CAR-T Treatment Research Articles

Cell therapy for scleroderma: progress in mesenchymal stem cells and CAR-T treatment

Cell therapy is an emerging strategy for precision treatment of scleroderma. This review systematically summarizes the research progress of mesenchymal stem cell (MSC) and chimeric antigen receptor T cell (CAR-T) therapies in scleroderma and discusses the challenges and future directions for development. MSCs possess multiple functions, including immunomodulation, anti-fibrosis, and promotion of vascular regeneration, all of which can improve multiple pathological processes associated with scleroderma. Studies have demonstrated that MSCs can alleviate skin fibrosis by inhibiting CCL2 production and reducing the recruitment of pathological macrophages; their paracrine effects can exert extensive regulatory functions. CAR-T cell therapy ca specifically target and eliminate autoreactive immune cells, exhibiting enhanced specificity and personalized potential. Different cell therapies may have complementary and synergistic effects in treating scleroderma, such as MSCs exerting their effects through paracrine mechanisms while CAR-T cells specifically eliminate pathological cells. Furthermore, cell-free therapies derived from MSCs, such as extracellular vesicles or exosomes, may help circumvent the limitations of MSC therapy. Although cell therapy has opened new avenues for the precision treatment of scleroderma, it still faces numerous challenges. In the future, it is essential to strengthen integration of basic and clinical research, establish standardized protocols for cell preparation and quality control, develop personalized treatment plans, and rationally combine cell therapy with existing treatment methods to maximize its advantages and improve patient prognosis and quality of life.

The Role of Electroencephalography Following CAR-T Cell Therapy in Clinical Practice.

Objectives:Neurotoxicity, encephalopathy, and seizures can occur following chimeric antigen receptor (CAR)-T cell therapy. Our aim was to assess what value electroencephalography (EEG) offers for people undergoing CAR-T treatment in clinical practice, including possible diagnostic, management, and prognostic roles. Methods: All patients developing CAR-T related neurotoxicity referred for EEG were eligible for inclusion. Reasons for EEG referral and qualitative EEG findings were analysed and reported. The relationship between objective quantitative EEG (QEEG) encephalopathy grade and clinical neurotoxicity (immune effector cell-associated neurotoxicity syndrome; ICANS) grade was determined. The prognostic ability of QEEG grade was assessed for survival and functional status. Results: Twenty-eight patients with 53 EEG recordings were included. Common reasons given on EEG referrals were possible seizure diagnosis (n = 38), reduced consciousness (n = 8), and superimposed cerebral infection (n = 4). Four focal seizures were detected on three (3/53; 5.7%) EEGs. There was a moderately positive correlation between QEEG grade and ICANS grade (r = + 0.41, p = .030). QEEG grade could not predict survival at 3 months (Area Under Curve; AUC = 0.673) or 6 months (AUC = 0.578), nor could it predict functional status at 1 month (r = + 0.40; p = .080), 3 months (r = + 0.19; p = .439), or time to return to baseline (r = + 0.32; p = .156). Conclusions: EEG was useful in seizure diagnosis. QEEG has a possible role as a specific biomarker of encephalopathy/neurotoxicity. EEG generated no tangible changes in patient management. QEEG was unable to prognosticate survival or functional status.

CAR-T cell therapies for T cell malignancies: does cellular immunotherapy represent the best chance of cure?

Chimeric antigen receptor T cell (CAR-T) therapy has proven successful for B cell lymphomas and leukaemias. This success has inspired the development of CAR-T for T cell malignancies. T cell lymphomas and T-ALL are highly heterogenous diseases but are united by poor prognosis in the relapsed/refractory (r/r) setting and the lack of any novel, targeted therapies. CAR-T therapy is a promising solution for these diseases but carries a number of challenges, principally that target antigens are typically shared between malignant and normal T cells. This can cause issues with fratricide and T cell aplasia. In this review we discuss the current state of CAR-T treatment for T-ALL and T cell lymphomas, highlighting recent novel clinical data for T cell malignancies and discuss lessons that can be learned for future research in this area.

Efficacy and safety of chimeric antigen receptor T cells targeting BCMA and GPRC5D in relapsed or refractory multiple myeloma

BackgroundClinical studies have demonstrated the high efficacy of using chimeric antigen receptor (CAR)-T cells targeting B-cell maturation antigen (BCMA) and orphan G protein-coupled receptor, class C group 5 member D (GPRC5D) to treat relapsed or refractory multiple myeloma (RRMM). In this study, we compared the efficacy and safety of BCMA CAR-T-cell therapy (BCMA CAR-T) and GPRC5D CAR T-cell therapy (GPRC5D CAR-T) in patients with RRMM.MethodsWe retrieved and included eligible clinical trials of BCMA or GPRC5D CAR-T for RRMM patients. The primary outcomes for efficacy were overall response rate (ORR), complete response rate (CRR), minimal residual disease (MRD) negativity, and relapse rate. The primary outcomes for safety were cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).ResultsWe incorporated 18 early-phase, single-arm clinical trials, which included 503 and 133 patients receiving BCMA CAR-T and GPRC5D CAR-T, respectively. For the GPRC5D CAR-T cohort, the estimated ORR, CRR, MRD negativity rate, and relapse rate were found to be 89.8% [95% confidence interval (CI), 82.8%–96.9%], 50.5% (95% CI, 38.0%–62.9%), 78.8% (95% CI, 53.0%–100%), and 26.0% (95% CI, 7.4%–44.6%), respectively. In the BCMA CAR-T group, the ORR was 76.3% (95% CI, 67.9%–84.7%), the CRR was 34.3% (95% CI, 25.9%–42.7%), the MRD negativity rate was 76.5% (95% CI, 63.1%–90.0%), and the recurrence rate was 57.3% (95% CI, 47.7%–66.9%). These values were significantly lower than those observed in the GPRC5D CAR-T cohort. Both BCMA and GPRC5D CAR-T demonstrated acceptable safety. The estimated incidence of BCMA CAR-T resulting in grade 3–5 CRS and ICANS was only 5.4% (95% CI, 2.0%–10.4%) and 3.3% (95% CI, 0.6%–8.0%), respectively. The estimated incidence of GPRC5D CAR-T resulting in grade 3–5 CRS and ICANS was only 1.6% (95% CI, 0.0%–6.5%) and 2.7% (95% CI, 0.7%–6.2%), respectively.ConclusionGPRC5D CAR-T potentially demonstrates enhanced effectiveness relative to BCMA CAR-T in treating patients with RRMM. Therefore, GPRC5D CAR-T can be regarded as the preferred therapeutic option for RRMM, particularly among patients who have undergone relapse subsequent to BCMA CAR-T treatment.

Gene Editing in Cancer Immunotherapy: Mechanisms, Advancements, Limitations and Future Directions

Gene editing has emerged as a transformative approach in cancer immunotherapy. Several gene editing tools have been employed for precise modification of the DNA of immune cells, enhancing their ability to target and eliminate cancer cells. This review examines the evolution and applications of key gene-editing tools, such as CRISPR-Cas9, TALENs, ZFNs, and recent innovations like base and prime editing in the field of cancer immunotherapy. Promising results have been observed in therapies such as CAR-T and tumor-infiltrating lymphocyte (TIL) treatments, which have shown success in cancers like leukemia and lymphoma. These technologies improve immune system function by disrupting checkpoints, boosting cytokine production, and modifying tumor microenvironments. Significant clinical trials have demonstrated promising outcomes, such as CRISPR-Cas9-engineered T cells targeting refractory cancers, which showed improved efficacy and safety. However, despite these advancements, there have been limitations, including off-target effects, delivery inefficiencies, immunogenicity, and ethical concerns, alongside the high costs that hinder widespread adoption. Future directions for gene editing in cancer therapy include the integration of AI and machine learning to enhance target accuracy and guide RNA design, as well as novel gene-editing systems such as the I-C Cascade-Cas3, which facilitates large-scale genomic deletions. Furthermore, CRISPR-based epigenome editing holds promise for further advancing cancer therapies. These innovations, combined with optimized delivery methods, are expected to improve the precision, efficacy, and accessibility of gene editing in cancer immunotherapy.

CAR-T Cell Therapy: An Advancement in Conventional Cancer Treatment Methods

Neoplastic tissues, often known as cancerous malignant tumors, are essentially just collections of aberrant cells that can invade nearby tissues, travel to lymph nodes, and even reach other organs. CAR-T cells, or genetically engineered T cells, express the CAR protein on their surface. A recognition region on the exterior and a signaling region on the inside make up the CAR protein. The antigen plays a crucial role in the development of CAR-T cells. Targeting tumor-specific or tumor-associated antigens that are either exclusively present on tumor cells or increased on the surface of cancer cells is the usual goal of CAR-T cell therapy. The FDA and EMA have approved the commercial sale of CAR T cell treatment out of all the different types of ACTs. Six different drugs have been approved in the US and Europe to treat seven different types of B cell cancer. Patients must be screened by their physicians before considering CAR-T cell therapy. Patients may need to go through therapeutic preparatory procedures including lymphodepletion and bridging therapy before receiving CAR-T cell treatment. CAR T cell therapy's remarkable outcomes have altered dire prognoses and prevented several fatalities from severe cancers. However, an increasing amount of clinical experience is exposing their limitations. Currently, CAR-T cell therapy is mostly used to treat certain blood cancer types. Nevertheless, fresh research is being planned to determine how to improve the effectiveness, lower the cost, and expand the potential applications of therapies. Research is now being done to increase the safety and efficacy of CAR-T cell treatment. Keywords: Chimeric antigen receptor, Major Histocompatibility Complex, Tumor-associated antigen, Cytokine storm syndrome, Cluster of differentiation.

Impact of TP53 mutations on the efficacy of CAR-T cell therapy in cancer

The efficacy of chimeric antigen receptor (CAR)-T therapy may not match initial expectations due to the influence of multiple circumstances, some of which cannot be predicted. CAR-T treatment groups include high-risk patients, particularly those with TP53 mutations. A significant body of research has demonstrated that mutations in the TP53 gene play a pivotal role in cancer development and progression. Any aberration in the TP53 gene in cancer is invariably associated with complications and a poor prognosis. Moreover, mutations in the TP53 gene have been observed to correlate with resistance to conventional chemotherapy, prompting the use of alternative therapeutic approaches, including CAR-T therapy. However, there is a possibility that abnormalities in the TP53 gene may affect patients after CAR-T cell administration reducing the efficacy of therapy. This review examines the link between TP53 mutations in cancer and the efficacy of CAR-T therapy, as well as the potential implications of this aspect in therapeutic planning.

Current Challenges and Potential Strategies in CAR-T Cell Therapy

Abstract. CAR-T therapy, involves modifying the patient's immune T cells in a laboratory setting to recognize antigens on tumor cells. Significant progress has been made in the treatment of hematologic malignancies, thanks to advancements in cancer treatment, namely the discovery of immunotherapies. Nevertheless, the therapy encounters obstacles such as antigen evasion, effects that target both tumor and non-tumor cells, restricted penetration into tumors, a tumor microenvironment that suppresses immune response, and adverse effects such as CRS and neurotoxicity. This paper analyzes the complexities of CAR-T treatment, its fundamental principles, and potential uses for many forms of cancer, including solid tumors. The primary objective is to improve the effectiveness and safety of the therapy by the manipulation of CAR-T cells, alteration of CAR structures, and investigation of combined treatment approaches. Although CAR-T therapy shows promise in transforming cancer treatment, additional refinement is necessary to optimize its therapeutic efficacy and decrease undesirable side effects. This will facilitate the development of more efficient and individualized cancer treatments.

IMMU-60. MYELOID POPULATIONS MODULATE GD2 CAR T CELL ACTIVITY IN DIFFUSE MIDLINE GLIOMA

Abstract H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal cancers in children and young adults. Our team previously demonstrated efficacy of GD2-targeting chimeric antigen receptor T cells (GD2-CAR T-cells) in preclinical models of DMG of the pons (also called diffuse intrinsic pontine glioma (DIPG) and DMG of the spinal cord, and opened a Phase I clinical trial (NCT04196413) treating patients with first intravenous (IV) followed by repeated infusions of intracerebroventricular (ICV) GD2-CAR T-cells. We employed high-dimensional analyses to define immune states contributing to CAR-T activity in patients. Single cell RNA-sequencing (scRNAseq) was conducted on 555,406 single cells from 115 cerebrospinal fluid (CSF) samples of 13 patients before and after CAR-T treatment. This is the largest CSF CAR-T dataset in central nervous system (CNS) tumors and provides insights into the immune biology surrounding CAR-T treatment for CNS malignancies. Patient CSF samples were dominated by T cell and myeloid populations. After CAR-T infusion, patient CSF exhibited an increased fraction of regulatory T cells and myeloid populations from baseline. Myeloid cells in early timepoints after ICV administration demonstrated a unique pro-inflammatory signature, while CSF samples from IV and late ICV timepoints exhibited a suppressive signature. To further explore the immune biology of these myeloid contributors, we developed a patient-derived xenograft model of DMG relapse following low-dose ICV GD2 CAR-T treatment. Using a pharmacological CSF1R-inhibitor, we demonstrate that depletion of microglia/myeloid cells at a specific window following CAR-T administration enhances durability of tumor control. Together, these data display the power of in-depth correlative analyses to identify distinct immune populations that drive durability of response. Key findings from these data will allow for optimization of CAR-T therapies for H3K27M+ DMG patients, providing hope to shift the paradigm of this fatal disease.

TMOD-02. PATIENT-DERIVED GLIOBLASTOMA ORGANOIDS AS REAL-TIME AVATARS FOR ASSESSING RESPONSES TO CLINICAL CAR-T CELL THERAPY

Abstract Patient-derived tumor organoids have been increasingly leveraged for disease modeling and preclinical studies, but rarely in real-time to aid with the interpretation of patient treatment responses in the clinical setting. Whether tumor organoids can be applied to mirror clinical activity in patients and even to predict responses for personalized medicine remains uncertain. We recently demonstrated promising early efficacy signals in a first-in-human, phase 1 study of dual-targeting chimeric antigen receptor T cells (EGFR-IL13Rα2 CAR-T cells) in patients with recurrent glioblastoma (clinical trial identifier: NCT05168423). Determination of meaningful clinical efficacy, in particular for CAR-T cell therapy, may take months to manifest. Given this challenge, real-time analysis of patient-derived glioblastoma organoids (GBOs) could help to provide early assessment of clinical efficacy and guide patient management. We analyzed six sets of GBOs generated on the same timeline as the production of patients’ CAR-T cell products. GBOs demonstrated the presence and retention of both targeted tumor-associated antigens EGFR and IL13Rα2 by immunohistochemistry. These GBOs were then treated with the same autologous CAR-T cell products received by patients in our phase 1 study in parallel with patient treatment. CAR-T cell treatment led to target antigen reduction assessed by immunohistochemistry and flow cytometry. Furthermore, we confirmed cytolysis of tumor cells in GBOs by cleaved caspase-3 immunostaining and by co-culture in the Axion Maestro Cellular Impedance platform. Importantly, the degree of cytolysis ex vivo significantly correlated with CAR-T cell engraftment detected in patients’ cerebrospinal fluid (CSF) for all six patients. Furthermore, cytotoxic activity of CAR-T cells as measured by TNFα, IL-2, and IFNγ release kinetics in GBOs mirrored cytokine levels in patient CSF samples over time. Our findings highlight a unique trial design and suggest GBOs as a valuable platform for real-time assessment of CAR-T cell bioactivity and for insights into immunotherapy efficacy.

Fluctuation of physical function during chimeric antigen receptor T-cell therapy during rehabilitation intervention: Real-world data and risk factor analyses.

Patients undergoing chimeric antigen receptor (CAR) T-cell therapy face prolonged treatment timelines and are prone to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) after infusion. Disabilities in physical function and the importance of rehabilitation during CAR-T-cell therapy to maintain physical function have been poorly documented. We performed a retrospective cohort study to assess changes in exercise tolerance via differences in a 6-min-walking distance (Δ6MWD) and factors influencing it. A total of 77 patients who underwent rehabilitation during CAR-T-cell therapy were enrolled, and their 6MWD was 450m (median, range 180-705m) before and 450.5m (107.0-735.0m) 30 days after CAR-T treatment. No significant alteration in Δ6MWD was observed overall (11.0m, 95% confidence interval, -56.1 to 88.2m). Multiple regression analyses indicated that age (over vs. under 65 years) revealed no notable differences in Δ6MWD (20 vs. 10m), while ΔHb (β=0.24, p=0.03), moderate/severe CRS (grade 1 with continuous fever or grade ≥2; β=-0.25, p=0.03), and ICANS (any grade; β=-0.22, p=0.04) were significantly associated with lower Δ6MWD. This real-world study indicated that CAR-T-cell therapy is less likely to reduce physical function even in older patients if rehabilitation is properly performed, whereas CRS and ICANS can be risk factors to deprive exercise tolerance.

The incidence and clinical significance of monoclonal and oligoclonal protein bands in multiple myeloma patients after BCMA-CAR-T cell therapy: A retrospective study based on LEGEND-2.

The emergence of abnormal protein bands (APBs), also known as oligoclonal protein bands, has been documented in patients with multiple myeloma (MM) post hematopoietic stem cell transplantation. However, the incidence rate and clinical significance of APBs remain contentious. Few studies have explored the occurrence and prognostic implications of APBs in patients with MM treated with B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR)-T therapy. In this retrospective study, we examined the frequency, isotypes, and duration of APBs, as well as their correlation with MM disease characteristics, treatment response, clinical outcomes, and immune signature in patients with relapsed/refractory MM who had received LCAR-B38M therapy at the Xi'an site of the phase 1 LEGEND-2 trial. Among 47 patients assessed, 23 (48.9%) developed APBs following CAR-T therapy, with IgG being the most common isotype. The median onset and duration of APBs post-CAR-T infusion were 3.6 and 5.8 months, respectively. Patients with APBs demonstrated significantly improved response to LCAR-B38M therapy, along with longer overall and progression-free survival. Furthermore, those with APBs exhibited enhanced recovery rates of immunoglobulins and higher absolute counts of white blood cells, neutrophils, and lymphocytes post-CAR-T treatment compared to those without APBs. However, no significant differences were observed between the two groups in the percentages of various T-cell subsets and natural killer cells. Overall, the presence of APBs in patients with MM following CAR-T treatment was associated with deeper remission and a more favorable prognosis, suggesting a robust humoral response and subsequent immune reconstitution.

ARI0003: Co-transduced CD19/BCMA dual-targeting CAR-T cells for the treatment of non-Hodgkin lymphoma

CD19 CAR-T therapy has achieved remarkable responses in relapsed/refractory non-Hodgkin lymphoma (NHL). However, challenges persist, with refractory responses or relapses after CAR-T administration linked to CD19 loss or downregulation. Given the co-expression of CD19 and BCMA in NHL, we hypothesized that dual targeting could enhance long-term efficacy. We optimized different dual-targeting approaches, including co-transduction of two lentiviral vectors, bicistronic, tandem, and loop and pool strategies, based on our academic anti-CD19 (ARI0001) and anti-BCMA (ARI0002h) CAR-T cells. Comparison with anti-CD19/CD20 or anti-CD19/CD22 dual targeting was also performed. We demonstrate that anti-CD19/BCMA CAR-T cells can be effectively generated through the co-transduction of two lentiviral vectors after optimization to minimize competition for cellular resources. Co-transduced Tcells, called ARI0003, effectively targeted NHL tumor cells with high avidity, outperforming anti-CD19 CAR-T cells and other dual-targeting approaches both invitro and invivo, particularly in low CD19 antigen density models. ARI0003 maintained effectiveness post-CD19 CAR-T treatment in xenograft models and in spheroids from relapsed CART-treated patients. ARI0003 CAR-T cells were effectively manufactured under Good Manufacturing Practice conditions, with a reduced risk of genotoxicity compared to other dual-targeting approaches. A first-in-human phase 1 clinical trial (CARTD-BG-01; this study was registered at ClinicalTrials.gov [NCT06097455]) has been initiated to evaluate the safety and efficacy of ARI0003 in NHL.

The dynamic evolution of lineage switch under CD19 CAR-T treatment in non-KMT2A rearranged B-ALL patients.

The dynamic evolution of lineage switch under CD19 CAR-T treatment in non-KMT2A rearranged B-ALL patients.

Impact of Allogeneic Stem Cell Transplant on Safety and Outcomes of Chimeric Antigen Receptor T Cell (CAR-T) Therapy in Patients with Multiple Myeloma (MM).

Background: Allogeneic stem cell transplantation (allo-SCT) has seen limited use in treating multiple myeloma (MM), despite its potential to offer long-term survival or even cure through the graft-versus-myeloma effect. Its limited application is largely due to concerns over serious complications like infections and graft-versus-host disease (GVHD). The possibility of GVHD exacerbation when CAR-T cells are administered to patients previously treated with allo-SCT remains a topic of concern. Ciltacabtagene autoleucel (Cilta-cel) and idecabtagene vicleucel (Ide-cel) are CAR-T therapies that have been FDA-approved for relapsed/refractory (R/R) MM. A recent study using data from the CARTITUDE-1 trial has shown promising safety and efficacy of Cilta-Cel in patients with a prior history of allo-SCT. This report outlines our real-world experience with CAR-T treatment in such patients. The objective of this study is to assess the safety and effectiveness of CAR-T therapy in R/R MM patients who have previously undergone allo-SCT. Methods: We conducted a retrospective analysis of adult patients (18-70 years old) with R/R MM treated with CAR-T therapy as part of an institutional IRB-approved protocol. Data were collected on safety and efficacy outcomes from the institution's records. Adverse events (AEs) were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded based on American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Efficacy metrics included overall response rate (ORR) and progression-free survival (PFS), analyzed through the Kaplan-Meier method, with PFS defined as the time from CAR-T initiation to disease progression or death. Results: Of the 56 patients treated with CAR-T therapy, 8 (14.3%) had previously undergone allo-SCT. These patients had a median of seven prior therapy lines (LOTs), compared to five LOTs in the non-allo-SCT group (p = 0.04). CAR-T infusion occurred a median of 98.8 months after allo-SCT, with a range from 57.9 months to 178.5 months. CRS occurred in 87.5% of the allo-SCT group versus 77.1% in the non-allo-SCT group (p = 0.48). One patient in the allo-SCT group developed hemophagocytic lymphohistiocytosis (HLH), requiring anakinra. At a median follow-up of 4.8 months, the ORR was 87.5% in the allo-SCT group versus 75% in the non-allo-SCT group (p = 0.4). Median PFS had not been reached for the allo-SCT group at the time of analysis compared to 11.9 months in the non-allo-SCT group (p = 0.5). No treatment-related mortality or acute GVHD was noted in the allo-SCT cohort. Conclusions: The study suggests that prior allo-SCT does not adversely affect the safety or efficacy of CAR-T therapy in patients with R/R MM. These findings highlight the need for further investigations with larger patient samples and longer follow-up to better understand the interaction between allo-SCT and CAR-T therapy.

Technical comment on: Trottmann M, et al. Real-world expenditures and survival time after CAR-T treatment for large B-cell lymphoma in Switzerland: a retrospective study using insurance claims data.

Technical comment on: Trottmann M, et al. Real-world expenditures and survival time after CAR-T treatment for large B-cell lymphoma in Switzerland: a retrospective study using insurance claims data.

Identification of pyrimidine structure-based compounds as allosteric ligands of the dopamine transporter as therapeutic agents for NeuroHIV.

The disruption of dopamine neurotransmission by the HIV-1 Transactivator of transcription (Tat) during HIV-1 infection has been linked to the development of neurocognitive disorders, even under combined antiretroviral therapy (cART) treatment. We have demonstrated that SRI-32742, a novel allosteric modulator of dopamine (DA) transporter (DAT), attenuates cocaine- and Tat-binding to DAT, alleviates Tat-induced cognitive deficits and potentiation of cocaine reward in inducible Tat transgenic mice. The current study determined the in vitro pharmacological profile of SRI-32743 and its optimized second-generation analogs and their effects as allosteric modulators. Through structure-activity relationship studies of SRI-32743, 170 compounds were synthesized and evaluated for their ability to modulate DAT function. We identified 21 analogs as atypical competitors of DAT (Emax {less than or equal to}60%). Four compounds, SRI-46564, SRI-47056, SRI-46286 and SRI-47867, displayed IC50 values for [3H]DA uptake inhibition from 9.33 {plus minus} 0.50 to 0.96 {plus minus} 0.05 µM and from 3.96 {plus minus} 1.36 to 1.29 {plus minus} 0.19 for DAT binding, respectively. The four analogs also displayed high potency at two different concentrations (0.5 nM and 0.05 nM) to attenuate Tat-induced inhibition of [3H]DA uptake and cocaine-mediated dissociation of [3H]WIN35,428 binding in CHO cells expressing hDAT, suggesting that the effects occur through an allosteric mechanism. In further ex vivo studies using Fast-Scan Cyclic Voltammetry, we demonstrated that the analogs do not disrupt the baseline phasic-like DA release. These findings provide a new insight into the potential for development of novel therapeutic agents to attenuate DAT-Tat interactions to normalize DA neurotransmission in NeuroHIV. Significance Statement The allosteric inhibition of the dopamine (DA) transporter by the HIV-1 Transactivator of transcription (Tat) disrupts dopamine homeostasis, leading to HIV-associated neurocognitive disorders (HANDs). Analogs of SRI-32743, a novel allosteric modulator of the Tat-DAT interaction, were evaluated in the current study and characterized as atypical ligands of DA uptake. Four novel lead compounds demonstrated high potency to attenuate Tat-induced inhibition of hDAT-mediated DA uptake in an allosteric modulatory manner with no effects on the dynamics of DA uptake-release in DAT.

Concurrent TB and HIV therapies effectively control clinical reactivation of TB during co-infection but fail to eliminate chronic immune activation.

The majority of Human Immunodeficiency Virus (HIV) negative individuals exposed to Mycobacterium tuberculosis (Mtb) control the bacillary infection as latent TB infection (LTBI). Co-infection with HIV, however, drastically increases the risk to progression to tuberculosis (TB) disease. TB is therefore the leading cause of death in people living with HIV (PLWH) globally. Combinatorial antiretroviral therapy (cART) is the cornerstone of HIV care in humans and reduces the risk of reactivation of LTBI. However, the immune control of Mtb infection is not fully restored by cART as indicated by higher incidence of TB in PLWH despite cART. In the macaque model of co-infection, skewed pulmonary CD4+ TEM responses persist, and new TB lesions form despite cART treatment. We hypothesized that regimens that concurrently administer anti-TB therapy and cART would significantly reduce TB in co-infected macaques than cART alone, resulting in superior bacterial control, mitigation of persistent inflammation and lasting protective immunity. We studied components of TB immunity that remain impaired after cART in the lung compartment, versus those that are restored by concurrent 3 months of once weekly isoniazid and rifapentine (3HP) and cART in the rhesus macaque (RM) model of LTBI and Simian Immunodeficiency Virus (SIV) co-infection. Concurrent administration of cART + 3HP did improve clinical and microbiological attributes of Mtb/SIV co-infection compared to cART-naïve or -untreated RMs. While RMs in the cART + 3HP group exhibited significantly lower granuloma volumes after treatment, they, however, continued to harbor caseous granulomas with increased FDG uptake. cART only partially restores the constitution of CD4 + T cells to the lung compartment in co-infected macaques. Concurrent therapy did not further enhance the frequency of reconstituted CD4+ T cells in BAL and lung of Mtb/SIV co-infected RMs compared to cART, and treated animals continued to display incomplete reconstitution to the lung. Furthermore, the reconstituted CD4+ T cells in BAL and lung of cART + 3HP treated RMs exhibited an increased frequencies of activated, exhausted and inflamed phenotype compared to LTBI RMs. cART + 3HP failed to restore the effector memory CD4+ T cell population that was significantly reduced in pulmonary compartment post SIV co-infection. Concurrent therapy was associated with the induction of Type I IFN transcriptional signatures and led to increased Mtb-specific TH1/TH17 responses correlated with protection, but decreased Mtb-specific TNFa responses, which could have a detrimental impact on long term protection. Our results suggest the mechanisms by which Mtb/HIV co-infected individuals remain at risk for progression due to subsequent infections or reactivation due of persisting defects in pulmonary T cell responses. By identifying lung-specific immune components in this model, it is possible to pinpoint the pathways that can be targeted for host-directed adjunctive therapies for TB/HIV co-infection.

Hematopoietic stem cell transplantation for DLBCL: a report from the European Society for Blood and Marrow Transplantation on more than 40,000 patients over 32 years

Autologous(auto-) and allogeneic(allo-) hematopoietic stem cell transplantation (HSCT) are key treatments for relapsed/refractory diffuse large B-cell lymphoma (DLBCL), although their roles are challenged by CAR-T-cells and other immunotherapies. We examined the transplantation trends and outcomes for DLBCL patients undergoing auto-/allo-HSCT between 1990 and 2021 reported to EBMT. Over this period, 41,148 patients underwent auto-HSCT, peaking at 1911 cases in 2016, while allo-HSCT saw a maximum of 294 cases in 2018. The recent decline in transplants corresponds to increased CAR-T treatments (1117 cases in 2021). Median age for auto-HSCT rose from 42 (1990–1994) to 58 years (2015–2021), with peripheral blood becoming the primary stem cell source post-1994. Allo-HSCT median age increased from 36 (1990–1994) to 54 (2015–2021) years, with mobilized blood as the primary source post-1998 and reduced intensity conditioning post-2000. Unrelated and mismatched allo-HSCT accounted for 50% and 19% of allo-HSCT in 2015–2021. Three-year overall survival (OS) after auto-HSCT improved from 56% (1990–1994) to 70% (2015–2021), p < 0.001, with a decrease in relapse incidence (RI) from 49% to 38%, while non-relapse mortality (NRM) remained unchanged (4%). After allo-HSCT, 3-year-OS increased from 33% (1990–1999) to 46% (2015–2021) (p < 0.001); 3-year RI remained at 39% and 1-year-NRM decreased to 19% (p < 0.001). Our data reflect advancements over 32 years and >40,000 transplants, providing insights for evaluating emerging DLBCL therapies.

CAR-T Cells Therapy in Glioblastoma: A Systematic Review on Molecular Targets and Treatment Strategies.

The most common primary brain tumor is glioblastoma (GBM), yet the current therapeutic options for this disease are not promising. Although immunotherapeutic techniques have shown poor success in GBM thus far despite efforts, new developments provide optimism. One of these developments is chimeric antigen receptor (CAR)-T cell treatment, which includes removing and genetically modifying autologous T cells to produce a receptor that targets a GBM antigen before reintroducing the cells into the patient's body. A number of preclinical studies have produced encouraging results, which have led to the start of clinical trials assessing these CAR-T cell treatments for GBM and other brain tumors. Although results in tumors such as diffuse intrinsic pontine gliomas and lymphomas have been promising, preliminary findings in GBM have not produced any clinical benefits. The paucity of particular antigens in GBM, their inconsistent expression patterns, and the possible immunoediting-induced loss of these antigens after antigen-targeted therapy are some possible causes for this discrepancy. The goal of this systematic literature review is to assess potential approaches for creating CAR-T cells that are more effective for this indication, as well as the clinical experiences that are already being had with CAR-T cell therapy in GBM. Up until 9 May 2024, a thorough search was carried out across the three main medical databases: PubMed, Web of Science, and Scopus. Relevant Medical Subject Heading (MeSH) terms and keywords associated with "glioblastoma", "CAR-T", "T cell therapy", "overall survival", and "progression free survival" were employed in the search approach. Preclinical and clinical research on the application of CAR-T cells as a therapeutic approach for GBM are included in the review. A total of 838 papers were identified. Of these, 379 articles were assessed for eligibility, resulting in 8 articles meeting the inclusion criteria. The included studies were conducted between 2015 and 2023, with a total of 151 patients enrolled. The studies varied in CAR-T cell types. EGFRvIII CAR-T cells were the most frequently investigated, used in three studies (37.5%). Intravenous delivery was the most common method of delivery (62.5%). Median OS ranged from 5.5 to 11.1 months across the studies. PFS was reported in only two studies, with values of 7.5 months and 1.3 months. This systematic review highlights the evolving research on CAR-T cell therapy for GBM, emphasizing its potential despite challenges. Targeting antigens like EGFRvIII and IL13Rα2 shows promise in treating recurrent GBM. However, issues such as antigen escape, tumor heterogeneity, and immunosuppression require further optimization. Innovative delivery methods, combination therapies, and personalized approaches are crucial for enhancing CAR-T cell efficacy. Ongoing research is essential to refine these therapies and improve outcomes for GBM patients.