Clinical Perspective: Treatment of Aggressive B Cell Lymphomas with FDA-Approved CAR-T Cell Therapies.
Ontology highlight
ABSTRACT:
SUBMITTER: Leick MB
PROVIDER: S-EPMC7854294 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Inflammation plays an important role in chimeric antigen receptor (CAR) T-cell therapy, especially in the pathophysiology of cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Clonal hematopoiesis of indetermined potential (CHIP) has also been associated with chronic inflammation. The relevance of CHIP in the context of CAR T-cell treatment is widely unknown. We evaluated the prevalence of CHIP, using a targeted deep sequencing approach, in a cohort of patients with relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma before and after CAR T-cell treatment. The aim was to define the prevalence and variation of CHIP over time and to assess the influence on clinical inflammation syndromes (CRS/ICANS), cytopenia, and outcome. Overall, 32 patients were included. CHIP was found in 11 of 32 patients (34%) before CAR T-cell therapy. CHIP progression was commonly detected in the later course. Patients with CHIP showed a comparable response rate to CAR T-cell treatment but had an improved overall survival (not reached vs 265 days, P = .003). No significant difference was observed in terms of the occurrence and severity of CRS/ICANS, therapeutic use of tocilizumab and glucocorticosteroids, paraclinical markers of inflammation (with the exception of ferritin), or dynamics of hematopoietic recovery. CHIP is commonly observed in patients undergoing CD19-directed CAR T-cell therapy and is not associated with an inferior outcome.
| S-EPMC8941459 | biostudies-literature
Project description:Most patients with aggressive non-Hodgkin lymphoma will be cured with initial chemoimmunotherapy; however, most patients with relapsed disease will not be cured and will die as a result of their disease. In these cases, continued treatment with conventional chemotherapy is typically not of benefit and can contribute to significant toxicities and decreased quality of life for patients. Fortunately, a number of therapies are currently available or under investigation for this group of patients, ranging from oral tyrosine kinase inhibitors targeting multiple pathways within the malignant cells to adoptive cellular therapies that harness the patient's immune system to fight disease. Additionally, many agents that are modestly effective as monotherapies can be safely combined with additional novel and conventional therapies to improve response rates and duration. Chimeric antigen receptor T cells are among the most promising group of therapies and provide the potential for cure for patients with relapsed/refractory lymphoma. In this chapter, we will review the currently available novel treatments as well as those still under investigation and discuss the most appropriate approach to patients with relapsed/refractory aggressive lymphoma. We will highlight the challenges associated with these therapies, as well as potential toxicities, and the need for additional clinical trials evaluating combinations and newer treatments.
| S-EPMC6245978 | biostudies-literature
Project description:In recent years, we have seen rapid expansion of chimeric antigen receptor T-cell (CAR-T) therapies in multiple malignancies. CAR-T therapy has profoundly altered the treatment landscape of non-Hodgkin lymphoma, B-cell acute lymphoblastic leukemia, and multiple myeloma. Currently available CD19 and B-cell maturation antigen-directed CAR-T therapies have shown high overall response rate and durable remissions in patients who have failed standard therapies. Multiple studies are underway exploring the role of CAR-T-cell therapy as earlier line of treatment. In high-grade B-cell lymphoma, CD19 CAR-T therapy may replace autologous hematopoietic cell transplantation as second line therapy in near future. CAR-T-cell therapy targeting novel tumor-associated antigens will help expand utility of this treatment modality in other hematological malignancies. It may also help overcome limitations of currently approved CAR-T-cell therapies. In this review, we have provided an overview of currently approved CAR-T therapies and upcoming clinical trials which may potentially impact the clinical practice.
| S-EPMC9175669 | biostudies-literature
Project description:Chimeric Antigen Receptor (CAR) T cell therapies - adoptive T cell therapies that have been genetically engineered for a new antigen-specificity - have displayed significant success in treating patients with hematologic malignancies, leading to three recent US Food and Drug Administration approvals. Based on the promise generated from these successes, the field is rapidly evolving to include new disease indications and CAR designs, while simultaneously reviewing and optimizing toxicity and management protocols. As such, this review provides expert perspective on the significance and clinical considerations of CAR T cell therapies in order to provide timely information to clinicians about this revolutionary new therapeutic class.
| S-EPMC6278156 | biostudies-literature
Project description:P-glycoprotein (also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) plays a crucial role in determining response against medications, including cancer therapeutics. It is now well established that p-glycoprotein acts as an ATP dependent pump that pumps out small molecules from cells. Ample evidence exist that show p-glycoprotein expression levels correlate with drug efficacy, which suggests the rationale for developing p-glycoprotein inhibitors for treatment against cancer. Preclinical and clinical studies have investigated this possibility, but mostly were limited by substantial toxicities. Repurposing FDA-approved drugs that have p-glycoprotein inhibition activities is therefore a potential alternative approach. In this review, we searched the Drugbank Database (https://www.drugbank.ca/drugs) and identified 98 FDA-approved small molecules that possess p-glycoprotein inhibition properties. Focusing on the small molecules approved with indications against non-cancer diseases, we query the scientific literature for studies that specifically investigate these therapeutics as cancer treatment. In light of this analysis, potential development opportunities will then be thoroughly investigated for future efforts in repositioning of non-cancer p-glycoprotein inhibitors in single use or in combination therapy for clinical oncology treatment.
| S-EPMC7704056 | biostudies-literature
Project description:Coronavirus disease is a highly infectious disease caused by the 2019 novel coronavirus, now recognized as severe acute respiratory syndrome coronavirus 2. This pandemic caused great stress in the general public and led to the collapse of healthcare system in some places. Till date, there has not been an effective vaccine or antiviral drug for its treatment. As at the time of write-up, scientists, researchers, and industries in different countries are working collaboratively to develop an effective therapy or alternative to combat this deadly and highly infectious virus. To combat or overcome these difficulties, the United States Food and Drug Administration launched an FDA Coronavirus Treatment Acceleration Program (CTAP) to accelerate the development of new investigational drugs, biological therapies, vaccines, and medical devices for the treatment of COVID-19 patients. This chapter provides details about this, the role of FDA CTAP and the drugs they are evaluating for the treatment of this disease.
| S-EPMC9217692 | biostudies-literature
Project description:Chimeric antigen receptor (CAR) T cells (CAR-T) have dramatically changed the treatment landscape of B-cell malignancies, providing a potential cure for relapsed/refractory patients. Long-term responses in patients with acute lymphoblastic leukemia and non Hodgkin lymphomas have encouraged further development in myeloma. In particular, B-cell maturation antigen (BCMA)-targeted CAR-T have established very promising results in heavily pre-treated patients. Moreover, CAR-T targeting other antigens (i.e., SLAMF7 and CD44v6) are currently under investigation. However, none of these current autologous therapies have been approved, and despite high overall response rates across studies, main issues such as long-term outcome, toxicities, treatment resistance, and management of complications limit as yet their widespread use. Here, we critically review the most important pre-clinical and clinical findings, recent advances in CAR-T against myeloma, as well as discoveries in the biology of a still incurable disease, that, all together, will further improve safety and efficacy in relapsed/refractory patients, urgently in need of novel treatment options.
| S-EPMC8327729 | biostudies-literature
Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas developed from Schwann cell lineage. They account for up to 10% of all soft tissue sarcomas. Although there is an unmet need for new therapeutic agents for MPNSTs, to date there have been few transcriptomic analyses of this tumor type. We studied FDA approved drugs for MPNST treatment and compared their transcriptomic changes in cell lines before and after treatment. We demonstrated that Fludarabine treated NF1 MPNST cells exhibited altered signaling pathways such as the upregulation of the Wnt/Ca+ pathway and downregulation of the hedgehog and hypoxia signaling pathways in the Ingenuity Pathway Analysis (IPA) and Gene Set Enrichment Analysis (GSEA) analysis. The combined Colchicine and Fludarabine treatment enhanced the cytotoxicity of sporadic MPNST cells through altered signaling pathways, including increased Wnt/β-catenin pathway and others. The transcriptomic analysis comparing NF1/sporadic MPNST cells and normal Schwann cells indicated that NF1 MPNST cells had more splicing events, fewer single nucleotide variants, and induced RNA expression than sporadic MPNST cells. In summary, we identified a transcriptomic differences between MPNSTs and Schwann cells, between sporadic MPNST cells and NF1 MPNST cells, and between drug treated MPNST cells and vehicle treated cells.
2023-10-21 | GSE159896 | GEO
Project description:The majority of patients with B-cell non-Hodgkin lymphoma (NHL) can be cured with standard chemoimmunotherapy. However, patients who fail first line therapy have dismal outcomes, particularly if they have disease that is resistant to salvage therapy, including chemoimmunotherapy, radiation and/or autologous stem cell transplantation. Indolent B-NHLs, such as follicular lymphoma (FL), although not generally considered curable may be treated over many years with good prognosis. However, a subset of B-NHLs can undergo histologic transformation into more aggressive subtypes with outcomes similar to aggressive B-NHLs. In recent years, T cells genetically modified with chimeric antigen receptors (CARs), have demonstrated a remarkable capacity to induce complete and durable clinical responses in patients with chemotherapy-refractory lymphomas. Indeed, two autologous CD19-directed CAR-modified T cell products have now been FDA-approved for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL) and transformed FL, while a plethora of other CAR-T cell targets are being explored in ongoing clinical trials. The purpose of this review is to summarize the clinical efficacy and unique toxicities of individually developed CAR-T cell products for the treatment of lymphomas, and their evolution from the laboratory bench to commercialization.
| S-EPMC6880960 | biostudies-literature
Project description:Chimeric antigen receptor T-cell (CAR T) therapy has shown promising efficacy in relapsed and refractory diffuse large B cell lymphoma (DLBCL). While most patients undergo CAR T infusion with active disease, the impact of some clinical variables, such as responsiveness to the pre-CAR T chemotherapy on the response to CAR T, is unknown. In this single-institution study, we studied the impact of several pre-CAR T variables on the post-CAR outcomes. Sixty patients underwent apheresis for axicabtagene-ciloleucel (axi-cel) and 42 of them (70.0%) had primary refractory disease. Bridging therapy between apheresis and lymphodepletion was given in 34 patients (56.7%). After axi-cel, the overall response rate was 63.3%. Responsiveness to the immediate pre-CAR T therapy did not show a significant association with response to axi-cel, progression-free (PFS) or overall (OS) survival. Multivariable analysis determined that bulky disease before lymphodepletion was independently associated with inferior outcomes, and patients that presented with high-burden disease unresponsive to immediate pre-CAR T therapy had a dismal outcome. This data supports proceeding with treatment in CAR T candidates regardless of their response to immediate pre-CAR T therapy. Interim therapeutic interventions should be considered in patients who have known risk factors for poor outcomes (bulky disease, high LDH).
| S-EPMC9753434 | biostudies-literature