Search

Simple Summary: This manuscript systematically reviews the role of positron emission tomography (PET) in the assessment of toxicity associated with chimeric antigen receptor T-cell therapy (CAR T-cell therapy). CAR T-cell therapy, a revolutionary form of immunotherapy, activates immune mechanisms against malignant cells. By doing so, it can also provoke immune-mediated responses against healthy tissues. These responses exhibit diverse clinical, radiological, and functional manifestations across multiple physiological systems. Adverse events include cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Both can cause life-threatening complications. Given the critical imperative of timely identification and vigilant monitoring of these adverse events to enable targeted interventions, PET has emerged as an indispensable imaging biomarker facilitating their detection, prediction, and surveillance. Hence, our investigation is specifically tailored to examine the utility of PET in evaluating adverse events induced by CAR T-cell therapy. The utilization of chimeric antigen receptor (CAR) T-cell therapy to target cluster of differentiation (CD)19 in cancer immunotherapy has been a recent and significant advancement. Although this approach is highly specific and selective, it is not without complications. Therefore, a systematic review was conducted to assess the current state of positron emission tomography (PET) in evaluating the adverse effects induced by CAR T-cell therapy. A thorough search of relevant articles was performed in databases such as PubMed, Scopus, and Web of Science up until March 2024. Two reviewers independently selected articles and extracted data, which was then organized and categorized using Microsoft Excel. The risk of bias and methodological quality was assessed. In total, 18 articles were examined, involving a total of 753 patients, in this study. A wide range of utilities were analyzed, including predictive, correlative, and diagnostic utilities. While positive outcomes were observed in all the mentioned areas, quantitative analysis of the included studies was hindered by their heterogeneity and use of varying PET-derived parameters. This study offers a pioneering exploration of this promising field, with the goal of encouraging further and more focused research in upcoming clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Light-chain (AL) amyloidosis is a rare disease similar to the more common disease, multiple myeloma (MM). Both are caused by proliferation of malignant plasma cells. In AL amyloidosis, disease is a result of the deposition of aggregates of proteins, namely immunoglobulin light chains, secreted by the malignant plasma cells, in target organs such as the heart or kidneys. Historically, treatment of AL amyloidosis has followed that of MM. A wide range of novel immunotherapies, i.e., therapies which utilize or activate immune mechanisms to eliminate the disease, are already established in MM and are gradually being adopted in AL amyloidosis as well. Although promising, the increased frailty of typical AL amyloidosis compared to MM patients is a concern in the administration of these therapies, which may be associated with severe side effects. We review both the promise and the challenges with the expansion of MM immunotherapies to AL amyloidosis. Light-chain (AL) amyloidosis is a rare plasma cell disorder characterized by the deposition of misfolded immunoglobulin light chains in target organs, leading to multi-organ dysfunction. Treatment approaches have historically mirrored but lagged behind those of multiple myeloma (MM). Recent advancements in MM immunotherapy are gradually being evaluated and adopted in AL amyloidosis. This review explores the current state of immunotherapeutic strategies in AL amyloidosis, including monoclonal antibodies, antibody–drug conjugates, bispecific antibodies, and chimeric antigen receptor T-cell therapy. We discuss the unique challenges and prospects of these therapies in AL amyloidosis, including the exposure of frail AL amyloidosis patients to immune-mediated toxicities such as cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS), as well as their efficacy in promoting rapid and deep hematologic responses. Furthermore, we highlight the need for international initiatives and compassionate programs to provide access to these promising therapies and address critical unmet needs in AL amyloidosis management. Finally, we discuss future directions, including optimizing treatment sequencing and mitigating toxicities, to improve outcomes for AL amyloidosis patients. [ABSTRACT FROM AUTHOR]

Simple Summary: This is a comprehensive overview of the approved chimeric antigen receptor T-cell products (CAR T-cells), their specific indications, treatment-related side effects, and scientific challenges. CAR T-cells have been introduced to modern hematology over the last years and have changed treatment outcomes in heavily pretreated patients with B-cell and plasma cell malignancies. To date, six commercially available CAR T-cell products have been approved by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency (EMA). These advanced therapeutic medicinal products induce strong treatment effects but can also cause adverse events that can potentially be life-threatening. Therefore, a thorough understanding of CAR T-cell function and characteristics is essential for safety and efficacy. This review provides a comprehensive overview of the clinical applications of CAR T-cells, focusing on the approved products and emphasizing their benefits but also indicating limitations and challenges. Chimeric antigen receptor (CAR) T-cell therapy has become a powerful treatment option in B-cell and plasma cell malignancies, and many patients have benefited from its use. To date, six CAR T-cell products have been approved by the FDA and EMA, and many more are being developed and investigated in clinical trials. The whole field of adoptive cell transfer has experienced an unbelievable development process, and we are now at the edge of a new era of immune therapies that will have its impact beyond hematologic malignancies. Areas of interest are, e.g., solid oncology, autoimmune diseases, infectious diseases, and others. Although much has been achieved so far, there is still a huge effort needed to overcome significant challenges and difficulties. We are witnessing a rapid expansion of knowledge, induced by new biomedical technologies and CAR designs. The era of CAR T-cell therapy has just begun, and new products will widen the therapeutic landscape in the future. This review provides a comprehensive overview of the clinical applications of CAR T-cells, focusing on the approved products and emphasizing their benefits but also indicating limitations and challenges. [ABSTRACT FROM AUTHOR]

Simple Summary: It is well recognized now that the development of drug resistance is one of the leading causes of treatment failure in conventional therapies. In comparison, recent improvements in immunotherapy showed promising results in eradicating cancer. Chimeric antigen receptor (CAR)-T-cell therapy is one of the cancer immunotherapies that uses patient's T cells and genetically modifies them to target cancer cells. Although CAR-T-cell therapy has shown remarkable success in treating blood cancer, it has proven far more limited in the treatment of solid tumors in different organs. This review article discussed the chronological development of CAR-T-cell therapies and their treatment options in different types of cancers. This article also addresses the current clinical challenges in CAR-T-cell therapy and recent advancements in developing novel therapeutic strategies with fewer side effects. In recent years, chimeric antigen receptor (CAR)-T-cell therapy has emerged as the most promising immunotherapy for cancer that typically uses patients' T cells and genetically engineered them to target cancer cells. Although recent improvements in CAR-T-cell therapy have shown remarkable success for treating hematological malignancies, the heterogeneity in tumor antigens and the immunosuppressive nature of the tumor microenvironment (TME) limits its efficacy in solid tumors. Despite the enormous efforts that have been made to make CAR-T-cell therapy more effective and have minimal side effects for treating hematological malignancies, more research needs to be conducted regarding its use in the clinic for treating various other types of cancer. The main concern for CAR-T-cell therapy is severe toxicities due to the cytokine release syndrome, whereas the other challenges are associated with complexity and immune-suppressing TME, tumor antigen heterogeneity, the difficulty of cell trafficking, CAR-T-cell exhaustion, and reduced cytotoxicity in the tumor site. This review discussed the latest discoveries in CAR-T-cell therapy strategies and combination therapies, as well as their effectiveness in different cancers. It also encompasses ongoing clinical trials; current challenges regarding the therapeutic use of CAR-T-cell therapy, especially for solid tumors; and evolving treatment strategies to improve the therapeutic application of CAR-T-cell therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Chimeric Antigen Receptor T-cell (CAR T) therapy has become the preferable therapeutic approach in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Detection of CAR Ts in peripheral blood smear (PBS) is challenging due to the low sensitivity of current morphological technologies. We provide herein a morphological analysis of CAR Ts during the production process and in consecutive PBS obtained from DLBCL patients undergoing CAR T therapy, employing a novel, highly sensitive microscopy platform. We found that activated morphology was attributed predominantly to transduced cells following engagement with target cells. The average number of day 5 CAR Ts, and their sustained presence, were significantly higher in patients obtaining complete response. Also, a high number of CAR Ts was associated with longer cytokine storm release syndrome. These data indicate that CAR T morphological surveillance in PB might serve as a simple, fast and inexpensive method to provide clinically relevant insights. Chimeric Antigen Receptor T-cell (CAR T) therapy has become the preferable treatment in relapsed/refractory diffuse large B-cell lymphomas (DLBCL) patients. Detection of CAR Ts in peripheral blood smear (PBS) is challenging due to insufficient data regarding their morphology and low sensitivity. The morphological evolution of CAR Ts along their production process, and in patients, was established by Full-Field Morphology (FFM), a novel digital microscopy approach that provides highly sensitive PBS analysis. At day 8 of production, 42.7 ± 10.8% of the CAR T transduced cells exhibited activated morphology compared with 9.3 ± 3.8% in untransduced cells. Moreover, engagement of transduced CAR Ts with target cells resulted in further morphological transformation into activated morphology (83 ± 5.6% of the cells). In patients, the average number of day 5 CAR Ts, and their sustained presence, were significantly higher in patients obtaining complete response. A high number of activated morphology CAR Ts at day 14 was associated with prolonged cytokine release storm. Overall, CAR Ts exhibited heterogeneous morphology, with the activated morphology attributed predominantly to transduced cells following engagement with target cells. Post-transfusion CAR T detection was associated with increased complete responses. FFM CAR T surveillance in PBS may serve as a simple inexpensive method to provide clinically relevant insights into this treatment modality. [ABSTRACT FROM AUTHOR]

Simple Summary: CAR T-cell therapy became standard of care for patients with relapsed or refractory large B-cell lymphoma. However, their administration can be accompanied by toxicities, such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. It is important to identify patients at risk for these toxicities in order to start an early intervention in high-risk patients and guide outpatient CAR T-cell treatment. As a consequence, several easy-to-use risk scores including the EASIX and its derivatives were developed. However, in the available studies, disparities existed among the used endpoints and cutoff values, hampering the utility of these tools in practice. This study aims to validate these EASIX scores in a population-based cohort. This can be used to select the best predictive model and to further guide optimization of the proposed risk scores. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can hamper the clinical benefit of CAR T-cell therapy in patients with relapsed/refractory large B-cell lymphoma (r/r LBCL). To assess the risk of CRS and ICANS, the endothelial activation and stress index (EASIX), the modified EASIX (m-EASIX), simplified EASIX (s-EASIX), and EASIX with CRP/ferritin (EASIX-F(C)) were proposed. This study validates these scores in a consecutive population-based cohort. Patients with r/r LBCL treated with axicabtagene ciloleucel were included (n = 154). EASIX scores were calculated at baseline, before lymphodepletion (pre-LD) and at CAR T-cell infusion. The EASIX and the s-EASIX at pre-LD were significantly associated with ICANS grade ≥ 2 (both p = 0.04), and the EASIX approached statistical significance at infusion (p = 0.05). However, the predictive performance was moderate, with area under the curves of 0.61–0.62. Validation of the EASIX-FC revealed that patients in the intermediate risk group had an increased risk of ICANS grade ≥ 2 compared to low-risk patients. No significant associations between EASIX scores and CRS/ICANS grade ≥ 3 were found. The (m-/s-) EASIX can be used to assess the risk of ICANS grade ≥ 2 in patients treated with CAR T-cell therapy. However, due to the moderate performance of the scores, further optimization needs to be performed before broad implementation as a clinical tool, directing early intervention and guiding outpatient CAR T-cell treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Chimeric antigen receptor (CAR) T-cell therapies targeting CD19 have greatly improved the outcomes of many B-cell non-Hodgkin lymphomas, including relapsed/refractory large B-cell lymphoma (R/R LBCL). Nevertheless, a significant number of patients do not benefit. In this single-center retrospective study of patients with R/R LBCL, the outcomes of 66 patients are reported. We demonstrate that older and more frail patients are able to safely undergo CAR T-cell therapy but have significantly more infectious complications. We also demonstrate that ≥2 sites of extranodal involvement and ECOG at the time of CAR T-cell therapy are significant predictors of progression-free survival. Lastly, we demonstrate that the outcomes of patients who relapse after CAR T-cell therapy are poor. Chimeric antigen receptor T-cell (CAR T-cell) therapy has revolutionized the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). We describe the real-world baseline characteristics, efficacy, safety, and post-relapse outcomes of adult patients with R/R LBCL who received CAR T-cell therapy at the University of California San Diego. A total of 66 patients with LBCL were treated with tisagenlecleucel or axicabtagene ciloleucel. The median age was 59.5, and 21% were over 70 years old. Additionally, 20% of the patients had an Eastern Cooperative Oncology Group (ECOG) performance score of ≥2. Cytokine release syndrome incidence was 88%; immune effector cell-associated neurotoxicity syndrome incidence was 56%. All-grade infection occurred in 48% of patients and in 79% of patients > 70 years old. Complete response (CR) was achieved in 53% and partial response in 14%. Median progression-free survival (PFS) was 10.3 months; median overall survival (OS) was 28.4 months. Patients who relapsed post-CAR T-cell therapy had poor outcomes, with a median OS2 of 4.8 months. Upon multivariate analysis, both ECOG (HR 2.65, 95% CI: 1.30–5.41; p = 0.007) and ≥2 sites of extranodal involvement (HR 2.22, 95% CI: 1.15–4.31; p = 0.018) were significant predictors of PFS. Twenty-six patients were R/R to CAR T-cell therapy; six patients were in remission at the time of data cut off, one of whom received allogeneic transplant. Overall, older patients can safely undergo CAR T-cell therapy, despite the increased risk of all-grade infection. In our cohort, ECOG performance score and ≥2 sites of extranodal disease are significant predictors of PFS. [ABSTRACT FROM AUTHOR]

Simple Summary: Bispecific T-cell engagers (BiTEs) and bispecific antibodies (BiAbs) have emerged as novel therapeutic modalities in the treatment of advanced hematological malignancies. BiTEs and BiAbs redirect T cells to attack tumors and facilitate T-cell-mediated cell death. Blinatumomab was the first BiTE to display proof-of-concept with its remarkable contribution towards the treatment of acute lymphoblastic leukemia. Nearly a decade later, several BiTEs/BiAbs targeting a range of tumor-associated antigens have transpired in the treatment of multiple myeloma, non-Hodgkin's lymphoma, acute myelogenous leukemia, and acute lymphoblastic leukemia. This review summarizes the most recent evidence emerging from clinical trials regarding the use of BiAbs and BiTEs in hematological malignancies whilst highlighting the limitations of these therapeutic options and providing practical insights towards overcoming these limitations. Bispecific T-cell engagers (BiTEs) and bispecific antibodies (BiAbs) have revolutionized the treatment landscape of hematological malignancies. By directing T cells towards specific tumor antigens, BiTEs and BiAbs facilitate the T-cell-mediated lysis of neoplastic cells. The success of blinatumomab, a CD19xCD3 BiTE, in acute lymphoblastic leukemia spearheaded the expansive development of BiTEs/BiAbs in the context of hematological neoplasms. Nearly a decade later, numerous BiTEs/BiAbs targeting a range of tumor-associated antigens have transpired in the treatment of multiple myeloma, non-Hodgkin's lymphoma, acute myelogenous leukemia, and acute lymphoblastic leukemia. However, despite their generally favorable safety profiles, particular toxicities such as infections, cytokine release syndrome, myelosuppression, and neurotoxicity after BiAb/BiTE therapy raise valid concerns. Moreover, target antigen loss and the immunosuppressive microenvironment of hematological neoplasms facilitate resistance towards BiTEs/BiAbs. This review aims to highlight the most recent evidence from clinical trials evaluating the safety and efficacy of BiAbs/BiTEs. Additionally, the review will provide mechanistic insights into the limitations of BiAbs whilst outlining practical applications and strategies to overcome these limitations. [ABSTRACT FROM AUTHOR]

Simple Summary: Our real-world experience confirmed that commercial CART therapy can be administered with minimal toxicity. The early referral of patients with low tumor burdens is important as CAR T indications continue to expand. Furthermore, close monitoring and the early recognition of side effects are beneficial to preventing major toxicities and may potentially expand the use of CAR T therapy. Commercially available anti-CD19 chimeric antigen receptor T cells (CARΤ cells) have offered long-term survival to a constantly expanding patient population. Given that novel toxicities including cytokine release syndrome (CRS) and neurotoxicity (ICANS) have been observed, we aimed to document the safety and toxicity of this treatment in a real-world study. We enrolled 31 adult patients referred to our center for CAR T therapy. Tisagenlecleucel was infused in 12 patients, axicabtagene ciloleucel in 14, and brexucabtagene autoleucel in 5. Cytokine release syndrome was noted in 26 patients while neurotoxicity was observed in 7. Tocilizumab was administered for CRS in 18 patients, along with short-term, low-dose steroid administration in one patient who developed grade III CRS and, subsequently, grade I ICANS. High-dose steroids, along with anakinra and siltuximab, were administered in only two MCL patients. With a median follow-up time of 13.4 months, nine patients were then in CR. The progression-free (PFS) and overall survival (OS) rates were 41.2% and 88.1% at one year, respectively. MCL diagnosis, which coincides with the administration of brexucabtagene autoleucel, was the only factor to be independently associated with poor OS (p < 0.001); meanwhile, increased LDH independently predicted PFS (p = 0.027).In addition, CRP at day 14 was associated with a poor OS (p = 0.001). Therefore, our real-world experience confirmed that commercial CAR T therapy can be administered with minimal toxicity. [ABSTRACT FROM AUTHOR]

Simple Summary: The tumor microenvironment (TME) has a vital role in cancer development, progression, and metastasis. It can shape immune infiltration and activation within tumors, including the role of macrophages, tumor effector cells, and the uptake of therapeutic drugs or nanoparticles. In this manuscript, we report on the feasibility and preliminary efficacy of administering E. coli phagelysate (EcPHL) as a primer to modify the TME, including the enhanced uptake of magnetic nanoparticles (mNP) by tumor-associated macrophages (TAM) and tumor cells. The tumor microenvironment (TME), where cancer cells reside, plays a crucial role in cancer progression and metastasis. It maintains an immunosuppressive state in many tumors and regulates the differentiation of precursor monocytes into M1 (anti-tumor)- and M2 (pro-tumor)-polarized macrophages, and greatly reduces anticancer drug and nanoparticle delivery. As a result, the effectiveness of recently developed chemo- and/or nanotechnology-mediated immune and magnetic nanoparticle hyperthermia (mNPH) therapies is inhibited significantly. One of the ways to overcome this limitation is to use E. coli phagelysate as a primer to modify the tumor microenvironment by switching tumor-associated M2 macrophages to anti-tumor M1 macrophages, and initiate the infiltration of tumor-associated macrophages (TAMs). Recently, bacteriophages and phage-induced lysed bacteria (bacterial phagelysates—BPLs) have been shown to be capable of modifying the tumor-associated environment. Phage/BPL-coated proteins tend to elicit strong anti-tumor responses from the innate immune system, prompting phagocytosis and cytokine release. It has also been reported that the microenvironments of bacteriophage- and BPL-treated tumors facilitate the conversion of M2-polarized TAMS to a more M1-polarized (tumoricidal) environment post-phage treatment. This paper demonstrates the feasibility and enhanced efficacy of combining E. coli phagelysate (EcPHL) and mNPH, a promising technology for treating cancers, in a rodent model. Specifically, we illustrate the EcPHL vaccination effect on the TME and mNP distribution in Ehrlich adenocarcinoma tumors by providing the tumor growth dynamics and histology (H&E and Prussian blue) distribution of mNP in tumor and normal tissue. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma, a cancer of the bone marrow, is the commonest cancer of adults in the Western World. Therapies have advanced dramatically in recent years, equating to improved survival and quality of life for patients, but those with resistant disease still have less favourable outcomes. Bispecific antibodies represent a new treatment option for patients with myeloma. These antibodies activate the patient's own T-cells to kill their tumour cells and have shown impressive results in relapsed refractory myeloma. In this review, we consider ways to improve the activity of these new therapies, as well as to reduce the risk of serious side effects. Bispecific antibodies are immune treatments. Given that the immune system is defective in myeloma, we discuss combining bispecific antibodies with other treatments to improve T-cell function in these patients. We also consider how to reduce the risk of cytokine release syndrome, an important side effect of these therapies. Multiple myeloma (MM) is the second most common haematological neoplasm of adults in the Western world. Overall survival has doubled since the advent of proteosome inhibitors (PIs), immunomodulatory agents (IMiDs), and monoclonal antibodies. However, patients with adverse cytogenetics or high-risk disease as determined by the Revised International Staging System (R-ISS) continue to have poorer outcomes, and triple-refractory patients have a median survival of less than 1 year. Bispecific antibodies (BsAbs) commonly bind to a tumour epitope along with CD3 on T-cells, leading to T-cell activation and tumour cell killing. These treatments show great promise in MM patients, with the first agent, teclistamab, receiving regulatory approval in 2022. Their potential utility is hampered by the immunosuppressive tumour microenvironment (TME), a hallmark of MM, which may limit efficacy, and by undesirable adverse events, including cytokine release syndrome (CRS) and infections, some of which may be fatal. In this review, we first consider the means of enhancing the efficacy of BsAbs in MM. These include combining BsAbs with other drugs that ameliorate the effect of the immunosuppressive TME, improving target availability, the use of BsAbs directed against multiple target antigens, and the optimal time in the treatment pathway to employ BsAbs. We then discuss methods to improve safety, focusing on reducing infection rates associated with treatment-induced hypogammaglobulinaemia, and decreasing the frequency and severity of CRS. BsAbs offer a highly-active therapeutic option in MM. Improving the efficacy and safety profiles of these agents may enable more patients to benefit from these novel therapies and improve outcomes for patients with high-risk disease. [ABSTRACT FROM AUTHOR]

Simple Summary: In 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. [ABSTRACT FROM AUTHOR]

Simple Summary: New approaches in adoptive immunotherapy using chimeric antigen receptor (CAR)-modified cells have been developing very quickly in recent years, entering into clinical trials and being accepted by health agencies worldwide. Although the classical CAR therapies using genetically engineered T cells (CAR-T) are quite effective in curing resistant and refractory blood disorders, they are less efficient in fighting solid tumors. Therefore, intense research is ongoing to modify the CAR constructs and to use different types of immune cells as platforms for CAR-based therapies in order to make them more efficient and safer. This review summarizes new approaches to CAR therapy, with a particular focus on recent achievements and the benefits of genetic engineering of NK cells. Chimeric antigen receptor (CAR)-modified T cell therapy has been rapidly developing in recent years, ultimately revolutionizing immunotherapeutic strategies and providing significant anti-tumor potency, mainly in treating hematological neoplasms. However, graft-versus-host disease (GVHD) and other adverse effects, such as cytokine release syndromes (CRS) and neurotoxicity associated with CAR-T cell infusion, have raised some concerns about the broad application of this therapy. Natural killer (NK) cells have been identified as promising alternative platforms for CAR-based therapies because of their unique features, such as a lack of human leukocyte antigen (HLA)-matching restriction, superior safety, and better anti-tumor activity when compared with CAR-T cells. The lack of CRS, neurotoxicity, or GVHD, in the case of CAR-NK therapy, in addition to the possibility of using allogeneic NK cells as a CAR platform for "off-the-shelf" therapy, opens new windows for strategic opportunities. This review underlines recent design achievements in CAR constructs and summarizes preclinical studies' results regarding CAR-NK therapies' safety and anti-tumor potency. Additionally, new approaches in CAR-NK technology are briefly described, and currently registered clinical trials are listed. [ABSTRACT FROM AUTHOR]

Simple Summary: 20–40% of patients with Burkitt lymphoma (BL) have relapsing or refractory (r/r) disease, and standard treatment for such patients is poorly established. An unexplored treatment option is the bispecific T-cell engager blinatumomab, as used for the treatment of r/r and minimal residual disease (MRD) positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL). So far, data on the use of blinatumomab in r/r BL are limited. In this retrospective multi-center case series, we investigated blinatumomab treatment in nine patients with r/r BL after 1–3 previous therapy lines. Data on safety and efficacy were collected. No high-grade (≥grade 3) adverse effects (AEs) occurred, and use of blinatumomab was found to be safe. The best response to blinatumomab and survival data varied considerably among patients, but with five from nine patients responding, blinatumomab seems to have activity in patients with r/r BL. Our data suggest that blinatumomab could be further explored in r/r BL. In patients with relapsed/refractory Burkitt lymphoma (r/r BL), overall survival (OS) is poor, and effective therapies and evidence for the best therapy are lacking. The monoclonal antibody blinatumomab may represent a novel option. However, only limited data on the use of blinatumomab in r/r BL are so far available. This multi-center, retrospective case series investigated nine patients with r/r BL treated with blinatumomab. The safety of blinatumomab was assessed with respect to frequency and severity of adverse effects (AEs) infections, cytokine release syndrome (CRS) and neurotoxicity. Progression-free survival (PFS), OS and overall response rate (ORR) were analyzed to assess efficacy. No AEs > grade 2 occurred, and AEs were generally treatable and fully reversible. The best response to blinatumomab was complete remission in 3/9 patients and partial remission in 2/9, whilst 4/9 presented with progressive disease. Median PFS and OS were 2 and 6 months, respectively, ranging from 5 days to 32 months and 11 days to 32 months, respectively. Blinatumomab treatment was a successful bridging treatment to stem cell transplantation in 3/9 patients. The response to blinatumomab varied widely, and only one patient survived longer term, but activity in patients with r/r BL was evident in some patients, with its use being safe, warranting its prospective investigation. [ABSTRACT FROM AUTHOR]

Simple Summary: Chimeric antigen receptor T cells (CAR T-cells) are engineered T cells that target tumor-associated antigens. CAR T-cell therapy is a novel developed immunotherapy initially for destroying hematological malignancies. Its great success in clinical practice of hematological malignancies encourages oncologists and scientists to use CAR T-cells for the treatment of solid cancers. However, the efficacy of CAR T-cells in solid tumors is not as good as expected in hematological malignancies. In this review, we summarized the efficacy, safety, and challenges of CAR T-cell therapy in the clinical management of solid tumors. We also discussed the potential strategies currently applied to improve the efficacy and safety of CAR T-cell therapy in solid tumors, and finally prospected the future study direction for CAR T-cell therapy. Immunotherapy has been the fifth pillar of cancer treatment in the past decade. Chimeric antigen receptor (CAR) T-cell therapy is a newly designed adoptive immunotherapy that is able to target and further eliminate cancer cells by engaging with MHC-independent tumor-antigens. CAR T-cell therapy has exhibited conspicuous clinical efficacy in hematological malignancies, but more than half of patients will relapse. Of note, the efficacy of CAR T-cell therapy has been even more disappointing in solid tumors. These challenges mainly include (1) the failures of CAR T-cells to treat highly heterogeneous solid tumors due to the difficulty in identifying unique tumor antigen targets, (2) the expression of target antigens in non-cancer cells, (3) the inability of CAR T-cells to effectively infiltrate solid tumors, (4) the short lifespan and lack of persistence of CAR T-cells, and (5) cytokine release syndrome and neurotoxicity. In combination with these characteristics, the ideal CAR T-cell therapy for solid tumors should maintain adequate T-cell response over a long term while sparing healthy tissues. This article reviewed the status, clinical application, efficacy, safety, and challenges of CAR T-cell therapies, as well as the latest progress of CAR T-cell therapies for solid tumors. In addition, the potential strategies to improve the efficacy of CAR T-cells and prevent side effects in solid tumors were also explored. [ABSTRACT FROM AUTHOR]

Simple Summary: Cytokine release syndrome is a potentially life-threatening complication of therapy with T-cell engaging bispecific antibodies. Here we evaluated the risk, characteristics and biomarkers of treatment-emergent cytokine release syndrome in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome who received weekly intravenous infusions of the CD3xCD123 bispecific antibody APVO436. Cytokine release syndrome was encountered in 10 of 46 patients (21.7%) treated with APVO436 with a cumulative Grade 3/4 cytokine release syndrome incidence of 8.7%. Cytokine profiling in patients who developed cytokine release syndrome after APVO436 infusion indicated that the predominant cytokine in this inflammatory cytokine response was IL-6. The findings from this research provide new insights regarding the biology and effective management of cytokine release syndrome in leukemia patients treated with T-cell redirecting bispecific antibodies. We evaluate the risk, characteristics and biomarkers of treatment-emergent cytokine release syndrome (CRS) in patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received APVO436 during the dose-escalation phase of a Phase 1B study (ClinicalTrials.gov, identifier: NCT03647800). Of four patients who developed Grade ≥ 3 CRS, two received steroid prophylaxis. The dose level, gender, race, obesity, or baseline hematologic parameters in peripheral blood did not predict the risk of CRS. Patients with a higher leukemia burden as determined by a higher total WBC, higher percentage of blasts in bone marrow, or higher percentage of blasts in peripheral blood (by hematopathology or immunophenotyping) did not have a higher incidence of CRS. There was an age difference between patients who did versus patients who did not develop CRS (72.9 ± 1.6 years (Median 73.5 years) vs. 63.3 ± 2.3 years (Median: 65.0 years), which was borderline significant (p = 0.04). Premedication with steroids did not eliminate the risk of CRS. Cytokine profiling in patients who developed CRS after APVO436 infusion indicates that the predominant cytokine in this inflammatory cytokine response was IL-6. APVO436-associated CRS was generally manageable with tocilizumab with or without dexamethasone. Notably, the development of CRS after APVO436 therapy did not appear to be associated with a response. The prolonged stabilization of disease, partial remissions and complete remissions were achieved in both patients who experienced CRS, as well as patients who did not experience CRS after APVO436 infusions. [ABSTRACT FROM AUTHOR]

Simple Summary: B-cell lymphomas are the most commonly occurring blood cancer and the second leading cause of cancer-related death among blood cancers. Chemotherapy and stem cell transplantation have long served as the standard therapies for relapsed or refractory aggressive B-cell lymphomas with very poor survival, historically. Recently, the development of multiple chimeric antigen receptor T-cell (CAR-T) products has translated into dramatically improved outcomes and survival for patients with relapsed or refractory B-cell lymphoma. Meanwhile, basic, translational and clinical development within the field has progressed rapidly. The aim of this review is to summarize the current state of the art of CAR-T therapies for B-cell lymphomas within this rapidly evolving field, focusing on current United States Food and Drug Administration (US FDA)-approved products and a selection of promising areas of future clinical development. Non-Hodgkin Lymphoma accounts for >460,000 cases and >240,000 deaths globally and >77,000 cases and >20,000 deaths in the U.S. annually, with ~85% of cases being B-cell malignancies. Until recently, patients with relapsed/refractory B-cell lymphoma following standard chemotherapy in combination with anti-CD20 monoclonal antibodies and autologous stem cell transplantation experienced a median overall survival (OS) of <6 months. However, with the approval of four different CD-19 CAR-T therapies between 2017 and 2021, approximately 60–80% of patients receiving CAR-T therapy now achieve an objective response with >3 years median OS. Here, we review the current state of the art of CD19 CAR-T therapies for B-cell lymphomas, focusing on current updates in US FDA-approved products, along with their associated efficacy and toxicities. Lastly, we highlight a selection of promising clinical developments in the field, including various novel strategies to increase CAR-T therapy efficacy while mitigating toxicity. [ABSTRACT FROM AUTHOR]

Simple Summary: CAR T-cell therapies have undoubtedly revolutionized the treatment of relapsed/refractory B-cell non-Hodgkin lymphoma. These therapies represent a valuable new treatment option, yielding impressive complete remission rates and improving survival. The aim of this article is to give an overview of emerging real-world evidence since data from every-day clinical practice are still scarce. We report effectiveness and safety data on 30 patients treated at our Institution. Treatment in this setting with CD19-targeted CAR T-cell therapies for relapsed/refractory B-cell non-Hodgkin lymphoma showed a manageable safety profile and high objective response rate, confirming the encouraging results of the pivotal clinical trials. Large B-cell lymphomas (LBCL) are the most common types of non-Hodgkin lymphoma. Although outcomes have improved thanks to the introduction of rituximab-based chemoimmunotherapy, certain LBCL still represents a challenge because of initial resistance to therapy or recurrent relapses. Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are second-generation autologous CD19-targeted chimeric antigen receptor (CAR) T-cell therapies approved for patients with relapsed/refractory (R/R) LBCL, based on the results of phase II pivotal single-arm trials ZUMA-1 (for axi-cel) and JULIET (for tisa-cel). Here, we report patients outcomes with axi-cel and tisa-cel in the standard of care (SoC) setting for R/R LBCL, treated at our Institution. Data were collected from patients who underwent leukapheresis between August 2019 and February 2021. Toxicities were graded and managed according to the institution's guidelines. Responses were assessed as per Lugano 2014 classification. Of the 30 patients who underwent leukapheresis, 18 (60%) received axi-cel, while 12 (40%) tisa-cel. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 10% and 16% patients, respectively. Best objective and complete response rates were 73.3% and 40%, respectively. Treatment in SoC setting with CD19 CAR T-cell therapies for R/R LBCL showed a manageable safety profile and high objective response rate. [ABSTRACT FROM AUTHOR]

Simple Summary: The incidence of metastatic melanoma has been increasing over the past years with current therapies showing limited efficacy to cure the disease. Therefore, other options are being investigated, such as adoptive cell therapy (ACT) where activated immune cells are infused into a patient to attack melanoma. Natural killer (NK) cells are part of the innate immune system and extremely suitable for this kind of therapy since they show minimal toxicities in the clinical setting. In this review, we focus on current strategies for NK cell therapy and the development of new approaches that hold great promise for the treatment of advanced melanoma. Adoptive cell therapy (ACT) represents a promising alternative approach for patients with treatment-resistant metastatic melanoma. Lately, tumor infiltrating lymphocyte (TIL) therapy and chimeric antigen receptor (CAR)-T cell therapy have shown improved clinical outcome, compared to conventional chemotherapy or immunotherapy. Nevertheless, they are limited by immune escape of the tumor, cytokine release syndrome, and manufacturing challenges of autologous therapies. Conversely, the clinical use of Natural Killer (NK) cells has demonstrated a favorable clinical safety profile with minimal toxicities, providing an encouraging treatment alternative. Unlike T cells, NK cells are activated, amongst other mechanisms, by the downregulation of HLA class I molecules, thereby overcoming the hurdle of tumor immune escape. However, impairment of NK cell function has been observed in melanoma patients, resulting in deteriorated natural defense. To overcome this limitation, "activated" autologous or allogeneic NK cells have been infused into melanoma patients in early clinical trials, showing encouraging clinical benefit. Furthermore, as several NK cell-based therapeutics are being developed for different cancers, an emerging variety of approaches to increase migration and infiltration of adoptively transferred NK cells towards solid tumors is under preclinical investigation. These developments point to adoptive NK cell therapy as a highly promising treatment for metastatic melanoma in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: Bispecific antibodies are a very effective immunotherapy against different types of cancer since they activate T cells in the presence of tumor cells. However, they can cause severe side effects, such as a systemic inflammation called cytokine release syndrome. We aimed to clarify an important mechanism that causes cytokine release syndrome. In cocultures of T cells with endothelial cells or lymphoid cells, application of bispecific antibodies can induce T cell activation and cytokine release in the absence of tumor cells. By blocking the adhesion molecule CD18, this interaction is interrupted and the unwanted T cell activation is diminished. CD18 blockade, however, does not interfere with T cell activation when tumor cells are present. Therefore, CD18 blockade could prevent side effects of bispecific antibodies without decreasing the anti-tumor effect. T cell-recruiting bispecific antibodies (bsAbs) are successfully used for the treatment of cancer. However, effective treatment with bsAbs is so far hampered by severe side effects, i.e., potentially life-threatening cytokine release syndrome. Off-target T cell activation due to binding of bispecific CD3 antibodies to T cells in the absence of target cells may contribute to excessive cytokine release. We report here, in an in vitro setting, that off-target T cell activation is induced by bsAbs with high CD3 binding affinity and increased by endothelial- or lymphoid cells that act as stimulating bystander cells. Blocking antibodies directed against the adhesion molecules CD18/CD54 or CD2/CD58 markedly reduced this type of off-target T cell activation. CD18 blockade—in contrast to CD2—did not affect the therapeutic activity of various bsAbs. Since CD18 antibodies have been shown to be safely applicable in patients, blockade of this integrin holds promise as a potential target for the prevention of unwanted off-target T cell activation and allows the application of truly effective bsAb doses. [ABSTRACT FROM AUTHOR]

Simple Summary: T cells modified with a chimeric antigen receptor (CAR) that targets BCMA, a protein expressed on malignant plasma cells, represent a novel treatment option for multiple myeloma. Despite initially eliminating the disease, the function of BCMA-directed CAR-T cells diminishes within a year of administration, leading to disease relapse. The aim of this research was to alter the cytokines used in the ex vivo expansion of anti-BCMA CAR-T cells, to avoid the development of an unfavorable phenotype that would impair in vivo function. We discovered that CAR-T cells expanded with IL-15 had reduced dysfunction and enhanced persistence compared to those grown with IL-2 or a combination of IL-15 and IL-7, which resulted in longer and improved anti-tumor responses in a mouse model. Therefore, the use of IL-15 alone in place of IL-2 or IL-15/IL-7 should be considered when designing CAR-T cell production protocols, to improve the duration of patient responses. Chimeric antigen receptor (CAR)-T cell immunotherapy has revolutionized the treatment of B-lymphoid malignancies. For multiple myeloma (MM), B-cell maturation antigen (BCMA)-targeted CAR-T cells have achieved outstanding complete response rates, but unfortunately, patients often relapse within a year of receiving the therapy. Increased persistence and reduced dysfunction are crucial features that enhance the durability of CAR-T cell responses. One of the factors that influence CAR-T cell in vivo longevity and loss of function, but which has not yet been extensively studied for BCMA-directed CAR-T cells, are the cytokines used during their production. We here compared the impact of IL-2, IL-15 and a combination of IL-15/IL-7 on the phenotype and function of ARI2h, an academic BCMA-directed CAR-T cell that is currently being administered to MM patients. For this study, flow cytometry, in vitro cytotoxicity assays and analysis of cytokine release were performed. In addition, ARI2h cells expanded with IL-2, IL-15, or IL-15/IL-7 were injected into MM tumor-bearing mice to assess their in vivo efficacy. We demonstrated that each of the cytokine conditions was suitable for the expansion of ARI2h cells, with clear in vitro activity. Strikingly, however, IL-15-produced ARI2h cells had improved in vivo efficacy and persistence. When explored further, it was found that IL-15 drove a less-differentiated ARI2h phenotype, ameliorated parameters related to CAR-T cell dysfunction, and lowered the release of cytokines potentially involved in cytokine release syndrome and MM progression. Moreover, we observed that IL-15 was less potent in inducing T cell senescence and DNA damage accumulation, both of which may contribute to an unfavorable CAR-T cell phenotype. These findings show the superiority of IL-15 to IL-2 and IL-15/IL-7 in the quality of anti-BCMA CAR-T cells, particularly their efficacy and persistence, and as such, could improve the duration of responses if applied to the clinical production of CAR-T cells for patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Available data on anti-BCMA CART-cell therapy has demonstrated efficacy and manageable toxicity in heavily pretreated R/R MM patients. Despite this, the main issues remain to be addressed. First of all, a significant proportion of patients eventually relapse. The potential strategy to prevent relapse includes sequential or combined infusion with CAR T-cells against targets other than BCMA, CAR T-cells with novel dual-targeting vector design, and BCMA expression upregulation. Another dark side of CAR T therapy is safety. Cytokine release syndrome (CRS) and neurologic toxicity are well-described adverse effects. In MM trials, most CRS events tended to be grade 1 or 2. Another critical point is the extended timeline of the manufacturing process and that only a few academic centers can perform these procedures. Recognizing these issues, the excellent response with BCMA-targeted CAR T-cell therapy makes it a treatment strategy of great promise. Despite the improvement in survival outcomes, multiple myeloma (MM) remains an incurable disease. Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) represents a new strategy for the treatment of relapsed/refractory MM (R/R). In this paper, we describe several recent advances in the field of anti-BCMA CAR T-cell therapy and MM. Currently, available data on anti-BCMA CART-cell therapy has demonstrated efficacy and manageable toxicity in heavily pretreated R/R MM patients. Despite this, the main issues remain to be addressed. First of all, a significant proportion of patients eventually relapse. The potential strategy to prevent relapse includes sequential or combined infusion with CAR T-cells against targets other than BCMA, CAR T-cells with novel dual-targeting vector design, and BCMA expression upregulation. Another dark side of CART therapy is safety. Cytokine release syndrome (CRS) andneurologic toxicity are well-described adverse effects. In the MM trials, most CRS events tended to be grade 1 or 2, with fewer patients experiencing grade 3 or higher. Another critical point is the extended timeline of the manufacturing process. Allo-CARs offers the potential for scalable manufacturing for on-demand treatment with shorter waiting days. Another issue is undoubtedly going to be access to this therapy. Currently, only a few academic centers can perform these procedures. Recognizing these issues, the excellent response with BCMA-targeted CAR T-cell therapy makes it a treatment strategy of great promise. [ABSTRACT FROM AUTHOR]

Simple Summary: Chimeric antigen receptor T (CAR-T) cells have become clinical practice for the treatment of acute lymphoblastic leukemia and non-Hodgkin lymphoma. The aim of this retrospective study was to assess infection complications after lymphodepletion and CAR-T cell therapy. Infections were commonly detected, but manageable in most cases. Fast and appropriate identification as well as treatment were critical, especially in this very vulnerable patient group. Effective strategies to prevent infections as well as adequate medical management also include standardized prophylaxis and additional supportive therapy. Chimeric antigen receptor T (CAR-T) cell therapy has proven to be very effective in patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). However, infections—related either due to lymphodepletion or the CAR-T cell therapy itself—can result in severe and potentially life-threatening complications, while side effects such as cytokine release syndrome (CRS) might complicate differential diagnosis. Sixty-seven dosings of CAR-T cells in sixty adult patients with NHL (85%) and ALL (15%) receiving CAR-T cell therapy were assessed for infectious complications. Almost two-thirds of patients (61%) developed fever following lymphodepletion and CAR-T cell dosing. Microbiological or radiological findings were observed in 25% of all cases (bacterial 12%, viral 5%, fungal 8%). Inpatient infections were associated with more lines of therapy and more severe CRS. However, overall serious complications were rare after CAR-T therapy, with one patient dying of infection. Pathogen detection after inpatient stay was infrequent and mostly occurred in the first 90 days after dosing. Infections in CAR-T cell treated patents are common. Fast and suitable identification and treatment are crucial in these heavily pretreated and immunocompromised patients. In most cases infectious complications are manageable. Nonetheless, standardized anti-infective prophylaxis and supportive therapy are mandatory to reduce morbidity and mortality in CAR-T cell therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: CAR-T therapy is a breakthrough treatment in our fight against cancer. It was recently approved for the treatment of advanced diffuse large B-cell lymphoma and acute lymphoblastic leukaemia after the failure of previous multiple therapies. The positive results achieved in the registration studies for those patients were remarkable. Unfortunately, this was not the end of this chapter. Disease relapses occur in the range of 30–60% of patients treated with CAR-T therapy. Cytokine release syndrome represents a major side effect for treatment with CAR-T therapy. Notwithstanding, the high positive results triggered the start of a huge research activity of CAR-T therapy in other haematologic malignancies such as acute myelogenous leukaemia, Hodgkin's disease, chronic lymphocytic leukaemia, and multiple myeloma. The research is also trying to overcome the hurdles stated above. These activities represent a new chapter in the management of haematologic malignancies with CAR-T therapy. Chimeric antigen receptor-T (CAR-T) therapy targeting CD19 has revolutionised the treatment of advanced acute lymphoblastic leukaemia (ALL) and diffuse large B-cell lymphoma (DLBCL). The ability to specifically target the cancer cells has shown high positive results as reported in the registration studies. The success of CAR-T therapy in the first two indications led to the initiation of a large number of studies testing CAR-T therapy in different haematologic tumours such as acute myelogenous leukaemia (AML), Hodgkin's disease (HD), chronic lymphocytic leukaemia (CLL), multiple myeloma (MM), as well as different solid tumours. Unfortunately, relapses occurred in patients treated with CAR-T therapy, calling for the development of effective subsequent therapies. Likewise, this novel mechanism of action was also accompanied by a different toxicity profile, such as cytokine release syndrome (CRS). Patients' access to the treatment is still limited by its cost. Notwithstanding, this did not prohibit further development of this new therapy to treat other malignancies. This research activity of CAR-T therapy moves it from being used as an end-stage treatment for ALL and DLBCL to a new therapeutic option for a wide range of patients with different haematologic and solid tumours. [ABSTRACT FROM AUTHOR]

Simple Summary: Interleukin-1 cytokines are key proinflammatory cytokines which have been implicated with differing pro- and antitumorigenic properties. Recent years have brought exciting insights and developments in IL-1-targeted therapies. Here, we present an overview of past and present research focusing on the role of IL-1 in cancer, with a special focus on clinical research and on therapeutic implications. With this, we strive to assist scientists in their future research objectives and to highlight possible directions for IL-1-targeting therapies in the coming years. Since its discovery, interleukin-1 has been extensively studied in a wide range of medical fields. Besides carrying out vital physiological functions, it has been implicated with a pivotal role in the progression and spreading of different cancer entities. During the last years, several clinical trials have been conducted, shedding light on the role of IL-1 blocking agents for the treatment of cancer. Additionally, recent developments in the field of immuno-oncology have implicated IL-1-induced signaling cascades as a major driver of severe chimeric antigen receptor T cell-associated toxicities such as cytokine release syndrome and immune effector cell-associated neurotoxicity. In this review, we summarize current clinical trials investigating the role of IL-1 blockade in cancer treatment and elaborate the proposed mechanism of these innovative treatment approaches. Additionally, we highlight cutting-edge developments utilizing IL-1 blocking agents to enhance the safety and efficacy of adoptive T cell therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: CD19+ Chimeric antigen receptor (CAR) T-cells are used against CD19+ hematologic malignancies, such as high-grade B-cell lymphoma and acute lymphoblastic leukemia. Since this is a relatively new treatment approach, not all potential side effects are well described, and the underlying pathobiology is often not well defined. Here, we summarize current data on the incidence and the current management of CD19+ CAR T-cell complications. We discuss frequently occurring toxicities and we highlight evidence for the occurrence of rarer side effects affecting different organ systems. In addition, we highlight new findings that shed light on the pathophysiology of CAR T-cell-related complications. Clinical trials demonstrated that CD19+ chimeric antigen receptor (CAR) T-cells can be highly effective against a number of malignancies. However, the complete risk profile of CAR T-cells could not be defined in the initial trials. Currently, there is emerging evidence derived from post approval studies in CD19+ CAR T-cells demonstrating both short-term and medium-term effects, which were unknown at the time of regulatory approval. Here, we review the incidence and the current management of CD19+ CAR T-cell complications. We highlight frequently occurring events, such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, cardiotoxicity, pulmonary toxicity, metabolic complications, secondary macrophage-activation syndrome, and prolonged cytopenia. Furthermore, we present evidence supporting the hypothesis that CAR T-cell-mediated toxicities can involve any other organ system and we discuss the potential risk of long-term complications. Finally, we discuss recent pre-clinical and clinical data shedding new light on the pathophysiology of CAR T-cell-related complications. [ABSTRACT FROM AUTHOR]