Challenges and advances in CAR-T cell therapy for B-ALL.

Acute Kidney Injury After the CAR-T Therapy Tisagenlecleucel

Incidence of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), infections and cardiovascular events across different chimeric antigen receptor (CAR) T-cell therapy products in large B-cell lymphoma (DLBCL): A nationwide analysis

Glofitamab based combined therapy as bridging therapy before stem cell transplants and CAR-T therapy in large B-cell lymphoma.

Safety and Efficacy of CD22/ CD19 CAR-T and Auto-HSCT “Sandwich” Strategy As Consolidation Therapy for Ph Negative B Cell Acute Lymphoblastic Leukemia

BackgroundCD19-directed Chimeric Antigen Receptor T-Cell (CAR-T) therapy has emerged as a promising and novel treatment for relapsed and refractory (r/r) B-cell malignancies. Efforts are directed towards increasing persistence of CAR-T...

CAR T-cell therapy for solid tumours

Managing CAR T-Cell Toxicity: Impact of Steroid Prophylaxis on Toxicity and Outcomes

Significant Long-Term Benefits of CAR T-Cell Therapy Followed By a Second Allo-HSCT for Relapsed/Refractory (R/R) B-Cell Acute Lymphoblastic Leukemia (B-ALL) Patients Who Relapsed after an Initial Transplant

Hbc-positive status for hepatis B virus does not affect CAR-T cell outcomes in lymphoma: Results from the CART-SIE study

Real-time interleukin-6 (IL-6) kinetics predict cytokine release syndrome (CRS) in patients receiving chimeric antigen receptor (CAR) T-cell therapy for Relapsed/Refractory B-cell malignancies

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common diagnosed aggressive B-cell lymphoma, with poor outcomes in those who experience relapsed or refractory (R/R) disease. Landmark clinical trials have demonstrated the efficacy and safety of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for patients with R/R DLBCL, though further exploration of real-world outcomes (RWOs) and safety data is warranted. Methods: A retrospective chart review was performed to collect patient and disease characteristics from patients with R/R DLBCL receiving CAR T-cell therapy for third-line treatment or beyond at the John Theurer Cancer Center as the standard of care. Results: We report on 82 patients with R/R DLBCL that successfully completed an infusion of an anti-CD19 CAR T-cell product at our institution. Best overall and complete response rates were 74.4% (95% CI, 64.9 to 83.8) and 67.1% (95% CI, 56.9 to 77.2), respectively. From the time of CAR T-cell infusion, median PFS was 26.5 months (95% CI, 8.6 months could not be estimated) and OS was not reached. Subgroup analyses revealed no statistical differences in outcomes by use of bridging therapy, Karnofsky performance status, transformed DLBCL status, and the type of CAR T-cell product used for this study. CAR T-cell therapy was well tolerated, with 58 patients (70.7%) experiencing cytokine-release syndrome and 17 patients (20.7%) experiencing immune effector cell-associated neurotoxicity syndrome. Conclusions: These results of RWOs in third-line patients with R/R DLBCL receiving anti-CD19 CAR T-cell therapy are comparable or superior to prior clinical trials and studies of RWOs, validating the strong efficacy and manageable toxicities of CAR T-cell therapy.

Evaluating Hematologist's Knowledge of CAR T-Cell Therapy in Hematologic Malignancies

Chimeric antigen receptor T-cell (CAR-T) therapy is a form of potent immune effector cell therapy for relapsed lymphoid and plasma cell malignancies.1 Evidence of the cytotoxic effects mediated by CAR-T has been reported primarily in preclinical in vivo and in vitro models.2 Demonstration of pathological features in patients during active therapy is challenging, and therefore limited, owing to the nature of the hematologic malignancies. Here, we present a case of refractory B-cell acute lymphoblastic leukemia (B-ALL) with known leukemia cutis (LC) that clinically flared in response to initiation of CAR-T therapy and present serial dermatopathology of LC prior to and during CAR-T therapy. A 36-year-old male with refractory B-ALL and a history of biopsy-proven LC (resolved 8 months prior) presented with asymptomatic, deep red-to-violaceous nodules on the back (Figure 1A) while receiving blinatumomab infusions. Punch biopsies demonstrated infiltrative blastic-appearing mononuclear cells (Figure 1B,C) that stained positive for CD19, CD34, TdT, and PAX-5 (Figure 1C–G), consistent with recurrent LC. Imaging demonstrated cystic and necrotic-appearing cervical, thoracic, and pelvic lymphadenopathy, later confirmed as recurrent B-ALL on biopsy, though bone marrow biopsy exhibited morphologic complete remission (CR) with measurable residual disease (MRD) by flow cytometry. We pursued CAR-T as a bridge to curative stem cell transplantation (SCT), given high risk disease. After T-cell harvesting, the patient underwent 7 weeks of lymphodepletion with IV fludarabine 25 mg/m2 and IV cyclophosphamide 900 mg/m2, before receiving an infusion of 1 × 108 CAR-positive viable T-cells. During lymphodepleting chemotherapy patient had significant improvement and near resolution of LC lesions. Clinical course following CAR-T was remarkable for grade II cytokine release syndrome (CRS) treated with tocilizumab. On Day 6 of therapy, patient again developed infiltrative reddish-orange, round plaques and nodules, first at the site of prior LC, and later involving the scalp, right cheek, left infraorbital skin, and bilateral extremities (Figure 2A). Biopsy of lesions demonstrated a population of lymphocytes expressing CD19, PAX-5, TdT, and CD34 consistent with the patient's known LC, as well as T-cell infiltrate, extensive cellular debris, and hemophagocytosis, suggesting a cytotoxic response to treatment (Figure 2B–H). The patient developed CRS with peak ferritin levels reaching 15 177 ng/mL suggesting systemic hyperinflammation with some overlapping features but not fully meeting criteria for hemophagocytic lymphohistiocytosis-like toxicity of CAR-T therapy (carHLH) as the patient did not have involvement of ≥2 organs.3 The patient's clinical recrudescence of LC with associated CRS and histopathologic findings was thought to represent response to CAR-T and CRS eventually resolved with supportive therapy. The cutaneous lesions improved following CAR-T therapy and repeat imaging and bone marrow biopsy confirmed CR and no MRD of the B-ALL. Two months later, patient received a planned 8/8 matched unrelated donor peripheral blood SCT. At the latest follow-up, patient remains in CR with no evidence of disease recurrence. In this report, we describe a case with convincing serial pathology demonstrating LC responding to CAR-T therapy. Histopathology in the days following infusion of CAR-T cells demonstrated a cutaneous leukemic infiltrate with immunohistochemical phenotype matching that of patient's known B-ALL with addition of hemophagocytosis and extensive cellular debris in association with significant T-cell infiltrates. CAR-T cells have previously been shown to be able to infiltrate the skin and eliminate covert LC.4 Case reports have also demonstrated flaring of LC in response to CAR-T and that disease flare may not necessarily be indicative of CAR-T therapy failure.4, 5 This report adds to this knowledge by demonstrating serial histopathology consistent with CAR-T cells at work within leukemic infiltrates.4, 5 Additionally, our case highlights that hemophagocytosis could also be an attribute of effector function of CAR-T, a known extreme variant of CRS, carHLH.6, 7 Indeed, the flare of LC and the noted T-cell infiltrate with cellular debris and phagocytosis following CAR-T infusion likely indicate a favorable response, but data are limited to allow definitive conclusions about the long term prognostic and predictive value of this finding. Prospective histopathologic correlates with long-term follow-up of LC patients undergoing CAR-T would provide further insights. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

Pediatric cancer poses a major health challenge globally, especially in low-middle-income countries like Indonesia. The survival rate of pediatric cancer in many high-income countries (HICs) reaches 90%, while it only ranges from 5 to 60% in LMICs. Over 80% of children with cancer live in low-middle-income countries, indicating the urgency to improve the survival rate of pediatric cancer in LMICs [1]. In Indonesia, the prevalence of pediatric cancer was 43.5% in 2020, making it the highest among Southeast Asian countries [2]. According to Dharmais Cancer Hospital (2024), the national cancer referral center for all of Indonesia, the 5-year survival rate of high-risk pediatric acute lymphoblastic leukemia is only 48.8% (unpublished data).One key factor contributing to the low survival rate of pediatric cancer in Indonesia is the lack of effective therapy options, especially for high-risk and relapsed or refractory patients. Several therapeutic approaches, such as immunotherapy, have been widely used in HICs but are still not very popular in Indonesia. CAR (Chimeric Antigen Receptor) T-cell therapy is one of the most promising immunotherapeutic approaches to treat pediatric cancer. Implementing CAR T Cell therapy in Indonesia offers promising prospects for improving the survival rates of pediatric cancer patients.CAR T cell therapy utilizes the body's immune system to specifically target and eliminate cancer cells. This innovative therapy entails extracting a patient's T cells, genetically modifying them to express chimeric antigen receptors specific to tumor-associated antigens, and then reinfusing them into the patient. Once infused, these engineered T cells recognize and eliminate cancer cells bearing the targeted antigen, thereby offering a highly targeted and potentially curative treatment option [3]. This innovative therapy has demonstrated remarkable success in treating certain hematologic malignancies, including pediatric leukemia. The most extensively studied case in childhood patients involves CAR T cells that target CD19, a B cell surface receptor [4].CAR T cell therapy holds great promise for improving survival rates among pediatric cancer patients in Indonesia. Children with refractory or relapsed leukemia, such as B-cell acute lymphoblastic leukemia (B-ALL), who have exhausted standard treatment options, can benefit from CAR T cell therapy. Most relapsed or refractory pediatric cancer patients in Indonesia do not have effective therapy options to treat the disease. CAR T cell therapy emerges as a novel therapy that can significantly improve the survival of this subset of patients. Numerous studies have documented high remission rates (ranging from 70% to 90%) in adults and children diagnosed with refractory B-ALL [4]. A study by Maude et al. [5] reported high remission rates and durable responses in young adults and children with refractory or relapsed B-ALL treated with CAR T cells. Similarly, Park et al. [6] demonstrated long-term remissions and improved survival in pediatric leukemia patients receiving CAR T cell therapy. Several groups also have observed the persistence of CAR T cells and sustained remission lasting over six months in the majority of patients examined [4]. Efforts have been made to implement CAR T cells in Indonesia. Dharmais Cancer Hospital, as a National Cancer Center in Indonesia, has initiated this effort by collaborating with iCarTAB Biomed Inc., a China-based CAR T cell manufacturer with one of its manufacturing sites located in Malaysia. However, this approach involves sending patients' blood samples that have been processed through leukapheresis to Malaysia for CAR T cell manufacturing, followed by the shipment of the manufactured cells back to Indonesia for administration to patients. This process is impractical and incurs intangible costs such as transportation and cryopreservation, ultimately making it more expensive for patients. Regulatory issues related to the shipment of cells across borders in the region and early preparation of patients for CAR T cell therapy soon after relapse before they succumb to treatment-related mortality or relapse-related complications are also challenges that need to be addressed [7]. Reflecting on the abovementioned issue, CAR T cell therapy adoption in Indonesia faces significant challenges. Limited healthcare infrastructure, including specialized facilities for cell therapy manufacturing and administration, poses logistical hurdles. Moreover, cost remains a major barrier, as CAR T cell therapy is often expensive and inaccessible to many patients in Indonesia. Furthermore, the lack of local expertise in cellular immunotherapy may impede the successful implementation of CAR T cell therapy programs.Efforts to address these challenges and maximize the potential of CAR T cell therapy in Indonesia are essential. This requires a multi-faceted approach involving investment in healthcare infrastructure, including establishing specialized centers equipped for CAR T cell therapy manufacturing and administration. Two alternative models have been proposed for manufacturing CAR-T cell therapy: centralized and de-centralized models [8]. In the centralized manufacturing model, point of manufacturing and point of care are located in different geographical areas, while decentralized manufacturing focuses on establishing point of care and manufacturing in close proximity. A decentralized manufacturing model might be the best approach to be implemented in LMICs like Indonesia. Building hospital-based cellular therapy manufacturing reduces the need for transportation and cryopreservation. The decentralized system's geographic proximity improves communication between manufacturing and treatment teams, facilitating the creation of customized products based on a patient's phenotype. This setup also reduces administration time and the risk of delays and mix-ups compared to centralized manufacturing, making hospital-based cellular therapy manufacturing a potentially more cost-effective option [8].In addition, initiatives to reduce the cost of therapy through partnerships with pharmaceutical companies, government subsidies, or philanthropic endeavors can improve affordability and access. Furthermore, capacity-building initiatives aimed at training local healthcare professionals in cellular immunotherapy techniques are essential for ensuring the successful implementation and sustainability of CAR T cell therapy programs in Indonesia. Collaboration between local institutions, international organizations, and industry stakeholders can facilitate knowledge transfer and technology transfer, fostering indigenous expertise in this cutting-edge treatment modality.CAR T cell therapy represents a transformative approach to improving survival rates among pediatric cancer patients in Indonesia. By harnessing the power of immunotherapy, specifically tailored to target cancer cells, CAR T cell therapy offers hope for children with refractory or relapsed leukemia who have limited treatment options. Through continued research, collaboration, and investment in healthcare infrastructure, CAR T cell therapy potentially could greatly improve the prognosis and quality of life for pediatric cancer patients in Indonesia.

Long-Term Outcomes and Adverse Events of CAR T-19 Cell Therapy in Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia - a Systematic Review and Meta-Analysis