Enhancing CAR-T cell therapy against solid tumor by drug-free triboelectric immunotherapy.

Chimeric antigen receptor (CAR) T cell therapy is a highly effective immunotherapy for hematological tumors, but its efficacy against most solid tumors remains challenging. Herein, a novel synergistic combination therapy of drug-free triboelectric immunotherapy and CAR-T cell therapy against solid tumor was proposed. A triboelectric nanogenerator (TENG) that can generate pulsed direct-current by coupling triboelectrification effect and electrostatic breakdown effect was fabricated. The TENG can generate up to 30 pulse direct-current peaks with peak current output ≈35 µA in a single sliding to power the triboelectric immunotherapy. The pulsed direct-current stimulation induced immunogenic cell death of tumor cells (survival rate of 35.9 %), which promoted dendritic cells maturation, accelerated the process of antigen presentation to CAR-T cells and enhanced the systemic adaptive immune response. Furthermore, triboelectric immunotherapy promoted M1-like macrophage polarization, reduced regulatory T cells differentiation and reprogrammed the tumor immunosuppressive microenvironment, which ultimately enhanced the efficacy of CAR-T cells to eradicate nearly 60 % of NALM6 solid tumor mass. Notably, considering that triboelectric immunotherapy is a safe and effective drug-free antitumor strategy, the combined therapy did not increase the burden of double-medication on patients.

Novel Therapies for Primary Central Nervous System Lymphomas.

PURPOSE OF REVIEW: Primary Central Nervous System Lymphoma (PCNSL) is an aggressive form of lymphoma that can involve the brain, spinal cord, leptomeninges and eyes. PCNSL prognosis continues to be poor, with 5-year survival rates of 30-40%. Therapeutic options are especially limited for relapsed/refractory (r/r) PCNSL. In recent years, studies shed light on the pathogenesis and oncogenic pathways driving PCNSL, leading to the development of novel therapeutics. In this review, we discuss the evidence supporting these novel agents and present ongoing clinical studies. RECENT FINDINGS: Key oncogenic drivers of PCNSL include activation of the NFkB pathway, cell cycle dysregulation, somatic hypermutation and immune evasion, leading to the investigation of targeted therapeutics and immunotherapeutics to inhibit these pathways. Such approaches include BTK inhibitors, mTOR/PI3K inhibitors, immunomodulatory agents (IMIDs), immune checkpoint inhibitors and CD19-based CAR T-cells. The therapeutic repertoire for PCNSL is rapidly evolving, and a multi-modality approach including intensive chemotherapy regimens and novel therapies will likely be utilized in the future.

Therapeutic targets of armored chimeric antigen receptor T cells navigating the tumor microenvironment.

Chimeric antigen receptor (CAR) T cell therapy, which targets tumors with high specificity through the recognition of particular antigens, has emerged as one of the most rapidly advancing modalities in immunotherapy, demonstrating substantial success against hematological malignancies. However, previous generations of CAR-T cell therapy encountered numerous challenges in treating solid tumors, such as the lack of suitable targets, high immunosuppression, suboptimal persistence, and insufficient infiltration owing to the complexities of the tumor microenvironment, all of which limited their efficacy. In this review, we focus on the current therapeutic targets of fourth-generation CAR-T cells, also known as armored CAR-T cells, and explore the mechanisms by which these engineered cells navigate the tumor microenvironment by targeting its various components. Enhancing CAR-T cells with these therapeutic targets holds promise for improving their effectiveness against solid tumors, thus achieving substantial clinical value and advancing the field of CAR-T cell therapy. Additionally, we discuss potential strategies to overcome existing challenges and highlight novel targets that could further enhance the efficacy of CAR-T cell therapy in treating solid tumors.

Automated manufacturing and characterization of clinical grade autologous CD20 CAR T cells for the treatment of patients with stage III/IV melanoma.

Introduction: Point-of-care (POC) manufacturing of chimeric antigen receptor (CAR) modified T cell has expanded rapidly over the last decade. In addition to the use of CD19 CAR T cells for hematological diseases, there is a growing interest in targeting a variety of tumor-associated epitopes. Methods: Here, we report the manufacturing and characterization of autologous anti-CD20 CAR T cells from melanoma patients within phase I clinical trial (NCT03893019). Using a second-generation lentiviral vector for the production of the CD20 CAR T cells on the CliniMACS Prodigy®. Results: We demonstrated consistency in cell composition and functionality of the products manufactured at two different production sites. The T cell purity was >98.5%, a CD4/CD8 ratio between 2.5 and 5.5 and transduction rate between 34% and 61% on day 12 (harvest). Median expansion rate was 53-fold (range, 42-65-fold) with 1.7-3.8×109 CAR T cells at harvest, a sufficient number for the planned dose escalation steps (1×105/kg, 1×106/kg, 1×107/kg BW). Complementary research of some of the products pointed out that the CAR+ cells expressed mainly central memory T-cell phenotype. All tested CAR T cell products were capable to translate into T cell activation upon engagement of CAR target cells, indicated by the increase in pro-inflammatory cytokine release and by the increase in CAR T cell amplification. Notably, there were some interindividual, cell-intrinsic differences at the level of cytokine release and amplification. CAR-mediated T cell activation depended on the level of CAR cognate antigen. Discussion: In conclusion, the CliniMACS Prodigy® platform is well suited for decentralized POC manufacturing of anti-CD20 CAR T cells and may be likewise applicable for the rapid and automated manufacturing of CAR T cells directed against other targets. Clinical trial registration: https://clinicaltrials.gov/study/NCT03893019?cond=Melanoma&term=NCT03893019&rank=1, identifier NCT03893019.

The efficacy and applicability of chimeric antigen receptor (CAR) T cell-based regimens for primary bone tumors: A comprehensive review of current evidence.

Primary bone tumors (PBT), although rare, could pose significant mortality and morbidity risks due to their high incidence of lung metastasis. Survival rates of patients with PBTs may vary based on the tumor type, therapeutic interventions, and the time of diagnosis. Despite advances in the management of patients with these tumors over the past four decades, the survival rates seem not to have improved significantly, implicating the need for novel therapeutic interventions. Surgical resection with wide margins, radiotherapy, and systemic chemotherapy are the main lines of treatment for PBTs. Neoadjuvant and adjuvant chemotherapy, along with emerging immunotherapeutic approaches such as chimeric antigen receptor (CAR)-T cell therapy, have the potential to improve the treatment outcomes for patients with PBTs. CAR-T cell therapy has been introduced as an option in hematologic malignancies, with FDA approval for several CD19-targeting CAR-T cell products. This review aims to highlight the potential of immunotherapeutic strategies, specifically CAR T cell therapy, in managing PBTs.

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

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

Peptide-guided adaptor-CAR T-Cell therapy for the treatment of SSTR2-expressing neuroendocrine tumors.

Somatostatin receptor type 2 (SSTR2) is one of the five subtypes of somatostatin receptors and is overexpressed on the surface of most gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs), pituitary tumors, paraganglioma, and meningioma, as well as hepatocellular carcinoma and breast cancer. Chimeric antigen receptor (CAR) T-cells are genetically engineered to express an artificial, T-cell activating binder, leading upon ligation to biocidal activity against target-antigen expressing cells. Adaptor-CAR T-cells recognize, via the CAR, a tag on an antigen-binding molecule, building an activating bridge between the CAR and the target cell. We hypothesized that a novel fluorescent-peptide antagonist of SSTR2, called Octo-Fluo, in combination with anti-FITC adaptor CAR (AdFITC(E2)-CAR) T-cells, may function as an on-off tunable activating bridge between the CAR and SSTR2 expressing target cells. In vitro studies confirmed the binding of Octo-Fluo to Bon1-SSTR2 mCherry-Luc cells without evidence of internalization. AdFITC(E2)-CAR T-cells were activated and efficiently induced Bon1-SSTR2 cell death in vitro, in an Octo-Fluo concentration-dependent manner. Similarly, AdFITC(E2)-CAR T-cells in combination with Octo-Fluo efficiently infiltrated the tumor and eliminated Bon1-SSTR2 tumors in immunodeficient mice in therapeutic settings. Both, AdFITC(E2)-CAR T-cell tumor infiltration and biocidal activity were Octo-Fluo concentration-dependent, with high doses of Octo-Fluo, saturating both the CAR and the SSTR2 antigen independently, leading to the loss of tumor infiltration and biocidal activity due to the loss of bridge formation. Our findings demonstrate the potential of using AdFITC(E2)-CAR T-cells with Octo-Fluo as a versatile, on-off tunable bispecific adaptor for targeted CAR T-cell immunotherapy against SSTR2-positive NETs.

EGFRVIII and EGFR targeted chimeric antigen receptor T cell therapy in glioblastoma.

Glioblastoma is the most common primary brain tumor. Although there have been significant advances in surgical techniques, chemo and immunotherapies, and radiation therapy, outcomes continue to be devastating for these patients with minimal improvements in survival. Chimeric antigen receptor T cell therapy is a revolutionary approach that is a new pillar in the treatment of cancer. CAR T cell therapy has produced remarkable results in hematological malignancies; however, multiple limitations currently prevent it from being a first-line therapy, especially for solid tumors. Epidermal growth factor receptor is classically amplified in glioblastoma, and a variant, EGFR variant III, is expressed on glioblastoma, making it an exciting potential target for CAR T cell therapy. Although preclinical has exciting potential, clinical data has been heterogeneous. In this review, we assess the state of field of EGFR-targeted CAR T cells.

Allogeneic CAR-T cells for cancer immunotherapy.

Autologous chimeric antigen receptor (CAR)-modified T (CAR-T) cell therapy has displayed high efficacy in the treatment of hematological malignancies. Up to now, 11 autologous CAR-T cell products have been approved for the management of malignancies globally. However, the application of autologous CAR-T cell therapy has many individual limitations, long time-consuming, highly cost, and the risk of manufacturing failure. Indeed, some patients would not benefit from autologous CAR-T cell products because of rapid disease progression. Allogeneic CAR-T cells especially universal CAR-T (U-CAR-T) cell therapy are superior to these challenges of autologous CAR-T cells. In this review, we describe basic study and clinical trials of U-CAR-T cell therapeutic methods for malignancies. In addition, we summarize the problems encountered and potential solutions.

[Box: see text].

Next-Generation Therapies for Multiple Myeloma.

Recent therapeutic advances have significantly improved the outcome for patients with multiple myeloma (MM). The backbone of successful standard therapy is the combination of Ikaros degraders, glucocorticoids, and proteasome inhibitors that interfere with the integrity of myeloma-specific superenhancers by directly or indirectly targeting enhancer-bound transcription factors and coactivators that control expression of MM dependency genes. T cell engagers and chimeric antigen receptor T cells redirect patients' own T cells onto defined tumor antigens to kill MM cells. They have induced complete remissions even in end-stage patients. Unfortunately, responses to both conventional therapy and immunotherapy are not durable, and tumor heterogeneity, antigen loss, and lack of T cell fitness lead to therapy resistance and relapse. Novel approaches are under development to target myeloma-specific vulnerabilities, as is the design of multimodality immunological approaches, including and beyond T cells, that simultaneously recognize multiple epitopes to prevent antigen escape and tumor relapse.

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

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

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

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

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

PD-1 blockade does not improve efficacy of EpCAM-directed CAR T-cell in lung cancer brain metastasis.

BACKGROUND: Lung cancer brain metastasis has a devastating prognosis, necessitating innovative treatment strategies. While chimeric antigen receptor (CAR) T-cell show promise in hematologic malignancies, their efficacy in solid tumors, including brain metastasis, is limited by the immunosuppressive tumor environment. The PD-L1/PD-1 pathway inhibits CAR T-cell activity in the tumor microenvironment, presenting a potential target to enhance therapeutic efficacy. This study aims to evaluate the impact of anti-PD-1 antibodies on CAR T-cell in treating lung cancer brain metastasis. METHODS: We utilized a murine immunocompetent, syngeneic orthotopic cerebral metastasis model for repetitive intracerebral two-photon laser scanning microscopy, enabling in vivo characterization of red fluorescent tumor cells and CAR T-cell at a single-cell level over time. Red fluorescent EpCAM-transduced Lewis lung carcinoma cells (EpCAM/tdtLL/2 cells) were implanted intracranially. Following the formation of brain metastasis, EpCAM-directed CAR T-cell were injected into adjacent brain tissue, and animals received either anti-PD-1 or an isotype control. RESULTS: Compared to controls receiving T-cell lacking a CAR, mice receiving EpCAM-directed CAR T-cell showed higher intratumoral CAR T-cell densities in the beginning after intraparenchymal injection. This finding was accompanied with reduced tumor growth and translated into a survival benefit. Additional anti-PD-1 treatment, however, did not affect intratumoral CAR T-cell persistence nor tumor growth and thereby did not provide an additional therapeutic effect. CONCLUSION: CAR T-cell therapy for brain malignancies appears promising. However, additional anti-PD-1 treatment did not enhance intratumoral CAR T-cell persistence or effector function, highlighting the need for novel strategies to improve CAR T-cell therapy in solid tumors.

[Update on treatment strategies for mantle cell lymphoma].

Mantle cell lymphoma (MCL) is a type of lymphoid malignancy that is rare in Japan. MCL is refractory to conventional chemotherapy and has dismal outcomes. Nonetheless, the prognosis of MCL has gradually improved with the advent of autologous stem cell transplantation and BTK inhibitors. First-line therapies incorporating BTK inhibitors are currently under development, and are expected to further improve the prognosis. Nevertheless, subsets with poor prognosis have been identified, including p53 abnormalities (TP53 mutations or deletions), blastoid variant, high MIPI-c, and POD24, and these show resistance to conventional treatments including BTK inhibitors. To overcome these challenges, novel therapies such as CAR-T therapy and combination therapy with BTK and BCL2 inhibitors are being developed, and should soon become clinically available in Japan. The therapeutic landscape for MCL is evolving dynamically, and this article will discuss the future of MCL treatment strategies in Japan.

[Role of CAR-T in multiple myeloma and coordination between referring and treating centers].

Immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 antibodies have been the three mainstays of myeloma treatment. B-cell maturation antigen (BCMA)-targeted immunotherapy, including chimeric antigen receptor T-cell therapy (CAR-T) and bispecific antibodies (BsAbs), is emerging as another important class of treatment. Two BCMA-targeting CAR-T products, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel, are approved in Japan, but only ide-cel is available for clinical use. Recently, a randomized phase III study comparing ide-cel with standard therapy in patients with refractory myeloma who had received 2 to 4 prior lines of therapy showed that ide-cel was superior in terms of both response rate and PFS. Based on these results, ide-cel was approved as a third-line therapy. The new availability of bispecific antibodies has also raised new clinical questions regarding how to use CAR-T and BsAbs for each patient, and in what order. Limited data have suggested that favorable responses can be achieved when BsAbs are administered after CAR-T, but responses are suboptimal when CAR-T is administered after BsAbs. Finally, it is important to note that coordination between referring centers and treating centers, including aspects such as timing of patient referral, bridging therapy, and long-term follow-up after CAR-T, is critical to optimization of CAR-T.

[Practical guidance for CAR T-cell therapy in adults].

Chimeric antigen receptor (CAR) T-cell therapy is an innovative treatment for B-cell malignancies and multiple myeloma. CAR T-cell therapy is now approved in Japan and has become one of the essential therapeutic options for chemotherapy-resistant disease. It has many unique features that distinguish it from conventional chemotherapies, including the limitations imposed by the production of CAR-T cells from autologous T cells, and the limited availability and mandatory waiting period for treatment. Importantly, each patient has only one opportunity to receive CAR T-cell therapy. To achieve the maximum therapeutic benefit from CAR T-cell therapy, it is necessary to understand all aspects of CAR T-cell therapy, including factors that influence its efficacy. The design of the entire treatment sequence, including before and after CAR T-cell therapy, is also important to optimize clinical outcomes. In addition, since this treatment is only available at a limited number of facilities, effective coordination between local hospitals and treatment centers is also important. This educational session will focus on the practical aspects of CAR T-cell therapy in adults and will provide indispensable knowledge for providing CAR T-cell therapy to patients with B-cell lymphoma and multiple myeloma.

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

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

CAR-T-cell therapy in meningioma: current investigations, advancements and insight into future directions.

Meningiomas, the most common tumors of the central nervous system (CNS), present significant challenges in treatment, particularly for atypical and anaplastic subtypes where standard therapies often fall short of therapeutic expectations. Chimeric antigen receptor (CAR) T-cell therapy, a groundbreaking immunotherapy approach, has demonstrated great success in hematological malignancies but faces obstacles in solid tumors, including CNS tumors like glioblastomas. This article provides a comprehensive review of the efficacy of CAR-T therapy in meningiomas, highlighting the tumor's immunogenic potential and the challenges associated with applying this therapy in clinical practice. Through an extensive literature review, the study explores potential antigens for CAR-T targeting in meningiomas, shedding light on the tumor-immune microenvironment interactions. Challenges such as tumor heterogeneity, blood-brain barrier penetration, off-target effects, and tumor recurrence are discussed, alongside potential strategies to overcome these obstacles. The study also investigates recent advancements in CAR-T therapy, including the identification of novel target antigens and the development of engineering approaches to enhance therapeutic efficacy. Furthermore, the article highlights the importance of ongoing research efforts in exploring the tumor-immune dynamics in meningiomas and underscores the urgent need for clinical trials to validate the safety and efficacy of CAR-T therapy in this context. By addressing these challenges, CAR-T therapy holds the promise of revolutionizing meningioma treatment, offering new hope for patients suffering from this disease.

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

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

The Current Landscape of Secondary Malignancies after CAR T-Cell Therapies: How Could Malignancies Be Prevented?

Chimeric antigen receptor (CAR) T-cell therapies have revolutionised the field of haematological malignancies by achieving impressive remission rates in patients with highly refractory haematological malignancies, improving overall survival. To date, six commercial anti-CD19 and anti-BCMA CAR T-cell products have been approved by the Food and Drug Administration (FDA) for the treatment of relapsed/refractory B-cell haematological malignancies and multiple myeloma. The indications for CAR T-cell therapies are gradually expanding, with these therapies being investigated in a variety of diseases, including non-malignant ones. Despite the great success, there are several challenges surrounding CAR T-cell therapies, such as non-durable responses and high-grade toxicities. In addition, a new safety concern was added by the FDA on 28 November 2023 following reports of T-cell malignancies in patients previously treated with either anti-CD19 or anti-BCMA autologous CAR T-cell therapies both in clinical trials and in the real-world setting. Since then, several reports have been published presenting the incidence and analysing the risks of other secondary malignancies after CAR T-cell therapies. In this opinion article, the current landscape of secondary malignancies after CAR T-cell therapies is presented, along with a proposed strategy for future research aiming at potentially diminishing or abrogating the risk of developing secondary malignancies after CAR T-cell therapies.