Remodeling memory T cells with chemotherapy and immune checkpoint inhibitors as host pre-conditioning to empower in vivo CAR-T therapy.

Characterizing and Risk Stratifying Musculoskeletal Toxicities after BCMA CAR-T Therapy for Relapsed/Refractory Multiple Myeloma

Simple SummaryIn 2017, two chimeric antigen receptor-T (CAR-T) therapies were approved by the FDA for advanced/resistant lymphoma and acute lymphoblastic leukemia. However, despite the breakthrough efficacy results, the safety of CAR-T treatment is still a concern for treating physicians and their patients. Moreover, the high rate of relapse in up to 60% of patients previously treated with CAR-T represents a major challenge. There is currently extensive research activity aimed at addressing these shortfalls; strategies include changing the administration plans of CAR-T, combining it with chemotherapy, and even developing new types of CAR-T therapies. This article will focus on new CAR-T strategies that are under investigation and the results of their studies.The year 2017 was marked by the Food and Drug Administration (FDA) approval of the first two chimeric antigen receptor-T (CAR-T) therapies. The approved indications were for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and for the treatment of patients up to 25 years of age with acute lymphoblastic leukemia (ALL) that is refractory or in a second or later relapse. Since then, extensive research activities have been ongoing globally on different hematologic and solid tumors to assess the safety and efficacy of CAR-T therapy for these diseases. Limitations to CAR-T therapy became apparent from, e.g., the relapse in up to 60% of patients and certain side effects such as cytokine release syndrome (CRS). This led to extensive clinical activities aimed at overcoming these obstacles, so that the use of CAR-T therapy can be expanded. Attempts to improve on efficacy and safety include changing the CAR-T administration schedule, combining it with chemotherapy, and the development of next-generation CAR-T therapies, e.g., through the use of CAR-natural killer (CAR-NK) and CAR macrophages (CAR-Ms). This review will focus on new CAR-T treatment strategies in hematologic malignancies, clinical trials aimed at improving efficacy and addressing side effects, the challenges that CAR-T therapy faces in solid tumors, and the ongoing research aimed at overcoming these challenges.

Total Car-T Cost of Care Beyond the Price of Car-T Cell Therapy in Patients with Multiple Myeloma

Total Costs of Care during Chimeric Antigen Receptor T-Cell Therapy in Patients with Relapsed/Refractory B Cell Non-Hodgkin Lymphoma: A Large Private Insurance Claim-Based Analysis

Objective:Chimeric antigen receptor T (CAR-T) cell therapies have already made an impact on the treatment of B-cell malignancies. Although CAR-T cell therapies are promising, there are concerns about commercial products regarding their affordability and sustainability. In this preliminary study, the results of the first production and clinical data of an academic CAR-T cell (ISIKOK-19) trial in Turkey are presented.Materials and Methods:A pilot clinical trial (NCT04206943) designed to assess the safety and feasibility of ISIKOK-19 T-cell therapy for patients with relapsed and refractory CD19+ tumors was conducted and participating patients received ISIKOK-19 infusions between October 2019 and July 2021. The production data of the first 8 patients and the clinical outcome of 7 patients who received ISIKOK-19 cell infusions are presented in this study.Results:Nine patients were enrolled in the trial [5 with acute lymphoblastic leukemia (ALL) and 4 with non-Hodgkin lymphoma (NHL)], but only 7 patients could receive treatment. Two of the 3 participating ALL patients and 3 of the 4 NHL patients had complete/ partial response (overall response rate: 72%). Four patients (57%) had CAR-T-related toxicities (cytokine release syndrome, CAR-T-related encephalopathy syndrome, and pancytopenia). Two patients were unresponsive and had progressive disease following CAR-T therapy. Two patients with partial response had progressive disease during follow-up.Conclusion:Production efficacy and fulfillment of the criteria of quality control were satisfactory for academic production. Response rates and toxicity profiles were also acceptable for this heavily pretreated/refractory patient group. ISIKOK-19 cells appear to be a safe, economical, and efficient treatment option for CD19+ tumors. However, the findings of this study need to be supported by the currently ongoing ISIKOK-19 clinical trial.

Editorial on the Research Topic Chimeric antigen receptor T (CAR-T) cells have shown promising efficacy in treating hematological malignancies, particularly CD19 CAR-T for B-cell acute lymphoblastic leukemia with a 70~94% complete remission rate (1). However, antigen escape presents a significant challenge for the long-term effectiveness of CAR-T (1-3), and using CAR-T to treat solid tumors faces obstacles due to the lack of safe and effective treatment targets (1). Therefore, finding new targets for CAR-T therapy is critical. The ideal target of CAR-T therapy should be specifically expressed or remarkably upregulated on the surface of tumor cells. In addition to this classic target screening method, there are also some new screening methods that deserve attention. For example, peptidecentric CARs have the potential to vastly expand the pool of immunotherapeutic targets to include non-immunogenic intracellular oncoproteins (4). In addition to screening new targets on tumor cells, we can also focus on targets on CAR-T cells, such as canonical BRG1/BRM-associated factor (5) and PD1 (6). The strategy of obtaining potential targets for immunotherapy through high-throughput data analysis (Chen et al.) has crucial implications for screening new targets for CAR-T therapy. The use of multidimensional omics data advanced CAR-T cell therapy (7). DNA sequencing have identified numerous tumor-associated somatic mutations, some of which might generate tumor-specific neoantigens and could potentially serve as novel targets for CAR-T therapy (8, 9). Genome-wide pooled CRISPR-Cas9 knockout library screening has resulted in the identification of key genes involved in T cell cytotoxicity (10) and genetic alterations in tumor cells that influence resistance to treatment (11). Epigenetic reprogramming of CAR-T cells also has the potential to enhance T cell cytotoxicity (12). Meanwhile, integrating proteomics and transcriptomics is also a reliable strategy for screening CAR-T therapeutic targets (13). Several new targets for CAR-T therapy in hematological malignancies have been reported. GPRC5D has been identified as a potential target for CAR-T treatment of multiple myeloma in preclinical research by Smith et al. (14) and confirmed by subsequent clinical trials (15-17). In this Research Topic, Wu et al. suggested in a preclinical study that Frontiers in Immunology frontiersin.org 01

Efficacy and Safety of the Second CAR-T Therapy in Patients with Refractory/Relapsed Acute B-Cell Lymphoblastic Leukemia

7021 Background: Chimeric antigen receptor T (CAR-T) cell therapy is a transformative treatment for hematologic malignancies, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and acute leukemia (AL). Despite its success, CAR-T therapy is associated with significant toxicities and an increased risk of infections, particularly cytomegalovirus (CMV) infection. CMV infection in CAR-T recipients has been linked to increased non-relapse mortality (NRM) and prolonged hospital stays; however, comprehensive data on its clinical impact remains limited. This study aimed to evaluate the clinical impact of CMV infection on outcomes in CAR-T therapy recipients. Methods: This retrospective cohort study utilized the HCUP-National Readmission Database (NRD) 2021 database to analyze adult hospitalized patients (≥18 years) who underwent CAR-T cell therapy for MM, NHL, or AL in the USA. Patients with a prior CMV diagnosis or discharged in the last three months of 2021 were excluded. Propensity score matching (PSM) was applied to balance baseline characteristics, and weighted estimates were used for outcome analysis. The primary outcome was all-cause mortality within three months post-discharge. Secondary outcomes included length of hospital stay (LOS) and CAR-T-related complications. Results: A total of 1806 hospitalizations met the inclusion criteria. The mean age was 61.9 years, with a male majority of 64.4%. The underlying disorders were NHL (73.7%), MM (21.6%), and AL (4.7%). The incidence of CMV infection during the index hospitalization was 2.2%, increasing to 4.2% within three months post-CAR-T therapy. Matched analysis showed higher three-month mortality in CMV-infected patients (15.8%) compared to non-CMV patients (2.5%) (risk ratio 6.32, 95% CI: 1.46-27.30, p=0.004). CMV-infected patients had a significantly longer mean LOS (41.5 vs. 15.9 days, adjusted mean difference 15.5 days, 95% CI: 6.7-24.2, p=0.001). CMV infection was significantly associated with encephalopathy (risk ratio 13.21, 95% CI: 1.66-105.2, p=0.015), while other complications such as cytokine release syndrome (CRS), AKI, and transaminitis did not show a statistically significant association. Conclusions: CMV infection in CAR-T cell therapy recipients is associated with increased mortality, prolonged hospitalization, and risk of encephalopathy. These findings underscore the need for vigilant CMV surveillance and targeted management strategies to improve patient outcomes.

Background Chimeric antigen receptor T (CAR-T) cell therapy has achieved unprecedented success among hematologic tumors, but its role in treating solid tumors is still unclear. Methods A comprehensive search of electronic databases up to June 1, 2018, was carried out by two independent reviewers. We included studies which focused on the association between CAR-T cell therapy and patient response rate and survival time in solid tumors. Results 22 studies with 262 patients were included in our meta-analysis. The overall pooled response rate of CAR-T cell therapy was 9% (95% confidence interval (CI): 4-16%). Subgroup analysis (analyses) demonstrated that CAR-T therapy could perform its best therapeutic effect on neuroblastoma, while barely works among gastrointestinal malignancies. Moreover, the treatment efficacy was not significantly impacted by different treatment strategies (lymphodepletion before T cell infusion, transfection method, cell culture duration, persistence of CAR-T cells, transfection efficacy, total cell dose, and administration of IL-2). Only T cell culture duration was associated with better clinical prognosis. Conclusions Although CAR-T cell therapy did not have satisfactory responses in solid tumors, researchers were still holding an optimistic attitude towards its future efficacy with more modifications of its structure.

CAR-T cell therapy: Advances in digestive system malignant tumors

Chimeric antigen receptor T (CAR-T) cell immunotherapy is becoming one of the most promising treatments for hematological malignancies, however, complications such as cytokine release syndrome (CRS) seriously threaten the lives of patients. Interleukin 6(IL-6) monoclonal antibody is the common and useful treatment of CRS, however, it is not clear whether prophylactic use IL-6 monoclonal antibody before CAR-T therapy can reduce the incidence of CRS. This study aims to systematically evaluate whether the prophylactic use of IL-6 monoclonal antibody can reduce the incidence of CRS. We searched the PubMed, Embase, web of Science, and Cochrane Library databases for studies that reported the prophylactic use of IL-6 monoclonal antibody in the treatment of CRS-related complications of CAR-T cell immunotherapy before December 2022. The literature is screened according to the established inclusion and exclusion criteria, relevant data are extracted, and the quality of the literature is evaluated using the scale Cochrane bias risk assessment tool, and the Review Manager 5.3 is used to draw for related charts. Since the two experimental data only provide the median, the maximum and minimum values of the data, the mean and standard (Standard Deviation, SD) are calculated by this document Delai, and finally use Review Manager for data processing, and STATA software for supplementation. A total of 2 trials with a total of 37 participants were included in this study. Meta-analysis showed that compared with no use of IL-6 monoclonal antibody to prevent CRS, IL-6 monoclonal antibody was given to patients at 8 mg/kg one hour before CAR-T cell infusion, which reduced the incidence of CRS [RR: 0.41 95% confidence interval (0.20, 0.86) I[2] = 0.0% P = 0.338 z = -2.369 (p = 0.018)]. In subgroup analysis, compared with those who did not use IL-6 monoclonal antibody to prevent CRS, IL-6 monoclonal antibody was given to patients at 8 mg/kg one hour before CAR-T cell infusion, which reduced lactate dehydrogenase (LDH)[MD: -617.21, 95% confidence interval (-1104.41, -130.01) I[2] = 0% P = 0.88 Z = 2.48 (P = 0.01)], prophylactic use of IL-6 monoclonal antibody has a significant effect on reducing peak C-reactive protein (CRP) after CAR-T therapy [MD: -11.58, 95% confidence interval (-15.28, -7.88) I[2] = 0.0% P = 0.73 z = 6.14 (p < 0.00001)]. The prophylactic use of IL-6 monoclonal antibody can significantly reduce the incidence of CRS complications after CAR-T therapy, can also reduce LDH vaule and peak CRP vaule after CAR-T therapy. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023487662, identifier CRD42023487662.

Secondary Myeloid Neoplasms after CD19 CAR-T Cell Therapy: Real-Life Multicenter Data from the Clonhema Study

Chimeric antigen receptor-T (CAR-T) therapy has been an effective treatment for leukemia and lymphoma. Unlike hematological cancers, solid tumors like prostate cancer utilize a dynamic microenvironment to evade the host immune defenses. We aimed to systematically review preclinical and clinical studies to evaluate how CAR-T therapies in prostate cancer modify the tumor microenvironment and influence patient outcomes. PubMed, Embase, and Scopus were screened for published, peer reviewed preclinical and clinical studies in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The CAR-T antigen, tumor eradication rates, change in prostate–specific antigen (PSA) expression, and tumor tissue infiltration were compared across studies. Nineteen preclinical trials examining xenograft mice models and 3 phase I clinical trials with 32 total patients were included in this review. Tumor eradication rates in mice treated with armored CAR-T therapy were significantly greater than that of mice treated with unarmored CAR-T cells (p–value &lt; .05). Ten of 32 clinical trial patients had a minimum of 30% PSA decline. Patients receiving higher doses of lymphocyte depletion (LD) therapy had higher peaks of CAR-T expansion, and those receiving LD therapy before CAR-T infusion experienced reduced dose–limiting toxicities. Immunohistochemistry staining of biopsied tumor tissue suggests CAR-T increased T cell proliferation markers and upregulated cytokines. CAR-T cells can modify the tumor microenvironment when armored or paired with LD therapy. Future studies should include expanded clinical investigations, particularly using armored CAR-T cells with LD regimens, to determine its safety and efficacy profiles in prostate cancer.

Chimeric antigen receptor T (CAR-T) cells that are obtained from the specific patient, modified genetically ex vivo, and possess the remarkable capability to identify and eradicate targeted cancer cells. These modified cells are subsequently reintroduced into the patient, effectively treating blood cancer. CAR-T therapy is approved to be applied in leukemia due to its great clinical therapeutic effect on B cell hematological malignancies. However, solid tumors are more resistant to this therapy for many reasons. The abnormal vascular structure of solid tumors hampers CAR-T cell trafficking. Various kinds of immunosuppressive cells and chemicals in the tumor microenvironment (TME) accelerates CAR-T cell exhaustion, showing poor persistence in vivo. More and more researches have demonstrated that T cell fate is strongly associated with epigenetic regulation. Epigenetic modification is not a direct addition or deletion of DNA, but a reversible method including modifications on DNA and histones, and non-coding RNA (ncRNA)-mediated regulations. The change of epigenetic landscape in CAR-T cells largely determines the therapeutic performance in vivo. This research outlines three major barriers in CAR-T therapy, including T cell exhaustion, differentiation and infiltration. Additionally, the research elucidates several promising epigenetic reprogramming strategies to reduce CAR-T cells exhaustion, modulate the cell differentiation process, and enhance their infiltration into solid tumors.

Single-Cell Analyses Identify Transcriptional Characterizations of Subsets Associated with Efficacy and Toxicity for CAR-T Immunotherapy in B-ALL Patients