Efficacy and Safety of BCMA-CAR-T Cell Therapy in Relapsed/Refractory Extramedullary Plasmacytoma: Exploring the Role of Consolidation Therapy

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for all of Indonesia, the 5-year survival rate of high-risk pediatric acute lymphoblastic leukemia is only 48.8% (unpublished data).One key factor contributing to the low survival rate of pediatric cancer in Indonesia is the lack of effective therapy options, especially for high-risk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.

Acute Kidney Injury After the CAR-T Therapy Tisagenlecleucel

Autoimmune Outcomes in Patients with Concurrent Autoimmune Disease Receiving CD19 CAR T-Cell Therapy for Lymphoma

Development and Evaluation of an Optimal Human Single-Chain Variable Fragment-Derived BCMA-Targeted CAR T Cell Vector.

217 Background: Neuroendocrine prostate cancers (NEPC) currently have no effective therapies. While CAR (Chimeric Antigen Receptor) T cell therapies targeting PSMA and PSCA receptors are currently in phase 1/2 studies in metastatic castrate-resistant prostate cancer (mCRPC), antigen targets for NEPC remain limited. Lewis Y antigen (LeY) is an oncofetal antigen expressed only in adult tumour cells and is considered a target for CAR T cell therapy in haematological, lung, ovarian and colon cancer. We previously found that LeY is a promising target for CAR T cell therapy in prostate cancer and that preconditioning LeY-directed CAR T cells with carboplatin further enhances tumour responses in mCRPC. We investigated if LeY can be used as a novel CAR T cell target for NEPC. Methods: The expression of the Lewis Y antigen was assessed in our patient-derived prostate cancer xenograft collection using immunohistochemistry (IHC). To assess the efficacy of LeY-CAR T cells, we used specimens established from a patient (Patient 508) with NEPC who had incurable metastatic disease and failed standard treatments. We generated CAR T cells from his peripheral blood mononuclear cells (PBMCs) to test their specificity and efficacy in vitro against established cell lines. Results: In our MURAL PDX collection of 59 prostate tumours, 81% (9/11) NEPCs expressed LeY antigen on IHC. Next, we successfully produced anti-LeY CAR T cells from the patient’s PBMCs using retroviral transduction. Flow cytometry verified efficient transduction of the CAR constructs. Previous studies found that a 1:1 ratio of CD4 + :CD8 + T cells improved outcomes following CAR T cell therapy 5,6 , so we further phenotyped patient T cells by flow cytometry. The CD4 + :CD8 + T cell ratio was nearly 1:1 (51.7% and 41.4% of total T cells, respectively). Next, we used an immunobead assay to investigate CAR-T specificity in releasing proinflammatory cytokines. Significant cytokine production was observed after a 4-hour co-culture with LeY+ human ovarian cancer cell line, OVCAR3, vs co-culture with control LeY- MDA-MB435 cells (p=0.0004), demonstrating the specificity of the CAR T cells.Lastly, we showed that patient CAR T cells effectively killed LeY+ cells (OVCAR3), but not control LeY- cells (MDA-MB435; p<0.0001). Tumour cell death was measured by the amount of released chromium following 16-hour co-culture. CAR T cells killed LeY+ target cells more effectively than their non-transduced equivalents at a range of effector-to-target ratios, with up to 15-fold increase in cell death. Conclusions: Our preclinical studies show that most NEPC tumors express the LeY antigen and that patient-derived CAR T cells specifically kill those cells. These findings identified a potential CAR T treatment target for NEPC for a phase 1/2 study.

Chimeric antigen receptor (CAR) T-cell therapy is a method that extracts T cells from the patient's blood and virally introduces a genetically engineered T cell receptor targeting a specific cancer antigen and subsequently readministering these genetically engineered CAR T cells to the patient. These T cells are then better at identifying the tumors and attaching to these tumor cells resulting in a stronger cytotoxic immune response. The development of CAR T cells has been a huge success as an immunotherapy, especially for the targeting of non-solid tumors. Since their original inception in 1987, there are now six independent FDA approved CAR T cell therapies targeting a variety of blood cancers, with the first being approved in 2017. As a relatively new treatment, there is a continuous effort in improving the safety and efficacy of CAR T cell therapies. As mentioned previously, CAR T cells have undoubtedly been successful in the treatment of non-solid tumors, however their efficacy towards treatment of solid tumors has been limited. Additionally, the safety and long-term effects of CAR T cell treatments is still a concern. Combination therapy utilizing CAR-T cells and immune checkpoint inhibitors is being explored to potentially mitigate some of the limitations associated with CAR-T cells.

Disclosure: W.J. Kulakowska: None. R.A. Taylor: None. W. Ranasinghe: None. P.K. Darcy: None. J.A. Trapani: None. G.P. Risbridger: None. Background and aims While CAR (Chimeric Antigen Receptor) T cell therapies targeting PSMA and PSCA receptors are currently in phase 1/2 studies in metastatic castrate-resistant prostate cancer (mCRPC), antigen targets for neuroendocrine prostate cancer (NEPC) remain limited. Lewis Y antigen (LeY) is an oncofetal antigen expressed only in adult tumour cells and is considered a target for CAR T cell therapy in haematological, lung, ovarian and colon cancer. We previously found that LeY is a promising target for CAR T cell therapy in prostate cancer and that preconditioning LeY-directed CAR T cells with carboplatin further enhances tumour responses in mCRPC. We investigated if LeY can be used as a novel CAR T cell target for NEPC. Methods: The expression of the Lewis Y antigen was assessed in our patient-derived prostate cancer xenograft (PDX) collection using immunohistochemistry (IHC). To assess the efficacy of LeY-CAR T cells, we used specimens established from a patient (Patient 508) with NEPC who had incurable metastatic disease and failed standard treatments. We generated CAR T cells from his peripheral blood mononuclear cells (PBMCs) to test their specificity and efficacy in vitro. Results: In our MURAL PDX collection of 59 prostate tumours, 81% (9/11) NEPCs expressed LeY antigen on IHC, including Patient 508. We successfully produced anti-LeY CAR T cells from the patient’s PBMCs using retroviral transduction. Generated CAR T cells presented a nearly 1:1 CD4+:CD8+ T cell ratio (51.7% and 41.4% of total T cells, respectively), which according to existing literature yields better treatment outcomes. Next, we used an immunobead assay to investigate CAR-T specificity in releasing proinflammatory cytokines. Significant cytokine production was observed after a co-culture with LeY+ human ovarian cancer cell line, OVCAR3, vs co-culture with control LeY- MDA-MB435 cells (p=0.0004), demonstrating the specificity of the CAR T cells. Lastly, we showed that patient CAR T cells effectively killed LeY+ cells (OVCAR3), but not control LeY- cells (MDA-MB435; p<0.0001) in a 16-hour chromium release assay. CAR T cells killed LeY+ target cells more effectively than their non-transduced equivalents at a range of effector-to-target ratios, with up to 15-fold increase in cell death. Conclusion: Our preclinical studies show that most NEPC tumors express the LeY antigen and that patient-derived CAR T cells can specifically kill those cells. These findings identified a potential CAR T treatment target for NEPC for a phase 1/2 study. Presentation: Monday, July 14, 2025

Identifying the Barriers of Clinical Trial Access after CAR T-Cell Therapy in Relapsed/Refractory Large B-Cell Lymphoma

Infectious Complications during Treatment with Commercial CAR T-Cell Therapy and Bispecific Antibodies for Relapsed/Refractory Multiple Myeloma

Advancing the Integration of CAR T-Cell Therapy in Community Oncology Centers: Key Findings from a Transformative Quality Improvement Initiative

Follicular lymphoma (FL) is traditionally considered treatable but incurable. In March 2021, the US Food and Drug Administration approved the use of chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed or refractory (R/R) FL after ≥2 lines of therapy. Priced at $373 000, CAR T-cell therapy is potentially curative, and its cost-effectiveness compared with other modern R/R FL treatment strategies is unknown. We developed a Markov model to assess the cost-effectiveness of third-line CAR T-cell vs standard of care (SOC) therapies in adults with R/R FL. We estimated progression rates for patients receiving CAR T-cell and SOC therapies from the ZUMA-5 trial and the LEO CReWE study, respectively. We calculated costs, discounted life years, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER) of CAR T-cell vs SOC therapies with a willingness-to-pay threshold of $150 000 per QALY. Our analysis was conducted from a US payer's perspective over a lifetime horizon. In our base-case model, the cost of the CAR T-cell strategy was $731 682 compared with $458 490 for SOC therapies. However, CAR T-cell therapy was associated with incremental clinical benefit of 1.50 QALYs, resulting in an ICER of $182 127 per QALY. Our model was most sensitive to the utilities associated with CAR T-cell therapy remission and third-line SOC therapies and to the total upfront CAR T-cell therapy cost. Under current pricing, CAR T-cell therapy is unlikely to be cost-effective in unselected patients with FL in the third-line setting. Both randomized clinical trials and longer term clinical follow-up can help clarify the benefits of CAR T-cell therapy and optimal sequencing in patients with FL.

BackgroundCD19-directed chimeric antigen receptor (CAR) T-cell therapy has revolutionized cancer care for patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Despite impressive responses seen with CAR T-cell treatment, nearly 30–50% of patients will relapse with very poor outcomes and the mechanism of relapse if oftentimes unknown. Next-generation sequencing (NGS) is a novel technology that can detect genomic biomarkers and provide insight into treatment resistance and cancer prognosis. This report highlights a case where NGS was able to detect the presence of the CAR T-cell construct in a patient after CAR T-cell therapy relapse.Case presentationWe present a 20-year-old, White, male patient with R/R DLBCL who was treated with CD19 CAR T-cell therapy and relapsed approximately six months after infusion. Biopsy showed CD19-negative disease. Interestingly, NGS detected the presence of the CAR T-cell construct even after the patient progressed following CAR T-cell therapy, suggesting continued persistence of the CAR T-cells.ConclusionsPrognosis of patients who relapse after CAR T-cell therapy for R/R DLBCL remains poor as mechanisms and predictors of relapse are not well understood. It is necessary to consider how novel technologies can be incorporated into the prognostication and monitoring of response to CAR T-cell therapy. In our case, the ability of NGS to distinguish the CAR T-cell product suggests that NGS may have the potential to ascertain CAR T-cell response and provide insight into the purported mechanism of relapse after CAR T-cell therapy. This report highlights a potentially new approach to monitoring patients with R/R DLBCL following CAR T-cell therapy using NGS technology.

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

Advancing CAR T-Cell Care in Relapsed/Refractory Multiple Myeloma: Insights from a Collaborative Quality Improvement Initiative

TP53 Deficiency in AML Confers Resistance to CAR T-Cells That Can be Overcome By Targeting the Cholesterol or Wnt Pathways