Chimeric Antigen Receptor T-Cells in B-Acute Lymphoblastic Leukemia: State of the Art and Future Directions.
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ABSTRACT:
SUBMITTER: Greenbaum U
PROVIDER: S-EPMC7480185 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Recent years have witnessed major advances that have improved outcome of adults with acute lymphoblastic leukemia (ALL). The emergence of the concept of measurable residual disease has fine-tuned our prognostic models and guided our treatment decisions. The treatment paradigms of ALL have been revolutionized with the advent of tyrosine kinase inhibitors targeting BCR-ABL1, monoclonal antibodies targeting CD20 (rituximab), antibody-drug conjugates targeting CD22 (inotuzumab ozogamicin), bispecific antibodies (blinatumomab), and CD19 chimeric antigen receptor T cell therapy (tisagenlecleucel). These highly effective new agents are allowing for novel approaches that reduce reliance on intensive cytotoxic chemotherapy and hematopoietic stem cell transplantation in first remission. This comprehensive review will focus on the recent advances and future directions in novel therapeutic strategies in adult ALL.
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Project description:Relapse after conventional chemotherapy remains a major problem in patients with myeloid malignancies such as acute myeloid leukemia (AML), and the major cause of death after diagnosis of AML is from relapsed disease. The only potentially curative treatment option currently available is allogeneic hematopoietic stem cell transplantation (allo-HSCT), which through its graft-vs.-leukemia effects has the ability to eliminate residual leukemia cells. Despite its long history of success however, relapse following allo-HSCT is still a major challenge and is associated with poor prognosis. In the field of adoptive therapy, CD19-targeted chimeric antigen receptor (CAR) T cells have yielded remarkable clinical success in certain types of B-cell malignancies, and substantial efforts aimed at translating this success to myeloid malignancies are currently underway. While complete ablation of CD19-expressing B cells, both cancerous and healthy, is clinically tolerated, the primary challenge limiting the use of CAR T cells in myeloid malignancies is the absence of a dispensable antigen, as myeloid antigens are often co-expressed on normal hematopoietic stem/progenitor cells (HSPCs), depletion of which would lead to intolerable myeloablation. This review provides a discussion on the current state of CAR T cell therapy in myeloid malignancies, limitations for clinical translation, as well as the most recent approaches to overcome these barriers, through various genetic modification and combinatorial strategies in an attempt to make CAR T cell therapy a safe and viable option for patients with myeloid malignancies.
| S-EPMC7218049 | biostudies-literature
Project description:PurposeThe anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel (CTL019) has an 81% response rate in children with relapsed or chemotherapy refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). Cytokine release syndrome (CRS) is a life-threatening treatment-related toxicity that limits the full therapeutic potential in adults. We report outcomes for adults with r/r ALL treated with an optimized CTL019 dosing and CRS management strategy.MethodsAdults with r/r B-cell ALL received CTL019 in 1 of 2 trials. Patients received lymphodepletion followed by CTL019 as either a one-time infusion or fractionated infusions split over 3 days (day 1, 10%; day 2, 30%; day 3, 60%), which allowed for day 2 and day 3 doses to be held for early CRS. Total planned CTL019 dose varied with adaptive protocol modifications in response to efficacy and CRS toxicity.ResultsThirty-five adults with r/r ALL received CTL019 in 1 of 3 dosing cohorts. The low-dose cohort (n = 9) received single or fractionated dosing and had manageable toxicity with a 33% complete remission (CR) rate. In the high-dose single infusion cohort, 3 of 6 patients with refractory CRS concurrent with culture-positive sepsis died, and 3 achieved CR. The 20 patients in the high-dose fractionated (HDF) cohort had a 90% CR rate and manageable CRS. The HDF cohort had the highest survival, with a 2-year overall survival of 73% (95% CI, 46% to 88%) and event-free survival of 49.5% (95% CI, 21% to 73%).ConclusionFractionated dosing of CTL019 with intrapatient dose modification optimizes safety without compromising efficacy in adults with r/r ALL.
| S-EPMC8312030 | biostudies-literature
Project description:ObjectiveInitial success with chimeric antigen receptor-modified T cell therapy for relapsed/refractory acute lymphoblastic leukemia is leading to expanded use through multicenter trials. Cytokine release syndrome, the most severe toxicity, presents a novel critical illness syndrome with limited data regarding diagnosis, prognosis, and therapy. We sought to characterize the timing, severity, and intensive care management of cytokine release syndrome after chimeric antigen receptor-modified T cell therapy.DesignRetrospective cohort study.SettingAcademic children's hospital.PatientsThirty-nine subjects with relapsed/refractory acute lymphoblastic leukemia treated with chimeric antigen receptor-modified T cell therapy on a phase I/IIa clinical trial (ClinicalTrials.gov number NCT01626495).InterventionsAll subjects received chimeric antigen receptor-modified T cell therapy. Thirteen subjects with cardiovascular dysfunction were treated with the interleukin-6 receptor antibody tocilizumab.Measurements and main resultsEighteen subjects (46%) developed grade 3-4 cytokine release syndrome, with prolonged fever (median, 6.5 d), hyperferritinemia (median peak ferritin, 60,214 ng/mL), and organ dysfunction. Fourteen (36%) developed cardiovascular dysfunction treated with vasoactive infusions a median of 5 days after T cell therapy. Six (15%) developed acute respiratory failure treated with invasive mechanical ventilation a median of 6 days after T cell therapy; five met criteria for acute respiratory distress syndrome. Encephalopathy, hepatic, and renal dysfunction manifested later than cardiovascular and respiratory dysfunction. Subjects had a median of 15 organ dysfunction days (interquartile range, 8-20). Treatment with tocilizumab in 13 subjects resulted in rapid defervescence (median, 4 hr) and clinical improvement.ConclusionsGrade 3-4 cytokine release syndrome occurred in 46% of patients following T cell therapy for relapsed/refractory acute lymphoblastic leukemia. Clinicians should be aware of expanding use of this breakthrough therapy and implications for critical care units in cancer centers.
| S-EPMC5452983 | biostudies-literature
Project description:Chimeric antigen receptor T-cell (CAR-T) therapy has transformed treatment paradigms for relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) in children and younger adults. We performed a systematic review to investigate the published literature on efficacy and toxicity of CAR-T therapy in adults with r/r B-ALL. We searched MEDLINE, Embase, and the Cochrane Library for prospective interventional studies and included published studies of ≥5 patients with median age at enrollment of ≥18 years. Risk of bias was assessed with a modified Institute of Health Economics tool. A total of 2566 records were assessed; 16 studies involving 489 patients were included in the final analysis. The mean complete remission (CR) rate was 81% and the measurable residual disease (MRD)-negative remission rate was 81% at 4 weeks after CAR-T infusion. With median follow-up across studies of 24 months, the cumulative 12-month probabilities of progression-free survival (PFS) and overall survival (OS) were 37% (95% CI, 26-48) and 57% (95% CI, 49-65), respectively. Relapse occurred in 40.3% of cases; target antigen was retained in 73.2% of relapses. Across studies, any grade of cytokine release syndrome (CRS) occurred in 82% of patients (95% CI, 61-95) and grade 3 or higher CRS in 27% (95% CI, 18-36). Neurotoxicity of any grade occurred in 34% of patients (95% CI, 24-47) and grade 3 or higher in 14% (95% CI, 1-25). In summary, CAR-T therapy achieves high early remission rates in adults with r/r B-ALL and represents a significant improvement over traditional salvage chemotherapy. Relapses are common and durable response remains a challenge.
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Project description: Not available
| S-EPMC9175730 | biostudies-literature
Project description:Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and advances in its clinical and laboratory biology have grown exponentially over the last few decades. Treatment outcome has improved steadily with over 90% of patients surviving 5 years from initial diagnosis. This success can be attributed in part to the development of a risk stratification approach to identify those subsets of patients with an outstanding outcome that might qualify for a reduction in therapy associated with fewer short and long term side effects. Likewise, recognition of patients with an inferior prognosis allows for augmentation of therapy, which has been shown to improve outcome. Among the clinical and biological variables known to impact prognosis, the kinetics of the reduction in tumor burden during initial therapy has emerged as the most important prognostic variable. Specifically, various methods have been used to detect minimal residual disease (MRD) with flow cytometric and molecular detection of antigen receptor gene rearrangements being the most common. However, many questions remain as to the optimal timing of these assays, their sensitivity, integration with other variables and role in treatment allocation of various ALL subgroups. Importantly, the emergence of next generation sequencing assays is likely to broaden the use of these assays to track disease evolution. This review will discuss the biological basis for utilizing MRD in risk assessment, the technical approaches and limitations of MRD detection and its emerging applications.
| S-EPMC8069391 | biostudies-literature
Project description:IntroductionThough 85% of children and young adults with acute lymphoblastic leukemia (ALL) are cured, until recently, the prognosis of relapsed or refractory disease has been dismal. The advent of chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of relapsed/refractory ALL. The most well-studied, successful CARs are autologous, murine-based anti-CD19 CARs, but new constructs are currently under clinical investigation.Areas coveredThis review describes the history and design of CAR T cells, clinical trial outcomes of anti-CD19 and newer CARs, treatment-related toxicities including cytokine release syndrome and neurotoxicity, and issues with resistance and relapse. A search of PubMed and clinicaltrials.gov spanning from 2012-present was used to select original reports investigating the use of CAR T in pediatric patients.Expert opinionCD19-targeted CARs have demonstrated remarkable response rates and produced durable remissions in very high-risk pediatric patient populations. The therapies, however, are limited by unique treatment-related toxicities and considerable rates of antigen-positive and antigen-negative relapses. Current research efforts focused on elucidating mechanisms of resistance/relapse and on developing strategies to prevent and treat relapse are critical to optimizing the use of CAR-T. In addition, ongoing trials testing CARs earlier in therapy and for new indications are key to informing their widespread usage.
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Project description:In the last decade, anti-CD19 CAR-T cell therapy has led to a treatment paradigm shift for B-cell non-Hodgkin lymphomas, first with the approval for relapsed/refractory (R/R) large B-cell lymphomas and subsequently for R/R mantle cell and follicular lymphoma. Many efforts are continuously being made to extend the therapeutic setting in the lymphoma field. Several reports are supporting the safety and efficacy of CAR-T cells in patients with central nervous system disease involvement. Anti-CD30 CAR-T cells for the treatment of Hodgkin lymphoma are in development and early studies looking for the optimal target for T-cell malignancies are ongoing. Anti-CD19/CD20 and CD19/CD22 dual targeting CAR-T cells are under investigation in order to increase anti-lymphoma activity and overcome tumor immune escape. Allogeneic CAR product engineering is on the way, representing a rapidly accessible 'off-the-shelf' and potentially more fit product. In the present manuscript, we will focus on recent advances in CAR-T cell therapy for lymphomas, including new settings and future perspectives in the field, reviewing data reported in literature in the last decade up to October 2023.
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Project description:Immune targeting of B-cell malignancies using chimeric antigen receptors (CARs) is a promising new approach, but critical factors impacting CAR efficacy remain unclear. To test the suitability of targeting CD22 on precursor B-cell acute lymphoblastic leukemia (BCP-ALL), lymphoblasts from 111 patients with BCP-ALL were assayed for CD22 expression and all were found to be CD22-positive, with median CD22 expression levels of 3500 sites/cell. Three distinct binding domains targeting CD22 were fused to various TCR signaling domains ± an IgG heavy chain constant domain (CH2CH3) to create a series of vector constructs suitable to delineate optimal CAR configuration. CARs derived from the m971 anti-CD22 mAb, which targets a proximal CD22 epitope demonstrated superior antileukemic activity compared with those incorporating other binding domains, and addition of a 4-1BB signaling domain to CD28.CD3 constructs diminished potency, whereas increasing affinity of the anti-CD22 binding motif, and extending the CD22 binding domain away from the membrane via CH2CH3 had no effect. We conclude that second-generation m971 mAb-derived anti-CD22 CARs are promising novel therapeutics that should be tested in BCP-ALL.
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