Assessing and Management of Neurotoxicity After CAR-T Therapy in Diffuse Large B-Cell Lymphoma.
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ABSTRACT:
SUBMITTER: Castaneda-Puglianini O
PROVIDER: S-EPMC8403007 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Patients with non-Hodgkin lymphomas (NHLs) resistant to standard therapies have a dismal prognosis. The outcome is even poorer in patients relapsing after autologous stem cell transplantation. Most of these patients do not qualify for an allogeneic hematopoietic cell transplantation (HCT) due to refractory disease, lack of a suitable allogeneic donor, higher age, or cumulative toxicity of previous chemotherapy. Despite patients undergoing allogeneic HCT normally profit from a graft-versus-lymphoma effect, overall survival in patients with NHL after HCT remains short. Therefore, novel treatment modalities are urgently needed. Chimeric antigen receptor (CAR)-T cells, a new class of cellular immunotherapy involving ex vivo genetic modification of T cells to incorporate an engineered CAR have been used in clinical trials. In the majority of studies, B cell malignancies treated with CD19 targeting CAR-T cells have been analyzed. Recently, results from 2 CD19 directed CAR-T cell trials with an increased follow-up of patients led to Food and Drug Administration and European Medicines Agency approval of tisagenlecleucel and axicabtagene ciloleucel. Common adverse events (AEs) include cytokine release syndrome and neurological toxicity, which may require admission to an intensive care unit, B cell aplasia and hemophagocytic lymphohistiocytosis. These AEs are manageable when treated by an appropriately trained team following established algorithm. In this review, we summarize the results of 3 large phase II CD19 CAR-T cell trials and focus on AEs. We also provide a perspective of ongoing activity in this field with the intend to improve the potency of this emerging novel therapy.
| S-EPMC6746029 | biostudies-literature
Project description:For approximately three decades, autologous hematopoietic cell transplantation (auto-HCT) has been the standard of care for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after frontline therapy. This approach is limited due to the intensity of chemotherapy and the proportion of patients who relapse after auto-HCT. Since the approval of anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy and novel agents, the treatment paradigm for DLBCL has changed remarkably. Anti-CD19 CAR-T therapy was first approved for relapsed DLBCL after two or more previous lines of therapy with long-lasting responses, with over 50% of patients still alive at 5-year follow-up. Here, we discuss recent randomized phase 3 clinical trials using axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel in the second-line therapy setting compared with the standard of care in transplant-eligible patients who have DLBCL R/R within 12 months of completing chemo-immunotherapy, potentially changing the treatment algorithm for DLBCL.
| S-EPMC9730015 | biostudies-literature
Project description:PurposeAxicabtagene ciloleucel (axi-cel) is a CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory diffuse large B-cell lymphoma. Bridging therapy may be required for lymphoma control during the manufacturing interval between collection of autologous T cells and final CAR T product administration. The optimal bridging therapy is not known and patients are often chemorefractory. We present a case series of patients receiving radiation as a bridge to axi-cel.Methods and materialsBetween December 2017 and October 2018, 12 patients were intended to receive bridging radiation before axi-cel. The group was characterized by highly aggressive disease including 6 of 12 with "double hit" lymphoma and 6 of 12 with disease ≥10 cm in diameter. All patients received 2 to 4 Gy/fraction to a median dose of 20 Gy (range, 6-36.5 Gy). Half of patients received either 30 Gy in 10 fractions or 20 Gy in 5 fractions. Seven patients received concurrent chemotherapy. Eleven patients underwent axi-cel infusion and one did not. Median follow-up was 3.3 months (range, 1.1-12.0 months).ResultsNo significant toxicities were identified during bridging radiation, and no patient experienced in-field progression of disease before axi-cel infusion. One patient experienced abdominal pain, which resolved after dose reduction. Two patients had out-of-field progression of disease during the bridging period. After axi-cel infusion, 3 of 11 patients (27%) experienced severe cytokine release syndrome or neurotoxicity. At 30 days, the objective response rate was 81.8% (11 of 12 evaluable; 1 stable disease, 1 out-of-field progression), with complete response in 27% (3 of 11). At last follow-up, the best objective response rate was 81.8%, with a complete response attained in 45% (5 of 11). Lymphocyte counts decreased slightly in 10 of 12 patients during radiation (median, 0.25 k/uL).ConclusionsRadiation (with or without concurrent chemotherapy) can be safely administered as a bridge to axi-cel in high-risk lymphoma. Caution should be taken if irradiation is started before apheresis, and lymphocyte counts should be monitored closely throughout. Future investigation is warranted to optimize the use of bridging radiation before CAR T therapy.
| S-EPMC6872916 | biostudies-literature
Project description:Chimeric antigen receptor (CAR) T-cell therapy has emerged as an option for relapsed/refractory aggressive B-cell lymphomas that have failed 2 lines of therapy. Failures usually occur early after infusion. The purpose of our study was to identify factors that may predict failure, particularly early progression (EP), within the first month after infusion. Characteristics of 116 patients were analyzed at the time of decision (TD) to use commercial CAR (axicabtagene ciloleucel, n = 49; tisagenlecleucel n = 67) and at the time of treatment (TT), together with total metabolic tumor volume (TMTV) at TT. With a median follow-up of 8.2 months, 55 patients failed treatment; 27 (49%) were early progressors. The estimated 12-month progression-free survival (PFS) and overall survival (OS) were 47.2% (95% confidence interval [CI], 38.0-58.6) and 67.0% (95% CI, 57-79), respectively. Univariate analyses for PFS and OS identified Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2, stage III/IV disease, extranodal (EN) sites ≥2, elevated lactate dehydrogenase (LDH), increased C-reactive protein (CRP), high International Prognostic Index at TD and at TT, as well as increased CRP, bulky mass, and high TMTV at TT, as risk factors. Multivariate analyses for PFS, EP, and OS identified elevated LDH and EN sites ≥2 at TD and the same predictors at TT (ie, increased CRP, EN sites ≥2, and TMTV >80 mL). In summary, risk factors identified for early progression at TD and at TT were EN involvement (≥2 sites) and lymphoma burden (LDH, TMTV).
| S-EPMC7686887 | biostudies-literature
Project description: Not available
| S-EPMC8436585 | biostudies-literature
Project description:Immunotherapy with T cells genetically modified with chimeric antigen receptors (CARs) has shown significant clinical efficacy in patients with relapsed/refractory B-cell lymphoma. Nevertheless, more than 50% of treated patients do not benefit from such therapy due to either absence of response or further relapse. Elucidation of clinical and biological features that would predict clinical response to CART19 therapy is of paramount importance and eventually may allow for selection of those patients with greater chances of response. In the last 5 years, significant clinical experience has been obtained in the treatment of diffuse large B-cell lymphoma (DLBCL) patients with CAR19 T cells, and major advances have been made on the understanding of CART19 efficacy mechanisms. In this review, we discuss clinical and tumor features associated with response to CART19 in DLBCL patients as well as the impact of biological features of the infusion CART19 product on the clinical response. Prognosis of DLBCL patients that fail CART19 is poor and therapeutic approaches with new drugs are also discussed.
| S-EPMC9299440 | biostudies-literature
Project description:Multiple rodent and primate preclinical studies have advanced CAR T cells into the clinic. However, no single model accurately reflects the challenges of effective CAR T therapy in human cancer patients. To evaluate the effectiveness of next-generation CAR T cells that aim to overcome barriers to durable tumor elimination, we developed a system to evaluate CAR T cells in pet dogs with spontaneous cancer. Here we report on this system and the results of a pilot trial using CAR T cells to treat canine diffuse large B cell lymphoma (DLBCL). We designed and manufactured CD20-targeting, second-generation canine CAR T cells for functional evaluation in vitro and in vivo using lentivectors to parallel human CAR T cell manufacturing. A first-in-species trial of five dogs with DLBCL treated with CAR T was undertaken. Canine CAR T cells functioned in an antigen-specific manner and killed CD20+ targets. Circulating CAR T cells were detectable post-infusion, however, induction of canine anti-mouse antibodies (CAMA) was associated with CAR T cell loss. Specific selection pressure on CD20+ tumors was observed following CAR T cell therapy, culminating in antigen escape and emergence of CD20-disease. Patient survival times correlated with ex vivo product expansion. Altering product manufacturing improved transduction efficiency and skewed toward a memory-like phenotype of canine CAR T cells. Manufacturing of functional canine CAR T cells using a lentivector is feasible. Comparable challenges to effective CAR T cell therapy exist, indicating their relevance in informing future human clinical trial design.
| S-EPMC6959441 | biostudies-literature
Project description:Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma (NHL), representing 30% of all lymphoma cases. Within the first 2-3 years following immunochemotherapy, 30-40% of patients will experience a relapse or a refractory disease, thereby exhibiting a poor prognosis. High-dose immunotherapy followed by autologous stem cell transplantation is the standard care for relapsed/refractory (RR) patients with DLBCL. However, >60% of patients are ineligible for a transplant, presenting a therapeutic challenge. Chimeric antigen receptor (CAR) T-cell therapy has shown promising efficacy in patients with DLBCL, including those with R/R disease. The present study conducted a meta-analysis that showed highly favorable outcomes [objective response rate (ORR): 69%; complete remission (CR): 49%] in B-cell NHL patients (n=419) who were treated with second-generation CAR T cells. The response rate varied in different types of B-cell NHL. In 306 patients with R/R DLBCL eligible for rate evaluation, the ORR and CR rate mean estimates were 68% [95% confidence interval (CI), 55-79%] and 46% (95% CI, 38-54%), respectively. Thus, the findings indicated that immunotherapy with CAR T cells has improved outcomes for patients with R/R DLBCL and other subtypes of B-cell NHL compared with standard chemotherapy regimens. The study revealed that grade ≥3 anemia (34%) and thrombocytopenia (30%) were the most common adverse effects of CAR T-cell therapy. Incidence of grade ≥3 cytokine release syndrome and neurotoxicity associated with CAR T-cell therapy was effectively managed.
| S-EPMC7416618 | biostudies-literature
Project description:Chimeric antigen receptor T-cell therapy (CART) has extended survival of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). However, limited durability of response and prevalent toxicities remain problematic. Identifying patients who are at high risk of disease progression, toxicity, and death would inform treatment decisions. Although the cumulative illness rating scale (CIRS) has been shown to correlate with survival in B-cell malignancies, no prognostic score has been independently validated in CART recipients. We retrospectively identified 577 patients with relapsed/refractory DLBCL indicated for CART at 9 academic centers to form a learning cohort (LC). Random survival forest modeling of overall survival (OS) and progression-free survival (PFS) was performed to determine the most influential CIRS organ systems and severity grades. The presence of a severe comorbidity (CIRS score ≥ 3) in the respiratory, upper gastrointestinal, hepatic, or renal system, herein termed "Severe4," had the greatest impact on post-CART survival. Controlling for other prognostic factors (number of prior therapies, Eastern Cooperative Oncology Group performance status, BCL6 translocation, and molecular subtype), Severe4 was strongly associated with shorter PFS and OS in the LC and in an independent single-center validation cohort (VC). Severe4 was also a significant predictor of grade ≥3 cytokine release syndrome in the LC, while maintaining this trend in the VC. Thus, our results indicate that adverse outcomes for patients with DLBCL meant to receive CART can be predicted using a simplified CIRS-derived comorbidity index.
| S-EPMC10362276 | biostudies-literature
Project description:Lymphomas arise from clonal expansions of B, T, or NK cells at different stages of differentiation. Because they occur in the immunocyte-rich lymphoid tissues, they are easily accessible to antibodies and cell-based immunotherapy. Expressing chimeric antigen receptors (CARs) on T cells is a means of combining the antigen-binding site of a monoclonal antibody with the activating machinery of a T cell, enabling antigen recognition independent of major histocompatibility complex restriction, while retaining the desirable antitumor properties of a T cell. Here, we discuss the basic design of CARs and their potential advantages and disadvantages over other immune therapies for lymphomas. We review current clinical trials in the field and consider strategies to improve the in vivo function and safety of immune cells expressing CARs. The ultimate driver of CAR development and implementation for lymphoma will be the demonstration of their ability to safely and cost-effectively cure these malignancies.
| S-EPMC4732525 | biostudies-other