cell engraftment. Recent studies have demonstrated that chemotherapy drugs can mitigate the suppressive impact of TME, eliminate the physical barrier by destroying the tumor stroma, and facilitate greater penetration of immune cells and CAR-T cells into the tumor. This, in turn, increases their survival, persistence, and cytotoxicity, as well as affects the metabolism of immune cells inside the tumor. However, the effectiveness of the combined approach against solid tumors depends on several factors, including the type of tumor, dosage, population of CAR-T cells, and individual characteristics of the body. This review examines the principal obstacles to the utilization of CAR-T cells against solid tumors, proposes solutions to these issues, and assesses the potential advantages of a combined approach to radiation exposure, which has the potential to enhance the sensitivity of the tumor to other agents.

Navigating the therapeutic landscape for breast cancer: targeting breast cancer stem cells.

Breast cancer is a common and deadly malignancy that affects women globally, and breast cancer stem cells (BCSCs) play an important role in tumorigenesis, development, metastasis, and recurrence. Traditional therapies often fail to eliminate BCSCs, leading to treatment resistance and relapse. This review explores the therapeutic strategies which are designed to target BCSCs, including inhibition of key signaling pathway and targeting receptor. This paper also explores the approaches to targeting BCSCs including chemotherapy, phytomedicines, and nanotechnology. Nanotechnology has gained a lot of importance in cancer therapy because of its ability to deliver therapeutic agents with more precision and minimal side effects. Various chemotherapeutic drugs, siRNAs, or gene editing tools are delivered efficiently with the use of nanocarriers which target pathways, receptors, and proteins associated with BCSCs. Over the past few years, stimuli-responsive and receptor-targeted nanocarriers have been explored for better therapeutic effects. In recent times, strategies such as chimeric antigen receptor (CAR) T-cell therapy, ablation therapy, and cell-free therapies are explored for targeting these stem cells. This review provides a recent developmental overview of strategies to attack BCSCs from conventional chemotherapeutic agents to nanotechnological platforms such as polymeric, lipidic, and metal-based nanoparticles and advanced technologies like CAR T cell therapies.

CD19/CD22 CAR-T-cell cocktail therapy following autologous transplantation is an optimizing strategy for treating relapsed/refractory central nervous system lymphoma.

Relapsed/refractory (R/R) primary and secondary central nervous system lymphomas (PCNSL, SCNSL) are associated with short survival and represent an unmet need, requiring novel effective strategies. We retrospectively compared the safety and efficacy of CD19/22 CAR-T-cell therapy following ASCT (ASCT + CAR-T group), CD19/22 CAR-T-cell cocktail therapy (CAR-T group) and chemoimmunotherapy (CIT group) in treating R/R CNSL patients. Analysis of the differences in clinical characteristics among the three groups revealed that the median age in the CIT group was older than that in the ASCT + CAR-T group and CAR-T group, and the median number of prior lines of therapy in the CIT group was less than that in the other groups. Patients in the two CAR-T-therapy groups exhibited comparable incidences and severities of CRS and ICANS. Grade 4-5 CRS and ICANS were not observed in either CAR-T-cell therapy group. The incidence of Grade 3/4 hematological toxicity in the ASCT + CAR-T and CAR-T groups was greater than that in the CIT group. The ORR was 82.75% in the ASCT + CAR-T group, 60.00% in the CAR-T group and 58.83% in the CIT group. As of December 31, 2022, the median follow-up after therapy was 16.73 months (range, 0.67-42.00 months). The median durations of PFS and OS were not reached in the ASCT + CAR-T group. The median PFS in the CAR-T group was 4.72 months, and OS was not reached. In the CIT group, the median PFS and OS were 6.63 months and 16.77 months, respectively. The 2-year PFS rate of patients in the ASCT + CAR-T group (65.52%) was significantly greater than that of patients in the CAR-T group (30.00%, P = 0.0321) and CIT group (23.53%, P = 0.0043). Our results support the development of CAR-T-cell therapy for R/R CNSL. With the durability of remission and low toxicity, ASCT combined with CAR-T-cell therapy appears to be a more effective and safer treatment option for primary and secondary R/R CNS lymphoma.

Hemophagocytic lymphohistiocytosis in a patient with Epstein-Barr virus-positive diffuse large B-cell lymphoma treated with chimeric antigen receptor T-cell therapy.

With the advent of chimeric antigen receptors T-cell therapy, understanding their role in the development of hemophagocytic lymphohistiocytosis has become increasingly complex. We describe a case of a young patient with Epstein-Barr virus-positive diffuse large B-cell lymphoma, who was treated with axicabtagene ciloleucel. The patient developed progressive cytopenia and, on Day 73 post-infusion, met criteria for hemophagocytic lymphohistiocytosis. Bone marrow evaluation revealed hemophagocytosis without evidence of clonal B cells. The patient was treated with tocilizumab, dexamethasone, etoposide and anakinra, which eventually led to improvement. Unfortunately, the patient succumbed to an infection. Disease progression was confirmed posthumously.This case report explores the differential diagnosis of hyperinflammatory syndromes following chimeric antigen receptor T-cell therapy and highlights the reduced efficacy of this treatment in patients with a T-cell/histiocyte-rich background.

Lymphoma is an aggressive type of blood cancer that is typically treated with chemotherapy. However, the disease sometimes persists despite the initial treatment and requires new therapeutic options. A novel therapy that uses the patient's own immune system, specifically a type of white blood cell called T lymphocytes, has recently been developed. These cells can be genetically modified to enhance recognition of cancer cells by expressing chimeric antigen receptors (CARs).CAR T-cell treatment is highly effective; however, it massively activates the patient's immune system. This can lead to hyperinflammatory complications, including hemophagocytic lymphohistiocytosis, which is frequently fatal. This complication can arise from infections, cancer, genetic alterations or new immunotherapies.We present a case of hemophagocytic lymphohistiocytosis after CAR T-cell therapy, discuss the underlying biology, differential diagnosis and treatment options for this rare complication.

Single center, real-world retrospective study of CAR-T cell therapy for relapsed/refractory large B-cell lymphoma beyond second line: five-year results at the University Hospitals Leuven.

INTRODUCTION: Large B-cell lymphomas (LBCL) are the most frequently aggressive B-cell non-Hodgkin lymphomas. Anti-CD19 chimeric antigen receptor (CAR)-T cell therapy has emerged as a new, powerful treatment for relapsed or refractory (R/R) disease. Two CAR-T cell products, tisagenlecleucel (tisa-cel,) and axicabtagene ciloleucel (axi-cel), are reimbursed in Belgium for R/R LBCL beyond second line. OBJECTIVES AND METHODS: We conducted a retrospective cohort study to report the outcome with tisa-cel and axi-cel for R/R LBCL beyond second line in the years 2019-2023 at the University Hospitals Leuven for 79 patients selected for apheresis and CAR-T infusion. RESULTS: Eleven patients (14%) did not proceed to CAR-T cell infusion. For infused patients (n = 68), the best overall response rate (ORR)/complete response (CR) rate was 64%/49% for tisa-cel and 88%/66% for axi-cel (p = 0.04 for ORR). After a median follow-up of 13.8 months, progression-free survival (PFS) and overall survival (OS) at 1 year were 30% and 43% for tisa-cel and 48% and 62% for axi-cel. Cytokine release syndrome (CRS) (all grades/grade ≥3) occurred in 82%/9% after tisa-cel and in 97%/0% after axi-cel. Immune effector cell-associated neurotoxicity syndrome (ICANS) (all grades/grade ≥3) occurred in 24%/18% after tisa-cel and in 54%/40% after axi-cel. The non-relapse mortality in the infusion cohort was 13%. CONCLUSION: Our real-world data show high and durable response rates, with a non-significant trend towards a higher efficacy and higher toxicity for axi-cel compared to tisa-cel. Our results are in line with other real-world registries except for a shorter median OS and more high-grade ICANS.

CRISPR/Cas9 technology for advancements in cancer immunotherapy: from uncovering regulatory mechanisms to therapeutic applications.

In recent years, immunotherapy has developed rapidly as a new field of tumour therapy. However, the efficacy of tumour immunotherapy is not satisfactory due to the immune evasion mechanism of tumour cells, induction of immunosuppressive tumour microenvironment (TME), and reduction of antigen delivery, etc. CRISPR/Cas9 gene editing technology can accurately modify immune and tumour cells in tumours, and improve the efficacy of immunotherapy by targeting immune checkpoint molecules and immune regulatory genes, which has led to the great development and application. In current clinical trials, there are still many obstacles to the application of CRISPR/Cas9 in tumour immunotherapy, such as ensuring the accuracy and safety of gene editing, overcoming overreactive immune responses, and solving the challenges of in vivo drug delivery. Here we provide a systematic review on the application of CRISPR/Cas9 in tumour therapy to address the above existing problems. We focus on CRISPR/Cas9 screening and identification of immunomodulatory genes, targeting of immune checkpoint molecules, manipulation of immunomodulators, enhancement of tumour-specific antigen presentation and modulation of immune cell function. Second, we also highlight preclinical studies of CRISPR/Cas9 in animal models and various delivery systems, and evaluate the efficacy and safety of CRISPR/Cas9 technology in tumour immunotherapy. Finally, potential synergistic approaches for combining CRISPR/Cas9 knockdown with other immunotherapies are presented. This study underscores the transformative potential of CRISPR/Cas9 to reshape the landscape of tumour immunotherapy and provide insights into novel therapeutic strategies for cancer patients.

Progress and challenges in glypican-3 targeting for hepatocellular carcinoma therapy.

INTRODUCTION: Glypican-3 (GPC3) is a cell membrane-anchored heparan sulfate proteoglycan that has recently garnered attention as a cancer antigen owing to its high expression in numerous cancers, particularly hepatocellular carcinoma (HCC), and to limited expression in adult normal tissue. AREAS COVERED: Here, we propose the potential of GPC3 as a cancer antigen based on our experience with the GPC3 peptide vaccine against HCC, having developed a vaccine that progressed from preclinical studies to first-in-human clinical trials. In this review, we present a summary of the current status and future prospects of immunotherapies targeting GPC3 by focusing on clinical trials; peptide vaccines, mRNA vaccines, antibody therapy, and chimeric antigen receptor/T-cell receptor - T-cell therapy and discuss additional strategies for effectively eliminating HCC through immunotherapy. EXPERT OPINION: GPC3 is an ideal cancer antigen for HCC immunotherapy. In resectable HCC, immunotherapies that leverage physiological immune surveillance, immune checkpoint inhibitors, and GPC3-target cancer vaccines appear promising in preventing recurrence and could be considered as a prophylactic adjuvant therapy. However, in advanced HCC, clinical trials have not demonstrated sufficient anti-tumor efficacy, in contrast with preclinical studies. Reverse translation, bedside-to-bench research, is crucial to identify the factors that have hindered GPC3 target immunotherapies.

CAR-T-Cell Therapy for Systemic Lupus Erythematosus: A Comprehensive Overview.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder characterized by the production of autoreactive B and T cells and cytokines, leading to chronic inflammation affecting multiple organs. SLE is associated with significant complications that substantially increase morbidity and mortality. Given its complex pathogenesis, conventional treatments for SLE often have significant side effects and limited efficacy, necessitating the exploration of novel therapeutic strategies. One promising approach is the use of chimeric antigen receptor (CAR)-T-cell therapy, which has shown remarkable success in treating refractory hematological malignancies. This review provides a comprehensive analysis of the current use of CAR-T-cell therapy in SLE.

A Case of Gastrointestinal Coccidiomycosis With Bowel Perforation Secondary to Relapsing DLBCL.

Coccidioides is a fungus endemic to the Southwestern United States, known for causing Valley Fever. While typically asymptomatic or presenting as a respiratory tract infection, rare cases of disseminated infection to the peritoneum have been reported. The patient in this case study presented with a small bowel obstruction, requiring an exploratory laparoscopy showing evidence of an inflammatory mass with a jejuna-colic fistula with adherence to the spleen. The patient underwent splenectomy with a cholecystectomy and small bowel resection. Intraabdominal cultures revealed Coccidioides, and so he started long-term antifungal treatment. The patient was also initiated on salvage chemotherapy for DLBCL, and ultimately received CAR T-Cell therapy at a tertiary center. This case report highlights a unique presentation of gastrointestinal Coccidioides infection, in the setting of an immunocompromised host with a hematologic malignancy. It also provides insight into the therapeutic challenges clinicians face when treating complicated patients such as this who require urgent chemotherapy while risking further immunosuppression in the setting of active infection.

A lesson from fatal invasive fungal infections after CAR-T cell therapy: a case report and literature review.

CD19 chimeric antigen receptor T (CAR-T) cell therapy represents an effective approach to treating patients with relapsed or refractory B-cell hematologic malignancies. Nevertheless, owing to the immunosuppressive effects of this regimen, patients undergoing CD19 CAR-T cell therapy may face an elevated risk of invasive fungal infections, which involve fungi penetrating the host's tissues or bloodstream, leading to life-threating infectious diseases. Herein, we present the case of a 17-year-old male diagnosed with acute lymphoblastic leukemia, who subsequently experienced a fatal invasive fungal infection following administration of CAR-T cell therapy. Furthermore, we delve into the identification of risk factors, implementation of preventive measures and exploration of therapeutic interventions for invasive fungal infections after CAR-T cell therapy.

A 17-year-old male was diagnosed with acute lymphoblastic leukemia and experienced disease relapse after undergoing multiple chemotherapy treatments. Subsequently, he participated in a clinical trial of CAR-T cell therapy at our institution. Due to a possible lung fungal infection, he was given oral antifungal medicine. Throughout the treatment period, he developed recurrent fever. After receiving immunosuppressive agents, he developed gangrene at the sinuses and was diagnosed with invasive fungal sinusitis. Although antifungal medication was adjusted, it failed to fully eradicate the infection, leading to the patient's recurrent shocks associated with the fungal infection. These findings underscore the importance for physicians to be vigilant regarding potential fungal infections when administering CAR-T cell therapy, particularly in patients with preexisting fungal infections prior to treatment. Likewise, caution should be exercised in the use of immunosuppressive agents, given their potential to increase the risk of fungal infections, among other complications. Early and timely surgical intervention in the presence of invasive fungal infections may be more effective than monotherapy in some patients with invasive fungal infections.

DeltaRex-G, tumor targeted retrovector encoding a CCNG1 inhibitor, for CAR-T cell therapy induced cytokine release syndrome.

Cytokine release syndrome is a serious complication of chimeric antigen receptor-T cell therapy and is triggered by excessive secretion of inflammatory cytokines by chimeric T cells which could be fatal. Following an inquiry into the molecular mechanisms orchestrating cytokine release syndrome, we hypothesize that DeltaRex-G, a tumor targeted retrovector encoding a cytocidal CCNG1 inhibitor gene, may be a viable treatment option for corticosteroid-resistant cytokine release syndrome. DeltaRex-G received United States Food and Drug Administration Emergency Use Authorization to treat Covid-19-induced acute respiratory distress syndrome, which is due to hyperactivated immune cells. A brief administration of DeltaRex-G would inhibit a certain proportion of hyperactive chimeric T cells, consequently reducing cytokine release while retaining chimeric T cell efficacy.

S100 as marker for immune effector cell-associated neurotoxicity syndrome.

Chimeric antigen receptor (CAR)-T cell therapy is a new and successful treatment for otherwise refractory malignancies but despite the growing number of applications, this form of treatment is still associated with significant toxicity. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) in particular are common and dangerous side effects. This report is about two patients who received CAR­T cell therapy and subsequently developed ICANS. This was successfully treated. During CAR­T cell therapy, a blood marker, S100, was monitored daily. It correlated with the occurrence and progression of ICANS.

Unlocking Apoptotic Pathways: Overcoming Tumor Resistance in CAR-T-Cell Therapy.

BACKGROUND: Chimeric antigen receptor (CAR)-T-cell therapy has transformed cancer treatment, leading to remarkable clinical outcomes. However, resistance continues to be a major obstacle, significantly limiting its efficacy in numerous patients. OBJECTIVES: This review critically examines the challenges associated with CAR-T-cell therapy, with a particular focus on the role of apoptotic pathways in overcoming resistance. METHODS: We explore various strategies to sensitize tumor cells to CAR-T-cell-mediated apoptosis, including the use of combination therapies with BH3 mimetics, Mcl-1 inhibitors, IAP inhibitors, and HDAC inhibitors. These agents inhibit anti-apoptotic proteins and activate intrinsic mitochondrial pathways, enhancing the susceptibility of tumor cells to apoptosis. Moreover, targeting the extrinsic pathway can increase the expression of death receptors on tumor cells, further promoting their apoptosis. The review also discusses the development of novel CAR constructs that enhance anti-apoptotic protein expression, such as Bcl-2, which may counteract CAR-T cell exhaustion and improve antitumor efficacy. We assess the impact of the tumor microenvironment (TME) on CAR-T cell function and propose dual-targeting CAR-T cells to simultaneously address both myeloid-derived suppressor cells (MDSCs) and tumor cells. Furthermore, we explore the potential of combining agents like PPAR inhibitors to activate the cGAS-STING pathway, thereby improving CAR-T cell infiltration into the tumor. CONCLUSIONS: This review highlights that enhancing tumor cell sensitivity to apoptosis and increasing CAR-T cell cytotoxicity through apoptotic pathways could significantly improve therapeutic outcomes. Targeting apoptotic proteins, particularly those involved in the intrinsic mitochondrial pathway, constitutes a novel approach to overcoming resistance. The insights presented herein lay a robust foundation for future research and clinical applications aimed at optimizing CAR-T cell therapies.

B-Cell Maturation Antigen-Directed Immunotherapies for the Treatment of Relapsed/Refractory Multiple Myeloma: A Review of the Literature and Implications for Clinical Practice.

OBJECTIVE: To review the pharmacology, efficacy, safety, dosing and administration, and relevance to patient care and clinical practice of B-cell maturation antigen (BCMA) directed immunotherapies, including chimeric antigen receptor T-cell (CAR-T) therapy and bispecific antibodies (BsAb), for the management of relapsed/refractory multiple myeloma (RRMM). DATA SOURCES: A literature review of PubMed (1966 to July 2024) was conducted using the keywords idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, elranatamab, and multiple myeloma. Data was also obtained from unpublished meeting abstracts and prescribing information. STUDY SELECTION AND DATA EXTRACTION: All relevant published articles, unpublished abstracts, and prescribing information on anti-BCMA immunotherapies for the treatment of RRMM were reviewed. DATA SYNTHESIS: Idecabtagene vicleucel and ciltacabtagene autoleucel are BCMA-directed CAR-T cell therapies that have been compared to standard of care (SOC) regimens for MM in early relapse in the phase III trials KarMMa-3 and CARTITUDE-4, respectively. Both studies demonstrated a significantly improved in response rates, depth of response, and progression-free survival compared to SOC. BsAbs teclistamab and elranatamab have been evaluated in the phase II trials MajesTEC-1 and MagnetisMM-3, respectively. Overall response rates of 63 and 61% were observed with teclistamab and elranatamab, respectively, in a population of patients with heavily pretreated RRMM. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: BCMA-directed immunotherapies have demonstrated efficacy in the treatment of RRMM. Safety issues with BCMA-directed immunotherapies include cytokine release syndrome, neurotoxicity, infections, and cytopenias. Operational challenges and issues with access to care exist with these therapies as they may be limited to institutions with the infrastructure to safely administer and monitor patients for toxicities. CONCLUSION: BCMA-directed immunotherapies represent an important advancement in the management of RRMM and have significantly added to the available treatment options for this disease.

Targeting metabolic pathway enhance CAR-T potency for solid tumor.

Chimeric antigen receptor (CAR) T cells have great potential in cancer therapy, particularly in treating hematologic malignancies. However, their efficacy in solid tumors remains limited, with a significant proportion of patients failing to achieve long-term complete remission. One major challenge is the premature exhaustion of CAR-T cells, often due to insufficient metabolic energy. The survival, function and metabolic adaptation of CAR-T cells are key determinants of their therapeutic efficacy. We explore how targeting metabolic pathways in the tumor microenvironment can enhance CAR-T cell therapy by addressing metabolic competition and immunosuppression that impair CAR-T cell function. Tumors undergo metabolically reprogrammed to meet their rapid proliferation, thereby modulating metabolic pathways in immune cells to promote immunosuppression. The distinct metabolic requirements of tumors and T cells create a competitive environment, affecting the efficacy of CAR-T cell therapy. Recent research on glucose, lipid and amino acid metabolism, along with the interactions between tumor and immune cell metabolism, has revealed that targeting these metabolic processes can enhance antitumor immune responses. Combining metabolic interventions with existing antitumor therapies can fulfill the metabolic demands of immune cells, providing new ideas for tumor immunometabolic therapies. This review discusses the latest advances in the immunometabolic mechanisms underlying tumor immunosuppression, their implications for immunotherapy, and summarizes potential metabolic targets to improve the efficacy of CAR-T therapy.

Antibody-Based Therapies for Peripheral T-Cell Lymphoma.

While antibody-based immunotherapeutic strategies have revolutionized the treatment of B-cell lymphomas, progress in T-cell lymphomas has suffered from suboptimal targets, disease heterogeneity, and limited effective treatment options. Nonetheless, recent advances in our understanding of T-cell biology, the identification of novel targets, and the emergence of new therapies provide hope for the future. In this review, we explore four areas of current and evolving antibody-based strategies for the treatment of peripheral T-cell lymphoma (PTCL): monoclonal antibodies (mAbs), bispecific antibodies (BsAs), chimeric antigen receptor T-cell therapy (CAR-T), and antibody-drug conjugates (ADCs). As part of this discussion, we will also include limitations, lessons learned, and potential future directions.

Impact of Malnutrition on the Length of Stay for Hospitalized Chimeric Antigen Receptor T-cell (CAR-T) Therapy Patients in the United States (2020).

Background Chimeric antigen receptor T-cell (CAR-T) therapy offers a promising treatment for certain malignancies but can be associated with complications. Malnutrition and cachexia are common in cancer patients and may worsen outcomes. This study investigated the impact of malnutrition on the length of hospital stay (LOS) in patients with hematologic malignancies undergoing CAR-T therapy. The analysis focused on different subpopulations, including those with acute lymphoblastic leukemia (ALL), multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), and non-Hodgkin lymphoma (NHL) excluding DLBCL. Methods Utilizing the 2020 National Inpatient Sample (NIS) data, we performed survey-based mean estimation analyses for LOS across various subpopulations of CAR-T therapy patients. These subpopulations were defined by specific diagnoses: ALL, myeloma, DLBCL, and NHL excluding DLBCL. We compared the LOS between patients with and without malnutrition using STATA accounting for the complex survey design. Cachexia was included as disease-induced malnutrition. Results The total CAR-T population used for analyses included 439 patients, and malnutrition was present in 50 (11.39%). The overall CAR-T population demonstrated a significantly longer LOS for patients with malnutrition (30.92 days, 95% CI: 24.30 to 37.54) compared to those without malnutrition (17.97 days, 95% CI: 15.48 to 20.46, p = 0.0002). This trend held true across subgroups. Specifically, the ALL population had a significantly longer LOS with malnutrition (45.25 days, 95% CI: 35.46 to 55.04) compared to non-malnourished patients (27.58 days, 95% CI: 16.74 to 38.42, p = 0.0279). For the DLBCL population, the mean LOS was 24.47 days (95% CI: 19.22 to 29.71) with malnutrition and 17.17 days (95% CI: 13.29 to 21.04, p = 0.0161) without malnutrition. The NHL population excluding DLBCL exhibited a mean LOS of 33.86 days (95% CI: 22.66 to 45.07) for malnourished patients and 17.44 days (95% CI: 14.76 to 20.11, p = 0.0055) for non-malnourished patients. The myeloma population showed a similar trend although not statistically significant, with a mean LOS of 39.00 days (95% CI: -3.54 to 81.54) for malnourished patients and 18.03 days (95% CI: 15.02 to 21.03, p = 0.3337) for non-malnourished patients. These findings highlight significant variations in LOS across different CAR-T-treated cancer subtypes, emphasizing the impact of malnutrition on healthcare resource utilization in oncology. Conclusion Malnutrition is associated with a significantly longer hospital stay among patients undergoing CAR-T therapy. This trend is consistent across various subpopulations, including those with ALL, DLBCL, and NHL (excluding DLBCL). While the impact of malnutrition on LOS was not statistically significant in the myeloma population, this could potentially be attributed to the smaller sample size in this group. Overall, these findings underscore the critical role of nutritional status in managing patients undergoing CAR-T therapy. Future studies should investigate the most effective methods for identifying and treating malnutrition in this patient population to reduce hospital stays and optimize overall patient care.

Sequencing of therapy for patients with diffuse large B-cell lymphoma in the era of novel drugs.

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma, accounting for ~40% of all cases in adults. Whilst approximately two-thirds of DLBCL patients can be cured by first-line therapy, one-third of patients are primary refractory or relapse after an initial response (r/r DLBCL). Recent advances in the treatment of DLBCL have been achieved by a plethora of novel drugs, such as monoclonal antibodies, antibody-drug conjugates (ADC), bi-specific T-cell engagers (BITEs), and CD-19 directed chimeric antigen receptor (CAR)-T-cell therapies. The increasing number of therapeutic options significantly improved the outcome of patients; however, the therapeutic algorithm has become increasingly complex. In this review, we provide an overview of novel therapies for DLBCL patients and potential treatment sequencing from first to second, third, and later lines.

Health-related quality of life dynamics: modeling insights from immunotherapy.

BACKGROUND: Understanding health-related quality of life (HRQoL) dynamics is essential for assessing and improving treatment experiences; however, clinical and observational studies struggle to capture their full complexity. We use simulation modeling and the case of Chimeric Antigen Receptor T-cell therapy-a type of cancer immunotherapy that can prolong survival, but carries life-threatening risks-to study HRQoL dynamics. METHODS: We developed an exploratory system dynamics model with mathematical equations and parameter values informed by literature and expert insights. We refined its feedback structure and evaluated its dynamic behavior through iterative interviews. Model simulated HRQoL from treatment approval through six months post-infusion. Two strategies-reducing the delay to infusion and enhancing social support-were incorporated into the model. To dynamically evaluate the effect of these strategies, we developed four metrics: post-treatment HRQoL decline, recovery time to pre-treatment HRQoL, post-treatment HRQoL peak, and durability of the peak. RESULTS: Model captures key interactions within HRQoL, providing a nuanced analysis of its continuous temporal dynamics, particularly physical well-being, psychological well-being, tumor burden, receipt and efficacy of treatment, side effects, and their management. Model analysis shows reducing infusion delays enhanced HRQoL across all four metrics. While enhanced social support improved the first three metrics for patients who received treatment, it did not change durability of the peak. CONCLUSIONS: Simulation modeling can help explore the effects of strategies on HRQoL while also demonstrating the dynamic interactions between its key components, offering a powerful tool to investigate aspects of HRQoL that are difficult to assess in real-world settings.

Understanding how treatments affect patients' quality of life over time is crucial, but capturing the complex interactions of health factors poses a challenge for clinical and observational research. To overcome this, we have turned to simulation modeling, a method that allows for a more thorough exploration of these dynamics. Our study focuses on cancer immunotherapy, a treatment that, despite its potential to prolong survival, also comes with life-threatening risks. We evaluated the effectiveness of two strategies aimed at improving quality of life: reducing the time to treatment infusion and enhancing social support. These strategies were assessed across three different patient scenarios: those not initially eligible for treatment, patients experiencing a relapse, and patients showing a complete response. By using simulation modeling, we demonstrated how this approach can help explore the dynamics and interactions of various health factors and the impact of specific strategies.

Patient-reported outcomes of chimeric antigen receptor T-cell therapy in hematologic malignancies: a systematic review and meta-analysis.

Few studies evaluated patient-reported outcomes (PROs) for patients with hematologic malignancies receiving with Chimeric Antigen Receptor T (CAR-T) cell therapy. We performed a systematic review and meta-analysis to evaluate the benefits of CAR-T cell therapies focused on PROs. A systematic literature searched from PubMed, Cochrane, and the Web of Science from inception to September 2023. Study selection and data extraction were conducted independently by two reviewers based on pre-specified criteria. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) Risk of Bias checklist was used to evaluate the methodological quality of the included studies. The random-effects model was employed to calculate the combined effect and 95% Confidence intervals. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline and the protocol was registered with PROSPERO (CRD42024586706). We identified 20,110 studies. Of those, 15 studies with 16 different PRO measures (PROMs) were included in the meta-analysis. CAR-T cell therapy improved PROs in the six domains of general health status, pain, fatigue, depression, social function, and cognitive function: from the general health status (SMD: 0.57, 95% CI: 0.34 to 0.81) to cognitive function (SMD: 0.25, 95% CI: 0.14 to 0.37). The current meta-analysis shows that CAR-T cell therapy produces clinically meaningful differences in PROs. These results suggest that the professional perspective and patient values and preferences should be weighed equally when considering CAR-T cell therapy for hematologic malignancies.