Chimeric antigen receptor T cells recognizing CD19 (19CAR-T) cell therapy has achieved robust clinical efficacy when treating some hematological malignancies, but which patient subgroups benefit mostly remains elusive. Here we summarized the data of 541 patients from 30 clinical trials who underwent 19 CAR-T therapy and analyzed the different clinical responses between young (<44 years), middle-aged (45-59 years) and elderly (>60 years) patients and found that the young patients showed a higher level of complete response (CR) rate. Therefore, we then summarize the advances of studies focusing on the effects of age on anti-tumor efficacy of CAR-T therapy and analyze the reasons for the low CR rate after CAR-T cell therapy in elderly patients with tumors, aiming to provide hints for oncologists to select the most suitable candidate for this cancer immunotherapy.

Chimeric antigen receptor (CAR)-modified NK (CAR-NK) cells are candidates for next-generation cancer immunotherapies. Here we generated CD19-specific CAR-NK cells with 4-1BB and CD3ζ signaling endo-domains (CD19-BBz CAR-NK) by transduction of cord blood-derived NK cells using baboon envelope pseudotyped lentiviral vectors and demonstrated their antitumor activity in preclinical B cell lymphoma models in female mice. We next conducted a phase 1 dose-escalation trial involving repetitive administration of CAR-NK cells in 8 patients with relapsed/refractory large B cell lymphoma (NCT05472558). Primary end points were safety, maximum tolerated dose, and overall response rate. Secondary end points included duration of response, overall survival, and progression-free survival. No dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. No cases of cytokine release syndrome, neurotoxicity, or graft-versus-host disease were observed. Results showed an overall response rate of 62.5% at day 30, with 4 patients (50%) achieving complete response. The median progression-free survival was 9.5 months, and the median overall survival was not reached. A post hoc exploratory single-cell RNA sequencing analysis revealed molecular features of CAR-NK cells associated with therapeutic efficacy and efficacy-related immune cell interaction networks. This study met the pre-specified end points. In conclusion, CD19-BBz CAR-NK cells were feasible and therapeutically safe, capable of inducing durable response in patients with B cell lymphoma.

Although anti-CD19 chimeric antigen receptor (CAR-T) cells demonstrate high response rates in relapsed/refractory B-cell lymphomas, a considerable proportion of patients eventually encounter disease progression or relapse. The short-term and long-term outcomes of CAR-T treatment are intricately linked to the tumor microenvironment (TME), wherein macrophages with polarized characteristics can exhibit either anti-tumorigenic or pro-tumorigenic roles. Despite evidence implicating the crucial involvement of macrophages in CAR-T cell-treated lymphoma, their dynamic distribution and immune function related to lymphoma progression remain poorly understood. Immunocompetent mice were utilized to establish syngeneic A20 lymphoma/leukemia models. The distribution and polarization of macrophages were detected using immunohistochemistry (IHC) and flow cytometry techniques. We observed that CD19 CAR-T therapy exhibited significant efficacy in protecting mice against lymphoma, leading to increased infiltration of macrophages into the tumor tissue. Notably, during remission stages, M1-like macrophages (CD11b+F4/80+C206-CD80+) were predominant, whereas in relapsed mice, there was a shift towards M2-like phenotypes (CD11b+F4/80+C206+CD80+). The transition from remissive to relapsed status was accompanied by a reduction in the M1/M2 ratio and a decrease in pro-inflammatory cytokines. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) analysis confirmed differential expression levels of CD206 and CD163 between remissive and relapsed mice, while signaling pathways involving PI3K and STAT3 may contribute to the skewing towards M2 polarization. In summary, our findings highlight the dynamic transformation of macrophage polarization during different stages of lymphoma progression and underscore its potential implications for immunotherapeutic interventions.

Long-term risks of gene therapy are not fully understood. In this study, we evaluated safety outcomes in 783 patients over more than 2,200 total patient-years of observation from 38 T cell therapy trials. The trials employed integrating gammaretroviral or lentiviral vectors to deliver engineered receptors to target HIV-1 infection or cancer. Eighteen patients (2.3%) developed secondary malignancies after treatment, with a median onset of 1.94 years (range: 51 d to 14 years). Where possible, incident tumor samples were analyzed for vector copy number, revealing no evidence of high-level marking or other indications of insertional mutagenesis. One T cell lymphoma was detected, but malignant T cells were not marked by vector integration. Analysis of vector integration sites in 176 patients revealed no pathological insertions linked to secondary malignancies, although, in some cases, integration in or near specific genes, including tumor suppressor genes, was associated with modest clonal expansion and sustained T cell persistence. These findings highlight the safety of engineered T cell therapies.

Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable efficacy in treating hematological malignancies and is expanding into other indications such as autoimmune diseases, fibrosis, aging and viral infection. However, clinical challenges persist in treating solid tumors, including physical barriers, tumor heterogeneity, poor in vivo persistence, and T-cell exhaustion, all of which hinder therapeutic efficacy. This review focuses on the critical role of tonic signaling in CAR-T therapy. Tonic signaling is a low-level constitutive signaling occurring in both natural and engineered antigen receptors without antigen stimulation. It plays a pivotal role in regulating immune cell homeostasis, exhaustion, persistence, and effector functions. The "Peak Theory" suggests an optimal level of tonic signaling for CAR-T function: while weak tonic signaling may result in poor proliferation and persistence, excessively strong signaling can cause T cell exhaustion. This review also summarizes the recent progress in mechanisms underlying the tonic signaling and strategies to fine-tune the CAR tonic signaling. By understanding and precisely modulating tonic signaling, the efficacy of CAR-T therapies can be further optimized, offering new avenues for treatment across a broader spectrum of diseases. These findings have implications beyond CAR-T cells, potentially impacting other engineered immune cell therapies such as CAR-NK and CAR-M.

Despite revolutionary efficacy of CD19-CAR-T cell therapy (CAR-T) in aggressive B cell lymphoma, many patients still relapse mostly early. In early failure, distinct drugs support CAR-T which makes reliable and early prediction of imminent relapse/refractoriness critical. A complete metabolic remission (CR) on Fluor-18-Deoxyglucose (FDG) Positron-Emission-Computed Tomography (PET) 30 days after CAR-T (PET30) strongly predicts progression-free survival (PFS), but still fails in a relevant proportion of patients. We aimed to identify additional routine parameters in PET evaluation to enhance CAR-T response prediction.

Thirty patients with aggressive B cell lymphoma treated with CAR-T were retrospectively analyzed. Pre-CAR-T, LDH was the strongest PFS-predictor also by multivariate analysis. Post-CAR-T, 10 out of 14 patients (71.4%) with PET30-CR remained in disease remission, while 12 out of 16 patients (75%) with incomplete metabolic remission (PET30-nCR) relapsed after CAR-T. 28.6% of patients with PET30-CR ultimately progressed. Change of liver FDG-uptake from baseline to day30 (Delta-Liver-SUVmean) was identified as an independent biomarker for response. PET30-nCR and a decrease of Delta-Liver-SUVmean were associated with a high risk of tumor progression (HR 4.79 and 3.99, respectively). The combination of PET30 and Delta-Liver-SUVmean identified patients at very low, at intermediate and at very high risk of relapse (PFS not reached, 7.5 months, 1.5 months, respectively).

Additionally to PET30 metabolic remission, longitudinal metabolic changes in Delta-Liver-SUVmean predicted CAR-T efficiency. Our results may guide early intervention studies aiming to enhance CAR-T particularly in the very high-risk patients.

More active high-dose chemotherapy (HDC) regimens are needed for autologous stem cell transplantation (ASCT) for refractory lymphomas. Seeking HDC enhancement with a PARP inhibitor, we observed marked synergy between olaparib and vorinostat/gemcitabine/busulfan/melphalan (GemBuMel) against lymphoma cell lines, mediated by the inhibition of DNA damage repair. Our preclinical work led us to clinically study olaparib/vorinostat/GemBuMel with ASCT.

Patients ages 15 to 65 years with refractory lymphoma and adequate end-organ function were eligible for this phase I trial. The olaparib dosage was escalated from 25 mg orally twice a day on days -11 to -3, plus vorinostat (1,000 mg orally/day, days -10 to -3), gemcitabine (2,475 mg/m2/day i.v., days -8 and -3), busulfan (target AUC 4,000 µmol/L.minute-1/day i.v., days -8 to -5), melphalan (60 mg/m2/day i.v., days -3 and -2), and rituximab (CD20+ tumors; 375 mg/m2, day -10), with ASCT.

Fifty patients were enrolled (23 with Hodgkin lymphoma, 18 with diffuse large B-cell lymphoma, and 9 with T-cell non-Hodgkin lymphoma); the median age was 35 years (range, 20-61); patients received a median of three prior lines of therapy (range, 2-7); 17 patients had previously relapsed after chimeric antigen receptor T-cell therapy or other cellular immunotherapies; 23 patients had PET-positive tumors at HDC (9 in progression). An olaparib dosage of 150 mg orally twice a day was identified as the recommended phase II dosage. The main extramedullary toxicity was mucositis. The overall response rate and complete response rate were 100% and 90%, respectively. At the median follow-up of 30 (range, 12-56) months, the event-free survival and overall survival rates were 72% and 82% in all patients and 71% and 88% in patients with prior CAR T-cell failure, respectively.

In this first trial combining a PARP inhibitor with HDC, olaparib/vorinostat/GemBuMel was safe and showed promising activity in refractory lymphomas, including post-CAR-T relapses.

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized cancer immunotherapy in the 21st century, providing innovative solutions and life-saving therapies for previously untreatable diseases. This approach has shown remarkable success in treating various hematological malignancies and is now expanding into clinical trials for solid tumors, such as prostate cancer and glioblastoma, as well as infectious and autoimmune diseases. CAR-T cell therapy involves harvesting a patient's T cells, genetically engineering them with viral vectors to express CARs targeting specific antigens and reinfusing the modified cells into the patient. These CAR-T cells function independently of major histocompatibility complex (MHC) antigen presentation, selectively identifying and eliminating target cells. This review highlights the key milestones in CAR-T cell evolution, from its invention to its clinical applications. It outlines the historical timeline leading to the invention of CAR-T cells, discusses the major achievements that have transformed them into a breakthrough therapy, and addresses remaining challenges, including high manufacturing costs, limited accessibility, and toxicity issues such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Additionally, the review explores future directions and advances in the field, such as developing next-generation CAR-T cells aiming to maximize efficacy, minimize toxicity, and broaden therapeutic applications.

B cell-directed CAR T cell therapy has fundamentally changed the treatment of haematological malignancies, and its scope of application is rapidly expanding to include other diseases such as solid tumours or autoimmune disorders. Therapy-refractoriness remains an important challenge in various inflammatory and non-inflammatory disorders of the CNS. The reasons for therapy failure are diverse and include the limited access current therapies have to the CNS, as well as enormous inter- and intra-individual disease heterogeneity. The tissue-penetrating properties of CAR T cells make them a promising option for overcoming this problem and tackling pathologies directly within the CNS. First application of B cell-directed CAR T cells in neuromyelitis optica spectrum disorder and multiple sclerosis patients has recently revealed promising outcomes, expanding the potential of CAR T cell therapy to encompass CNS diseases. Additionally, the optimization of CAR T cells for the therapy of gliomas is a growing field. As a further prospect, preclinical data reveal the potential benefits of CAR T cell therapy in the treatment of primary neurodegenerative diseases such as Alzheimer's disease. Considering the biotechnological optimizations in the field of T cell engineering, such as extension to target different antigens or variation of the modified T cell subtype, new and promising fields of CAR T cell application are rapidly opening up. These innovations offer the potential to address the complex pathophysiological properties of CNS diseases. To use CAR T cell therapy optimally to treat CNS diseases in the future while minimizing therapy risks, further mechanistic research and prospective controlled trials are needed to assess seriously the disease and patient-specific risk-benefit ratio.

Regulatory T cells (Tregs) are key regulators in maintaining tissue homeostasis. Disrupted immune homeostasis is associated with Crohn's disease (CD) pathogenesis. Thus, Treg therapy represents a promising long-acting treatment to restore immune balance in the diseased intestine. Chimeric antigen receptor (CAR) T-cell therapy has revolutionized cancer treatment. This innovative approach also provides the opportunity to improve therapy for CD. By targeting a disease-relevant protein, interleukin-23 receptor (IL23R), we engineered Tregs expressing IL23R-CAR for treating active CD.

Intestinal IL23R expression from active CD was verified by immunohistochemical analysis. Phenotypic and functional characteristics of IL23R-CAR Tregs were assessed using in vitro assays and their migration capacity was monitored in a xenograft tumor model. Transcriptomic and proteomic analyses were performed to associate molecular profiles with IL23R-CAR Treg activation against colon biopsy-derived cells from active CD patients.

Our study showed that IL23R-CAR displayed negligible tonic signaling and a strong signal-to-noise ratio. IL23R-CAR Tregs maintained regulatory phenotype during in vitro expansion, even when chronically exposed to proinflammatory cytokines and target antigen. IL23R engagement on IL23R-CAR Tregs triggered CAR-specific activation and significantly enhanced their suppressive activity. Also, IL23R-CAR Tregs migrated to IL23R-expressing tissue in humanized mice. Finally, IL23R-CAR Tregs elicited a specific activation against colon biopsy-derived cells from active CD, suggesting an efficient CAR engagement in active CD. Molecular profiling of CD patient biopsies also revealed transcriptomic and proteomic patterns associated with IL23R-CAR activation.

Overall, our results demonstrate that IL23R-CAR Tregs represent a promising therapy for active CD.

This study reveals differences in IR patterns after CAR-T therapy in patients with large B-cell lymphoma, with early NK cell recovery emerging as a key predictor of survival. These findings provide potential future avenues of research for improving patient outcomes and tailoring post-therapy management strategies to mitigate relapse risk.

CD19-CAR-T-cells emerge as a major therapeutic option for relapsed/refractory B-cell-derived malignancies, however approximately half of patients eventually relapse. To identify resistance-driving factors, we repeatedly exposed B-cell lymphoma/B-cell acute lymphoblastic leukemia to 4-1BB/CD28-based CD19-CAR-T-cells in vitro. Generated models revealed costimulatory domain-dependent differences in CD19 loss. While CD19-4-1BB-CAR-T-cells induced combination epitope/total CD19 protein loss, CD19-CD28-CAR-T-cells did not drive antigen-escape. Consistent with observations in patients relapsing after CD19-4-1BB-CAR-T-cells, we identified CD19 frameshift/missense mutations affecting residues critical for FMC63 epitope recognition. Mathematical simulations revealed that differences between CD19-4-1BB- and CD19-CD28-CAR-T-cells activity against low-antigen-expressing tumor contribute to heterogeneous therapeutic responses. By integrating in vitro and in silico data, we propose a biological scenario where CD19-4-1BB-CAR-T-cells fail to eliminate low-antigen tumor cells, fostering CAR-resistance. These findings offer mechanistic insight into the observed clinical differences between axi-cel (CD28-based) and tisa-cel (4-1BB-based)-treated B-cell lymphoma patients and advance our understanding on CAR-T resistance. Furthermore, we underscore the need for specific FMC63 epitope detection to deliver information on antigen levels accessible for CD19-CAR-T-cells.

CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has achieved marvelous results in the treatment of patients with relapsed and/or refractory B-cell lymphomas, B-cell acute lymphoblastic leukemia, and multiple myeloma. As a new treatment method that has changed the existing treatment paradigm, there has been a short time from its emergence to FDA approval. However, with the increasing number of cases and the passage of time, hidden problems have gradually been exposed. In this review, we summarize the short- and long-term toxicity, such as secondary T-cell tumors and lethal CAR tumors, of patients with hematologic malignancies treated with CD19-CAR-T cells, including cytokine release syndrome (CRS), ICANS, and secondary malignancies with low occurrence rates but high mortality, such as secondary T cell tumors and lethal CAR tumors, which may be related to the gene modification mechanism of viral vectors currently approved for CAR-T cells. We also discuss potential investigational strategies designed to improve the safety of CAR-T-cell therapy.

Cancer immunotherapy has revolutionized cancer treatment, but therapeutic ineffectiveness-driven by the tumor microenvironment and immune evasion mechanisms-continues to limit its clinical efficacy. This challenge underscores the need to explore innovative approaches, such as multimodal immunotherapy. Phytochemicals, bioactive compounds derived from plants, have emerged as promising candidates for overcoming these barriers due to their immunomodulatory and antitumor properties. This review explores the synergistic potential of phytochemicals in enhancing immunotherapy by modulating immune responses, reprogramming the tumor microenvironment, and reducing immunosuppressive factors. Integrating phytochemicals with conventional immunotherapy strategies represents a novel approach to mitigating resistance and enhancing therapeutic outcomes. For instance, nab-paclitaxel has shown the potential in overcoming resistance to immune checkpoint inhibitors, while QS-21 synergistically enhances the efficacy of tumor vaccines. Furthermore, we highlight recent advancements in leveraging nanotechnology to engineer phytochemicals for improved bioavailability and targeted delivery. These innovations hold great promise for optimizing the clinical application of phytochemicals. However, further large-scale clinical studies are crucial to fully integrate these compounds into immunotherapeutic regimens effectively.

Chimeric Antigen Receptor (CAR) T-cell therapy is characterised by the heterogeneous cellular kinetic profile seen across patients. Unlike traditional chemotherapy, which displays predictable dose-exposure relationships resulting from well-understood pharmacokinetic processes, CAR T-cell dynamics rely on complex biologic factors that condition treatment response. Computational approaches hold potential to explore the intricate cellular dynamics arising from CAR T therapy, yet their ability to improve cancer treatment remains elusive. Here we present a comprehensive framework through which to understand, construct, and classify CAR T-cell kinetics models. Current approaches often rely on adapted empirical pharmacokinetic methods that overlook dynamics emerging from cellular interactions, or intricate theoretical multi-population models with limited clinical applicability. Our review shows that the utility of a model does not depend on the complexity of its design but on the strategic selection of its biological constituents, implementation of suitable mathematical tools, and the availability of biological measures from which to fit the model.

Chimeric antigen receptor (CAR) T cells have recently shown remarkable promise in treating rheumatic diseases, including systemic lupus erythematosus (SLE), idiopathic inflammatory myopathies, and systemic sclerosis. Currently, there are 37 clinical trials registered for CAR T-cell therapy in rheumatic diseases and many more are being planned. Much of this enthusiasm is justifiable, but widespread adoption of CAR T-cell therapy in rheumatology faces several barriers. The trajectory of autoimmune diseases differs from malignancies and a surprisingly narrow population could be eligible for CAR T-cell therapy. Current CAR T-cell approaches rely on B-cell depletion, which has a mixed record of success for many diseases. The high cost of CAR T-cell therapy and potential safety concerns, such as cytokine release syndrome and long-term infection risks, also pose substantial challenges. Moving forward, more targeted CAR T-cell approaches, such as antigen-specific chimeric autoantibody receptors or chimeric autoantigen T-cell receptors, could offer greater efficacy and safety in treating rheumatic diseases.

Chimeric Antigen Receptor (CAR) T-cell therapies represents a major advancement in the treatment of refractory hematologic malignancies, with high remission rates for relapsed B-cell lymphomas and leukemias. However, it is associated with a broad spectrum of potentially life-threatening toxicities, many of which require intensive care unit (ICU) management. Key complications include Cytokine Release Syndrome (CRS) and Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS), as well as severe infections, Immune Effector Cell-associated Hematotoxicity (ICAHT), coagulopathies, and organ dysfunctions resulting from the intense inflammatory response induced by CAR T-cells. Approximately one third of patients undergoing CAR T-cell therapy require ICU admission. Among those patients, CRS is the leading indication. ICANS and sepsis are other major causes of admission to the ICU. This review provides a comprehensive overview of ICU considerations for managing CAR T-cell-related toxicities, covering criteria for ICU admission, approaches to grading and treating complications, and interdisciplinary recommendations to optimize patient outcomes. Enhanced awareness and early intervention are critical in reducing ICU mortality and improving overall survival in patients receiving CAR T-cell therapy.

Over the past decade, drug shortages have become increasingly more problematic for clinicians, with over 300 drug shortages reported in the first quarter of 2023. Shortages of chemotherapy drugs can have a negative impact on patient care, as omission or delay of treatment can lead to worse outcomes. Although many articles have been published on this topic, currently no review articles discuss strategies for using alternative regimens or substitutions in the event of severe chemotherapy drug shortages.

In this article, we review the literature on antineoplastic agents used to treat hematologic malignancies that experienced a drug shortage from 2010 through 2023, providing recommendations for substitutions and alternative regimens in the event of a critical shortage. In particular, we discuss how shortages of fludarabine, cytarabine, daunorubicin, methotrexate, and platinum agents may be addressed, including supporting clinical evidence.

Further publications assessing possible alternatives and substitutions for chemotherapy agents and examining the efficacy of previous strategies are needed to mitigate potentially devastating interruptions to care for patients with cancer during severe drug shortages.

Chimeric antigen receptor T-cell (CAR-T)-mediated therapies have shown promising clinical benefit in patients with refractory or relapsing (R/R) diffuse large B-cell lymphoma (DLBCL). However, CAR-T treatment presents challenges such as lack of drug accessibility, financial barriers, variable physician preference or experience, and risk assessment based on patient-specific characteristics. This article thus aims to provide an overview of the CAR-T landscape for R/R DLBCL in Asia, with a focus on identifying barriers to access, from the perspective of Asian and international lymphoma experts. Presently, existing clinical data indicate that CAR-T therapy is a potentially curative strategy for R/R DLBCL in addition to stem cell transplantation, provided the patient's disease profile and treatment history have been thoroughly considered. However, longer-term follow-up data from large-scale studies are needed to confirm curative potential and define optimal sequencing of CAR-T in the context of novel emerging treatments, such as bi-specific antibodies, in the management of R/R DLBCL. Consequently, further research into CAR-T would benefit from collaboration between institutions. Furthermore, there is a wide disparity in CAR-T accessibility across regions due to complicated logistics and cost, which represent a significant barrier to patients in Asia. Hence, there is a need to increase representation and engagement across different stakeholders such as policymakers, payers, and the industry to arrive at a consensus on patient selection, establish clear guidelines, and develop strategies to lower CAR-T costs. Ultimately, data can support a multi-stakeholder approach when devising strategies to make CAR-T feasible and sustainable for patients.

Diffuse large B-cell lymphoma (DLBCL) is the most prevalent non-Hodgkin lymphoma, with increasing incidence, in Japan. It is associated with substantial economic burden and relatively poor survival outcomes for relapsed/ refractory (r/r) DLBCL patients. Despite its association with economic burden and the relatively limited number of eligible patients in Japan as reported in previous real-world studies, Japanese clinical guidelines recommend stem-cell transplantation (SCT) for transplant-eligible r/r DLBCL patients. This is the first study to elucidate the total healthcare cost, associated cost drivers and healthcare resource use of SCT among patients with r/r DLBCL in a nationwide setting. The study design included a follow-up period of up to 24 months with subsequent lines of therapies using retrospective nationwide claims data from the Medical Data Vision Co., Ltd. Health Insurance Association from April 2012 to August 2022. Included patients had a confirmed diagnosis of DLBCL, received allogeneic SCT (allo-SCT) or autologous SCT (ASCT) after the first DLBCL diagnosis, and received high-dose chemotherapy during the 6-month look-back period. The results confirmed that no patients had allo-SCT, hence only ASCT was included in the analysis. Structural equation modeling was used to identify potential total healthcare cost drivers by evaluating direct, indirect, and total effects and provide a benchmark reference for future innovative therapies. A total of 108 patients (3.8%) among all DLBCL patients who received SCT met the eligibility criteria and were considered ASCT patients; majority of which were males (n = 63, 58.33%), with a mean [median] (SD) age of 52.04 [55] (9.88) years. A total of 15 patients (13.89%) received subsequent therapies. The most frequent subsequent therapy was GDP-based with or without rituximab (n = 8, 7.41%). The mean [median] (SD) number of follow-up hospitalizations on or after SCT-related hospitalizations was 1.66 [1] (1.36), with a mean [median] (SD) length of hospital stay being 36.88 [34] (12.95) days. The total mean [median] (SD) healthcare cost after adjustment incurred per patient per year during follow-up was $79,052.44 [$42,722.82] ($121,503.65). Number of hospitalizations and Charlson Comorbidity Index scores (+5) were the key drivers of total healthcare costs in patients with r/r DLBCL. Index years 2020-2022 and heart disease as a complication were other statistically significant factors that had positive effects as increase on total healthcare costs.

Long-term durable remission in patients with B cell malignancies following chimeric antigen receptor (CAR)-T cell immunotherapy remains unsatisfactory, often due to antigen escape. Malignant B cell transformation and oncogenic growth relies on efficient ATP synthesis, although the underlying mechanisms remain unclear. Here, we report that YTHDF2 facilitates energy supply and antigen escape in B cell malignancies, and its overexpression alone is sufficient to cause B cell transformation and tumorigenesis. Mechanistically, YTHDF2 functions as a dual reader where it stabilizes mRNAs as a 5-methylcytosine (m5C) reader via recruiting PABPC1, thereby enhancing their expression and ATP synthesis. Concomitantly, YTHDF2 also promotes immune evasion by destabilizing other mRNAs as an N6-methyladenosine (m6A) reader. Small-molecule-mediated targeting of YTHDF2 suppresses aggressive B cell malignancies and sensitizes them to CAR-T cell therapy.

Chimeric Antigen Receptor T-Cell (CAR-T) therapy is an effective therapy and promising frontier in the treatment of hematologic malignancies. However, this revolutionary treatment has led to new challenges for patients, caregivers, and the healthcare system. In this review article, we discuss the various difficulties patients face both in the acute and long-term period following CAR-T infusion. We highlight the various ways these difficulties are addressed, as well as further areas of research and support needed to improve patient experience. Additionally, we consider the difficulties and burdens placed on caregivers and healthcare systems, as well as barriers to accessing CAR-T therapy. Finally, we address future directions of research and intervention development to meet patient and caregiver needs and improve equitable access. We pose early integration of specialty palliative care for individuals and their caregivers undergoing CAR-T therapy as one promising strategy to help improve patient experience and meet their needs.

Cancer immunotherapy-including immune checkpoint inhibition (ICI) and adoptive cell therapy (ACT)-has become a standard, potentially curative treatment for a subset of advanced solid and liquid tumors. However, most patients with cancer do not benefit from the rapidly evolving improvements in the understanding of principal mechanisms determining cancer immune responsiveness (CIR); including patient-specific genetically determined and acquired factors, as well as intrinsic cancer cell biology. Though CIR is multifactorial, fundamental concepts are emerging that should be considered for the design of novel therapeutic strategies and related clinical studies. Recent advancements as well as novel approaches to address the limitations of current treatments are discussed here, with a specific focus on ICI and ACT.

T cell-based immunotherapies have demonstrated effectiveness in treating diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) but predicting response and understanding resistance remains a challenge. To address this, we developed syngeneic models reflecting the genetics, epigenetics, and immunology of human FL and DLBCL. We show that EZH2 inhibitors reprogram these models to re-express T cell engagement genes and render them highly immunogenic. EZH2 inhibitors do not harm tumor-controlling T cells or CAR-T cells. Instead, they reduce regulatory T cells, promote memory chimeric antigen receptor (CAR) CD8 phenotypes, and reduce exhaustion, resulting in a decreased tumor burden. Intravital 2-photon imaging shows increased CAR-T recruitment and interaction within the tumor microenvironment, improving lymphoma cell killing. Therefore, EZH2 inhibition enhances CAR-T cell efficacy through direct effects on CAR-T cells, in addition to rendering lymphoma B cells immunogenic. This approach is currently being evaluated in two clinical trials, NCT05934838 and NCT05994235, to improve immunotherapy outcomes in B cell lymphoma patients.

The proliferation of CAR-T cells was hindered and cannot play its killing function well in solid tumors. And yet the regulatory mechanism of CAR-T cell proliferation is not fully understood. Here, we showed that recombinant expression of CD19CAR in T cells significantly increased the basal activation level of CAR-T cells and LCK activation. Both LCK and SMAD4 were essential for CAR-T cells proliferation since over-express LCK or SMAD4 significantly promotes CAR-T cells proliferation, while knock-down LCK or SMAD4 expression inhibited the proliferation of CAR-T cells seriously. More cells go into apoptosis when knock-down LCK or SMAD4 expression, and the cell cycle was arrested in G2/M or S phase, respectively. Over-express LCK or SMAD4 significantly promotes phosphorylation of PI3K and Akt, while it was inhibited when cells were treated with PI3K and Akt inhibitors (LY294002 or MK2206). Further mechanism exploration experiments showed that SMAD4 bound on the promoter region of LCK regulating its expression. Taken together, we reported that the transcription factor SMAD4 regulated the expression of LCK and further involved in the PI3K/Akt signaling pathway to affect the proliferation of CAR-T cells.

The treatment landscape for relapsed/refractory follicular lymphoma (RR-FL) is marked by a pivotal debate between chimeric antigen receptor T-cell (CAR-T) therapy and bispecific antibodies (BsAbs). While both CAR-T therapy and BsAbs target similar immunobiology and molecular markers, their efficacy comparisons are hindered by the lack of direct clinical trial comparisons. Key trials, such as the ZUMA-5 study, underscore axicabtagene ciloleucel (axi-cel)'s efficacy in treating RR-FL, achieving a 79% complete response rate with a median duration of response exceeding 3 years. Similarly, lisocabtagene maraleucel (liso-cel) in the TRANSCEND FL study reports a 94% complete response rate, emphasizing robust outcomes in heavily pretreated patients. Among BsAbs, mosunetuzumab showed promise in the GO29781 trial, with a 62% overall response rate in heavily pretreated RR-FL patients. Thus, CAR-T therapy offers potential curative benefits with a single infusion. However, its efficacy is tempered by significant adverse events such as cytokine release syndrome (CRS), neurotoxicity, and cytopenias, requiring specialized management and patient monitoring. In contrast, BsAbs provide a more tolerable treatment option counterbalancing by lower response rates and frequent dosing requirements. Personalized treatment strategies are crucial because of these distinct efficacy and safety profiles. When considering cost-effectiveness, both therapies need to be evaluated in the context of their clinical outcomes and quality of life improvements. Cost-effectiveness considerations are essential; while CAR-T therapies incur higher initial costs, their potential for long-term remission may mitigate expenses associated with repeated treatments or hospitalizations. Future research into resistance mechanisms and optimal therapeutic sequencing will further refine RR-FL management strategies.

Autoimmune rheumatic diseases (ARDs), such as rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis, involve dysregulated immune responses causing chronic inflammation and tissue damage. Despite advancements in clinical management, many patients do not respond to current treatments, which often show limited efficacy due to the persistence of autoreactive B cells. Chimeric antigen receptor (CAR)-T cell therapy, which has shown success in oncology for B cell malignancies, targets specific antigens and involves the adoptive transfer of genetically engineered T cells. CD19 CAR-T cells, in particular, have shown promise in depleting circulating B cells and achieving clinical remission. This review discusses the potential of CD19 CAR-T cells in ARDs, highlighting clinical achievements and addressing key considerations such as optimal target cell populations, CAR construct design, acceptable toxicities, and the potential for lasting immune reset, crucial for the safe and effective adoption of CAR-T cell therapy in autoimmune treatments.

The US Food and Drug Administration announcement in November 2023 regarding reports of the occurrence of secondary T-cell lymphomas in patients receiving chimeric antigen receptor T cells (CAR-Ts) for B-cell malignancies resulted in widespread concern among patients, clinicians, and scientists. Little information relevant to assessing causality, most importantly whether CAR retroviral or lentiviral vector genomic insertions contribute to oncogenesis, was initially available. However, since that time, several publications have provided clinical and molecular details on 3 cases showing clonal CAR vector insertions in tumor cells but without firm evidence these insertions played any role in oncogenic transformation. In addition, several other cases have been reported without vector detected in tumor cells. In addition, epidemiologic analyses as well as institutional long-term CAR-T recipient cohort studies provide important additional information suggesting the risk of T-cell lymphomas after CAR-T therapies is extremely low. This review will provide a summary of information available to date, as well as review relevant prior research suggesting a low susceptibility of mature T cells to insertional oncogenesis and documenting the almost complete lack of T-cell transformation after natural HIV infection. Alternative factors that may predispose patients treated with CAR-Ts to secondary hematologic malignancies, including immune dysfunction and clonal hematopoiesis, are discussed, and likely play a greater role than insertional mutagenesis in secondary malignancies after CAR therapies.

This study explores a novel therapeutic strategy for relapsed/refractory (R/R) Burkitt lymphoma (BL) by integrating autologous hematopoietic stem cell transplantation (ASCT) with tandem anti-CD19/CD22 chimeric antigen receptor (CAR) T cell therapy. A 20-year-old Asian male with refractory BL, whose lymphoma had not responded to multiple chemoimmunotherapy regimens, received myeloablative ASCT followed three days later by infusion of a novel third-generation CAR T cells engineered with CD28 and CD3ζ signaling domains, along with a TLR2 costimulatory domain. This resulted in sustained complete remission at the 306-day follow-up, without experiencing any severe complications. This case suggests that combining myeloablative ASCT with tandem anti-CD19/CD22 CAR T cell therapy could be an effective approach for R/R BL, warranting further clinical validation.

Refractory aggressive lymphomas can be treated with allo-SCT, pursuing a graft-vs-lymphoma effect. While reduced intensity conditioning is safe, tumors often progress rapidly, indicating the need for more active conditioning regimens. The preclinical synergy we saw between gemcitabine (Gem), clofarabine (Clo) and busulfan (Bu) against lymphoma cell lines led us to study Gem/Clo/Bu clinically. Eligibility: age 12-65, refractory aggressive B-NHL, T-NHL or Hodgkin, with a matched donor. Infusional Gem was dose-escalated on days (d) -6 and -4 (475-975 mg/m2/day), followed by Clo (40 mg/m2/day) and Bu (target AUC, 4000 μMol min/day) (d -6 to -3). CD20+ tumors received rituximab. GVHD prophylaxis included ATG (MUD), tacrolimus and MMF. We compared their outcomes to matched-pair concurrent controls receiving Flu/Mel + matched allo-SCT. We enrolled 64 patients, median age 46 (17-63), 31 B-NHL/22 T-NHL/11 Hodgkin, 36 MSD/28 MUD (all PBPC), median 4 (2-10) prior therapies; 18 prior auto-SCT, 42 active diseases at allo-SCT (12 PD). Toxicities (mucositis and transaminitis) were manageable. Gem/Clo/Bu was myeloablative yielding early full donor chimerism. Grades II-IV/III-IV acute GVHD rates of 37% and 18%; chronic GVHD of 33% (13% severe); NRM at D100/1 year was 7% and 18%. ORR/CR rates: 78%/71% (B-NHL), 93%/93% (T-NHL), 67%/67% (Hodgkin). At a median follow-up of 60 (12-110) months, EFS/OS rates: 36%/47%. Gem/Clo/Bu patients had better median EFS (12 vs. 3 months, P = 0.001) and OS (25 vs. 7 months, P = 0.003) than 113 Flu/Mel matched-pair controls. The new myeloablative regimen Gem/Clo/Bu has limited toxicity and high activity in allo-SCT for aggressive lymphomas, yielding better outcomes than concurrent matched-pair controls receiving Flu/Mel.