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Summary: Chimeric antigen receptor T‐cell (CAR‐T) therapy and bispecific T‐cell engagers (BsAb) have emerged as promising immunotherapeutic modalities in patients with relapsed and/or refractory multiple myeloma (RRMM). However, there is limited data on the safety and efficacy of CAR‐T and BsAb therapies in MM patients with a prior history of allogeneic transplantation (allo‐HCT). Thirty‐three MM patients with prior allo‐HCT received CAR‐T (n = 24) or BsAb (n = 9) therapy. CAR‐T therapy demonstrated an ORR of 92% (67% ≥ CR), and 73% were MRD negative. BsAb therapy resulted in an ORR of 44% (44% ≥ CR) and 44% MRD negative. Safety analysis showed grade ≥3 AEs in 92% of CAR‐T and 56% of BsAb patients. Cytokine release syndrome (CRS) occurred in 83% of CAR‐T and 78% of BsAb recipients, while immune effector cell‐associated neurotoxicity syndrome (ICANS) was observed in three CAR‐T patients. Infections of grade ≥3 were reported in 50% of CAR‐T and 44% of BsAb recipients. No exacerbation of graft‐versus‐host disease occurred except in one BsAb recipient. CAR‐T and BsAb therapies appear to be feasible, safe and provide deep and durable responses in MM patients with prior allo‐HCT. [ABSTRACT FROM AUTHOR]

Summary: Varnimcabtagene autoleucel (var‐cel) is an academic anti‐CD19 chimeric antigen receptor (CAR) product used for the treatment of non‐Hodgkin lymphoma (NHL) in the CART19‐BE‐01 trial. Here we report updated outcomes of patients with NHL treated with var‐cel. B‐cell recovery was compared with patients with acute lymphoblastic leukaemia (ALL). Forty‐five patients with NHL were treated. Cytokine release syndrome (any grade) occurred in 84% of patients (4% grade ≥3) and neurotoxicity in 7% (2% grade ≥3). The objective response rate was 73% at Day +100, and the 3‐year duration of response was 56%. The 3‐year progression‐free and overall survival were 40% and 52% respectively. High lactate dehydrogenase was the only covariate with an impact on progression‐free survival. The 3‐year incidence of B‐cell recovery was lower in patients with NHL compared to ALL (25% vs. 60%). In conclusion, in patients with NHL, the toxicity of var‐cel was manageable, while B‐cell recovery was significantly prolonged compared to ALL. This trial was registered as NCT03144583. [ABSTRACT FROM AUTHOR]

Summary: The success of CD19 Chimeric antigen receptor (CAR) T‐cell therapy in large B‐cell lymphoma (LBCL) has been partially offset by toxicity and logistical challenges, which off‐the‐shelf agents like CD20xCD3 bispecific antibodies might potentially overcome. However, when using CAR T outcomes as the ʽstandard‐of‐care comparator̕ for relapsed/refractory (r/r) LBCL, a potential learning curve with implementing a novel, complex therapy like CAR T needs to be considered. To address this, we analysed 726 UK patients intended to be treated with CD19 CAR T for r/r LBCL and compared outcomes between the first year of the national CAR T programme (Era 1; 2019) and the more recent treatment era (Era 2; 2020–2022). We identified significant improvements for Era 2 versus Era 1 in dropout rate (17% vs. 27%, p = 0.001), progression‐free survival (1‐year PFS 50% vs. 32%, p < 0.001) and overall survival (1‐year OS 60% vs. 40%, p < 0.001). We also observed increased use of bridging therapy, improvement in bridging outcomes, more tocilizumab/corticosteroid use, reduced high‐grade cytokine release syndrome (4% vs. 9%, p = 0.01) and intensive care unit admissions (20% vs. 32%, p = 0.001). Our results demonstrate significant improvement in CAR T outcomes over time, highlighting the importance of using up‐to‐date clinical data when comparing CAR T against new treatment options for r/r LBCL. [ABSTRACT FROM AUTHOR]

Summary: CD19‐directed chimeric antigen receptor (CAR) T‐cell therapy is an important therapy for relapsed or refractory acute lymphoblastic leukaemia, but its use carries the risk of immune effector cell‐associated neurotoxicity syndrome (ICANS). In children, severe ICANS is almost universally reported in association with cytokine release syndrome and is reversible. We describe two cases of severe, intractable neurotoxicity following CAR T‐cell therapy in children with pre‐existing central nervous system (CNS) vulnerabilities. The cases were atypical in their delayed onset and independence from cytokine release syndrome and did not respond to standard therapies. [ABSTRACT FROM AUTHOR]

Summary: Chimeric antigen receptor T (CAR‐T) cell therapy is highly effective in inducing complete remission in haematological malignancies. Severe cytokine release syndrome (CRS) is the most significant and life‐threatening adverse effect of this therapy. This multi‐centre study was conducted at six hospitals in China. The training cohort included 87 patients with multiple myeloma (MM), an external validation cohort of 59 patients with MM and another external validation cohort of 68 patients with acute lymphoblastic leukaemia (ALL) or non‐Hodgkin lymphoma (NHL). The levels of 45 cytokines on days 1–2 after CAR‐T cell infusion and clinical characteristics of patients were used to develop the nomogram. A nomogram was developed, including CX3CL1, GZMB, IL4, IL6 and PDGFAA. Based on the training cohort, the nomogram had a bias‐corrected AUC of 0.876 (95% CI = 0.871–0.882) for predicting severe CRS. The AUC was stable in both external validation cohorts (MM, AUC = 0.907, 95% CI = 0.899–0.916; ALL/NHL, AUC = 0.908, 95% CI = 0.903–0.913). The calibration plots (apparent and bias‐corrected) overlapped with the ideal line in all cohorts. We developed a nomogram that can predict which patients are likely to develop severe CRS before they become critically ill, improving our understanding of CRS biology, and may guide future cytokine‐directed therapies. [ABSTRACT FROM AUTHOR]

Summary: The use of CD19 chimeric antigen receptor T‐cell (CAR‐T) therapy for relapsed/refractory solid organ transplantation (SOT)‐related post‐transplant lymphoproliferative disorder (PTLD) is not well studied. We conducted a multicentre, retrospective analysis of adults with relapsed/refractory SOT‐associated PTLD. Among 22 relapsed/refractory SOT‐PTLD patients, the pathology was monomorphic B cell. Prior SOTs included 14 kidney (64%), three liver (14%), two heart (9%), one intestinal (5%), one lung (5%), and one pancreas after kidney transplant (5%). The median time from SOT to PTLD diagnosis was 107 months. Pre‐CAR‐T bridging therapy was used in 55% of patients, and immunosuppression was stopped completely before CAR‐T infusion in 64%. Eighteen (82%) patients experienced cytokine release syndrome: one (5%) each grade (G) 3 and G4. The immune effector cell‐associated neurotoxicity syndrome was observed in 16 (73%) patients: six (27%) G3 and two (9%) G4. The overall response rate was 64% (55% complete response). Three patients (14%) experienced allograft rejection after CAR‐T. The two‐year progression‐free survival and overall survival rates were 35% and 58%, respectively. Additionally, the achievement of CR post‐CAR‐T was strongly associated with survival. Collectively, the safety and efficacy of CD19 CAR‐T therapy in relapsed/refractory SOT‐related PTLD appeared similar to pivotal CAR‐T data, including approximately one‐third of patients achieving sustained remission. [ABSTRACT FROM AUTHOR]

Summary: Haemophagocytic lymphohistiocytosis‐like toxicity following chimeric antigen receptor T cells (CAR‐HLH) is being increasingly recognized, while published data are limited and criteria for recognition are elusive. We describe three patients who developed CAR‐HLH after infusion of brexucabtagene autoleucel (n = 2) or axicabtagene ciloleucel (n = 1). All three patients presented following cytokine release syndrome, with fever, recurrent or worsening cytopenias, hyperferritinaemia, elevated soluble interleukin (IL)‐2 receptor, hypofibrinogenaemia, hypertriglyceridaemia, elevated liver transaminases, and decreasing C‐reactive protein and IL‐6. Clinical improvement following treatment with anakinra (n = 2) and ruxolitinib (n = 1) was observed. Our report offers an opportunity for prompt recognition and initiation of potentially life‐saving treatment for CAR‐HLH. [ABSTRACT FROM AUTHOR]

Summary: Outcomes remain poor for patients with relapsed/refractory B‐cell non‐Hodgkin lymphoma (R/R B‐NHL). While chimeric antigen receptor (CAR) T‐cell therapy has revolutionised treatment, a significant proportion of patients relapse or fail to respond. Odronextamab is a CD20 × CD3 bispecific antibody that has demonstrated durable responses and a manageable safety profile in patients with R/R B‐NHL in a first‐in‐human trial (NCT02290951). Here, we document two patients with diffuse large B‐cell lymphoma refractory to CART‐cell therapy. Both achieved complete responses that remain ongoing for ≥2 years following odronextamab. Neither patient experienced Grade ≥3 cytokine release syndrome or Grade ≥3 neurological adverse events during treatment. [ABSTRACT FROM AUTHOR]

Decreased serum phosphate levels are a useful biomarker to predict occurrence and severity of cytokine release syndrome in chimeric antigen receptor T-cell therapy Key sentences CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy is an innovative treatment[1] for patients with diffuse large B-cell lymphoma (DLBCL). Keywords: chimeric antigen receptor T cell (CAR-T); cytokine release syndrome (CRS); hypophosphataemia; predictive marker EN chimeric antigen receptor T cell (CAR-T) cytokine release syndrome (CRS) hypophosphataemia predictive marker e1 e3 3 12/22/22 20230101 NES 230101 Decreased serum iP can be a predictive marker for subsequent severe CRS. [Extracted from the article]

Summary: In the relapsed/refractory setting for treatment of large B‐cell lymphoma (LBCL), chimeric antigen receptor T‐cell (CAR‐T) therapy has emerged as an effective treatment modality. Patients often have aggressive disease that requires prompt treatment in the form of bridging therapy (BT) for disease stabilisation while CAR‐T cells are manufactured. Patients (n = 75) undergoing CAR‐T therapy infusion for LBCL at our institution were identified. A total of 52 (69·3%) received BT and 23 (30·7%) received no BT (NBT). BT modalities included systemic BT (SBT) in 28 patients, radiation BT (RBT) in 14, and high‐dose steroid BT (HDS) in 10. There was no difference in incidence of cytokine release syndrome or immune effector cell‐associated neurotoxicity syndrome between BT and NBT (P = 0·18 and P = 0·53 respectively). Prolonged cytopenias at Day 180 were more common in BT than NBT (50% vs. 13·3%, P = 0·04). The SBT and RBT subgroups had more cytopenias at Day 180 compared to the HDS and NBT subgroups (58·3% and 57·1% vs. 20% and 13·3% respectively, P = 0·04). Disease response at last follow‐up, progression‐free survival and overall survival were similar between BT, NBT, and BT subgroups. In summary, BT can be safely considered in patients undergoing CAR‐T therapy. However, those undergoing BT with SBT or RBT are at higher risk of prolonged cytopenias after CAR‐T therapy. [ABSTRACT FROM AUTHOR]

Summary: Axicabtagene ciloleucel (axi‐cel) is an autologous anti‐CD19 chimeric antigen receptor (CAR) T‐cell therapy approved for relapsed or refractory large B‐cell lymphoma (R/R LBCL). To reduce axi‐cel–related toxicity, several exploratory safety management cohorts were added to ZUMA‐1 (NCT02348216), the pivotal phase 1/2 study of axi‐cel in refractory LBCL. Cohort 4 evaluated the rates and severity of cytokine release syndrome (CRS) and neurologic events (NEs) with earlier corticosteroid and tocilizumab use. Primary endpoints were incidence and severity of CRS and NEs. Patients received 2 × 106 anti‐CD19 CAR T cells/kg after conditioning chemotherapy. Forty‐one patients received axi‐cel. Incidences of any‐grade CRS and NEs were 93% and 61%, respectively (grade ≥ 3, 2% and 17%). There was no grade 4 or 5 CRS or NE. Despite earlier dosing, the cumulative cortisone‐equivalent corticosteroid dose in patients requiring corticosteroid therapy was lower than that reported in the pivotal ZUMA‐1 cohorts. With a median follow‐up of 14·8 months, objective and complete response rates were 73% and 51%, respectively, and 51% of treated patients were in ongoing response. Earlier and measured use of corticosteroids and/or tocilizumab has the potential to reduce the incidence of grade ≥ 3 CRS and NEs in patients with R/R LBCL receiving axi‐cel. [ABSTRACT FROM AUTHOR]

Summary: Chimeric antigen receptor T‐cell (CAR T‐cell) therapy is associated with significant toxicities secondary to immune activation, including a rare but increasingly recognised severe toxicity resembling haemophagocytic lymphohistiocytosis (carHLH). We report the development of carHLH in 14·8% of paediatric patients and young adults treated with CD19‐specific CAR T‐cell therapy with carHLH, occurring most commonly in those with high disease burden. The diagnosis and treatment of carHLH required a high index of suspicion and included multidrug immunomodulation with variable response to therapies. Compared to patients without carHLH, patients with carHLH had both reduced response to CAR T‐cell therapy (P‐value = 0·018) and overall survival (P‐value = < 0·0001). [ABSTRACT FROM AUTHOR]

Summary: Chimeric antigen receptor (CAR) T cells are a rapidly emerging form of cancer treatment, and have resulted in remarkable responses in refractory lymphoid malignancies. However, their widespread clinical use is limited by toxicity related to cytokine release syndrome and neurotoxicity, the logistic complexity of their manufacturing, cost and time‐to‐treatment for autologous CAR‐T cells, and the risk of graft‐versus‐host disease (GvHD) associated with allogeneic CAR‐T cells. Natural killer (NK) cells have emerged as a promising source of cells for CAR‐based therapies due to their ready availability and safety profile. NK cells are part of the innate immune system, providing the first line of defence against pathogens and cancer cells. They produce cytokines and mediate cytotoxicity without the need for prior sensitisation and have the ability to interact with, and activate other immune cells. NK cells for immunotherapy can be generated from multiple sources, such as expanded autologous or allogeneic peripheral blood, umbilical cord blood, haematopoietic stem cells, induced pluripotent stem cells, as well as cell lines. Genetic engineering of NK cells to express a CAR has shown impressive preclinical results and is currently being explored in multiple clinical trials. In the present review, we discuss both the preclinical and clinical trial progress made in the field of CAR NK‐cell therapy, and the strategies to overcome the challenges encountered. [ABSTRACT FROM AUTHOR]

Two CD19 chimeric antigen receptor (CAR) T cell therapies are now approved by the US Food and Drug Administration for the treatment of relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and histological variants: axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) (Neelapu I et al i , [6]; Schuster I et al i , [9]). Clinically, it remains unclear as to when the HLH features of CRS are significant enough to consider treatment with therapies used for non-CAR T-associated HLH, such as etoposide or methotrexate (Neelapu I et al i , [8]). Our case series suggests that the timing of onset of CAR T-associated HLH may differ between patients, with concern when delayed or recurrent HLH symptoms occur with a rising ferritin level, which is when HLH-directed therapies should be considered. [Extracted from the article]

Summary: Chimeric antigen receptor‐modified (CAR)‐T cells have demonstrated impressive results in the treatment of haematological malignancies. However, cytokine release syndrome (CRS) and neurotoxicity are common toxicities which are potentially life‐threatening in severe cases. Risk factors for CRS and neurotoxicity identified so far include disease burden, lymphodepletion intensity and CAR‐T cell dose administered. Risk‐adapted dosing, with lower CAR‐T cell doses administered to B‐cell acute lymphoblastic leukaemia patients with high marrow blast counts, has been successful at decreasing severe CRS rates in this population. Intervention with therapies, such as tocilizumab and corticosteroids, have been effective at ameliorating toxicity, enabling CAR‐T cells to be administered safely to many patients without significantly compromising efficacy. Deeper understanding of the pathophysiology of underlying CRS and neurotoxicity will enable the development of novel approaches to reduce toxicity and improve outcomes. [ABSTRACT FROM AUTHOR]

The article reports on the case of a ten-year-old boy who developed serious cytokine release syndrome (CRS), a complication of chimeric antigen receptor (CAR)-modified T cell (CAR-T) therapy in a phase-one clinical trial. The patient, who was diagnosed with B-cell acute lymphoblastic leukaemia eight years ago, suffered from central nervous system (CNS) symptoms and coagulopathy. The importance of timely diagnosis and the right approach to the management of CNS problems is emphasized.

Idecabtagene vicleucel (ide-cel, Abecma, Bristol Myers Squibb [BMS], New York, NY, USA), is the first FDA-approved cell-based gene therapy for multiple myeloma, the first chimaeric antigen receptor (CAR) T cell therapy directed at B-cell maturation antigen (BCMA), and a drug with an astonishing price tag.1 BMS and Bluebird Bio, marketing in unison, have listed the CAR T-cell therapy at a price of $419 500 per treatment.2 Approval was based in part on the KarMMa study (NCT03361748), a phase 2 trial that found a 73% response rate and a median progression-free survival of 8-8 months based on a modified intention-to-treat analysis.3 This recent approval serves as an opportunity to assess ide-cel's clinical implications and explore whether this price tag is sustainable for a therapy that does not appear to cure even a fraction of patients. Since this treatment is likely non-curative, physicians may anticipate an eventual relapse and justify maintenance therapy with active but expensive agents such lenalidomide, carfilzomib, bortezomib, or daratumumab. The treatment-free interval and theoretical accompanying QoL gain anticipated for patients responding to ide-cel per the KarMMa study protocol would then vanish, with patients unable to escape the burden of therapy-related toxicities (both medical and financial). [Extracted from the article]