Combined CD28 and 4-1BB Costimulation Potentiates Affinity-tuned Chimeric Antigen Receptor-engineered T Cells.
Drent Esther,Poels Renée,Ruiter Ruud,van de Donk Niels W C J,Zweegman Sonja,Yuan Huipin,de Bruijn Joost,Sadelain Michel,Lokhorst Henk M,Groen Richard W J,Mutis Tuna,Themeli Maria
Clinical cancer research : an official journal of the American Association for Cancer Research
PURPOSE:Targeting nonspecific, tumor-associated antigens (TAA) with chimeric antigen receptors (CAR) requires specific attention to restrict possible detrimental on-target/off-tumor effects. A reduced affinity may direct CAR-engineered T (CAR-T) cells to tumor cells expressing high TAA levels while sparing low expressing normal tissues. However, decreasing the affinity of the CAR-target binding may compromise the overall antitumor effects. Here, we demonstrate the prime importance of the type of intracellular signaling on the function of low-affinity CAR-T cells. EXPERIMENTAL DESIGN:We used a series of single-chain variable fragments (scFv) with five different affinities targeting the same epitope of the multiple myeloma-associated CD38 antigen. The scFvs were incorporated in three different CAR costimulation designs and we evaluated the antitumor functionality and off-tumor toxicity of the generated CAR-T cells and . RESULTS:We show that the inferior cytotoxicity and cytokine secretion mediated by CD38 CARs of very low-affinity ( < 1.9 × 10 mol/L) bearing a 4-1BB intracellular domain can be significantly improved when a CD28 costimulatory domain is used. Additional 4-1BB signaling mediated by the coexpression of 4-1BBL provided the CD28-based CD38 CAR-T cells with superior proliferative capacity, preservation of a central memory phenotype, and significantly improved antitumor function, while preserving their ability to discriminate target antigen density. CONCLUSIONS:A combinatorial costimulatory design allows the use of very low-affinity binding domains ( < 1 μmol/L) for the construction of safe but also optimally effective CAR-T cells. Thus, very-low-affinity scFvs empowered by selected costimulatory elements can enhance the clinical potential of TAA-targeting CARs.
Chimeric Antigen Receptor T Cells for B-Cell Acute Lymphoblastic Leukemia.
Ceppi Francesco,Gardner Rebecca A
Cancer journal (Sudbury, Mass.)
Chimeric antigen receptor (CAR) T-cell therapy is transforming the landscape for treatment of B-lineage acute lymphoblastic leukemia (B-ALL). Chimeric antigen receptor T-cell therapy makes use of T cells that have been modified to target a cancer-specific cell surface antigen. There is currently 1 Food and Drug Administration-approved CD19-directed CAR T-cell therapy for relapsed/refractory B-ALL with numerous other CAR T-cell products under clinical investigation. This review covers the development of CAR T cells for B-ALL, citing the remarkable efficacy of inducing remissions in a very high-risk population of patients. However, following the first round of CAR T-cell trials targeting CD19 in B-ALL, it has been found that approximately 50% of patients who initially respond will ultimately recur. Current efforts in the field are focusing on the identification of targets beyond CD19 as well as advancing strategies to promote more durable remissions as work is ongoing to move this therapy upfront.
Subcutaneous immunoglobulin replacement following CD19-specific chimeric antigen receptor T-cell therapy for B-cell acute lymphoblastic leukemia in pediatric patients.
Arnold Danielle E,Maude Shannon L,Callahan Colleen A,DiNofia Amanda M,Grupp Stephan A,Heimall Jennifer R
Pediatric blood & cancer
Twenty-eight patients were maintained on subcutaneous immunoglobulin replacement for persistent B-cell aplasia and agammaglobulinemia following CD19-targeted chimeric antigen receptor T-cell therapy for B-cell lymphoblastic leukemia. Patients were transitioned from intravenous to subcutaneous immunoglobulin replacement at a median of 11.5 months (range, 4-20). Increasing serum IgG level was significantly associated with a lower rate of sinopulmonary infection (P = 0.0072). The median serum IgG level during infection-free periods was 1000 mg/dL (range, 720-1430), which was significantly higher than IgG levels in patients with sinopulmonary infections. As such, we recommend maintaining a goal IgG level > 1000 mg/dL to provide optimal protection.
Chimeric antigen receptor T cells for acute lymphoblastic leukemia.
Frey Noelle V
American journal of hematology
Chimeric antigen receptor (CAR) modified T cells targeted to CD19 have resulted in unprecedented remission rates for adult and pediatric patients with relapsed and refractory B cell acute lymphoblastic leukemia (ALL). With regulatory approval for tisagenlecleucel and many other agents under active investigation, the use of CAR T cells for ALL continues to expand. While some remissions from anti-CD19 CAR T cells are durable without a consolidative allogeneic stem cell transplantation, CD19 positive and negative relapses remain a significant concern fueling investigations into the biology of CAR T cell persistence and the development of CARTs that target more than 1 antigen. The treatment related toxicities of cytokine release syndrome and neurologic events are potentially life threatening but recent advances have improved understanding and management strategies. This review summarizes outcomes for patients with ALL treated with CD19-CAR T cells while exploring the field's challenges and future directions.
Functional Improvement of Chimeric Antigen Receptor Through Intrinsic Interleukin-15Rα Signaling.
Nair Sushmita,Wang Jing-Bo,Tsao Shih-Ting,Liu Yuchen,Zhu Wei,Slayton William B,Moreb Jan S,Dong Lujia,Chang Lung-Ji
Current gene therapy
INTRODUCTION:Recent studies on CD19-specific chimeric antigen receptor (CAR)-modified T cells (CARTs) have demonstrated unprecedented successes in treating refractory and relapsed B cell malignancies. The key to the latest CART therapy advances can be attributed to the improved costimulatory signals in the CAR design. METHODS:Here, we established several novel CARs by incorporating T cell signaling domains of CD28 in conjunction with intracellular signaling motif of 4-1BB, CD27, OX40, ICOS, and IL-15Rα. These novel CARs were functionally assessed based on a simple target cell killing assay. RESULTS:The results showed that the CD28/IL-15Rα co-signaling (153z) CAR demonstrated the fastest T cell expansion potential and cytotoxic activities. IL-15 is a key cytokine that mediates immune effector activities. The 153z CARTs maintained prolonged killing activities after repetitive rounds of target cell engagement. Consistent with the enhanced target killing function, the 153z CARTs produced increased amount of effector cytokines including IFN-γ, TNFα and IL-2 upon interaction with the target cells. CONCLUSION:In a follow-up clinical study, an acute lymphoblastic leukemia (ALL) patient, who experienced multiple relapses of central nervous system leukemia (CNSL) and failed all conventional therapies, was enrolled to receive the CD19-specific 153z CART treatment. The patient achieved complete remission after the 153z CART cell infusion. The translational outcome supports further investigation into the safety and enhanced therapeutic efficacy of the IL-15Rα-modified CART cells in cancer patients.
[Clinical Efficacy of Humanized Anti-CD19 Chimeric Antigen Receptor T Cells in the Treatment of Acute B Lymphocytic Leukemia].
Han Xiao,Ye Chun-Ying,Zhang Chang-Xiao,Cheng Hai,Qi Kun-Ming,Chen Wei,Cao Jiang,Xu Kai-Lin
Zhongguo shi yan xue ye xue za zhi
OBJECTIVE:To study the safety and effectiveness of humanized CD19-targeted CAR-T cells (hCART19s) for treatment of patients with refractory/relapsed (R/R) B-ALL. METHODS:The analyzed patients were 15 children and adults with relapsed/refractory B-ALL who not received treatment with murine CD19 CAR-T cells. The patients received a single dose (1×10/kg) of autologous hCART19 infusion after lymphodepletion chemotherapy based on cyclophosphamide and fludarabine. RESULTS:Among the 15 patients, 13/14 (92.9%) evaluable patients achieved complete remission (CR) or CR with incomplete recovery of blood cells (CRi) on day 30 after hCART19s infusion. At day 180 after the infusion, the overall survival rate was 73.3%, and the leukemia-free survival rate was 69.2%. The cumulative incidence of relapse was 24.5% and non-relapse mortality rate was 7.7%. During treatment,12/15 patients (80%) developed cytokine release syndrome (CRS) of grade 1-2, and 3 patients (20.0%) developed CRS of grade 3-5. Only one patient (6.7%) suffered from the reversible neurotoxicity. CONCLUSION:hCART19s can effectively treat refractory/relapsed (R/R) adult and children with B-ALL, and the incidence of treatment-related CRS and neurotoxicity is low.
[Efficacy of CD19 Chimeric Antigen Receptors T Cells in the Treatment of Relapsed Patients with B Cell Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation].
Chen Hui-Ren,Zhang Yuan,Chen Peng,Liu Xiao-Dong,Huang Qing,Zhang Juan,Li Hui-Min,Liu Bing
Zhongguo shi yan xue ye xue za zhi
OBJECTIVE:To study the long-term efficacy and safety of CD19 chimeric antigen receptor T cells (CAR-T) in the treatment of relapsed patients with B-cell acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS:A total of 7 patients with B-cell ALL relapsed after allo-HSCT were treated with CD19 CAR-T cells from September 2015 to March 2018. Among them, 6 had hematological recurrence and 1 had positive of MRD. They all were treated with a single infusion of CAR-T cells. FC chemotherapy regimen was administered before transfusion. The median number of CAR-T cells transfused was 6.0 (range 4.0-8.6) )×10/kg. Long-term efficacy and toxicity were evaluated. RESULTS:Bone marrow examination performed at d 30 after CAR-T infusion showed that all 7 patients achieved complete remission and MRD negative, grade I CRS for 1 case and grade II CRS for 6 cases, two of them had mild neurotoxicity, which was controlled by treatment. Two patients presented grade VI intestinal GVHD after CAR-T infusion. The median follow-up time was 18 months (range 12-42). Follow-up showed that two patients relapsed at 9 months and 14 months after treatment, out of 2 patients one died of progressive disease and the other reachived the hematological remission, but MRD was positive after CD22 CAR-T cell therapy. At present, five patients are disease-free survival, moreover showed complete donor chimerism. One year after CAR-T cell therapy, the results of immune reconstitution showed that CD4 level was more than 300×10/L in 5 patients who disease-free survived. Among them, 3 patients had poor recovery of immunoglobulin and received gamma globulin replacement therapy. CONCLUSION:All patients are followed up for at least one year. The preliminary efficacy and safety are satisfactory. CAR-T cell infusion is an effective method for the treatment of B-ALL recurrence after allo-HSCT.
Use of chimeric antigen receptor T cells in allogeneic hematopoietic stem cell transplantation.
Liu Jun,Zhang Xi,Zhong Jiang F,Zhang Cheng
The chimeric antigen receptor T (CAR-T) cells play an antileukemia role, and can be used to treat or prevent relapse by targeting minimal residual disease for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the infusion of allogeneic CAR-T cells may also cause graft-versus-host disease, which limited their applications during and after allo-HSCT. In this review, we discuss the clinical trials that applying CAR-T cells before allo-HSCT and the use of donor-derived CAR-T cells as conditioning regimen during allo-HSCT. At last, we analyzed the effect of donor-derived CAR-T cells on preventive infusion after allo-HSCT.
Chimeric antigens receptor T cell therapy as a bridge to haematopoietic stem cell transplantation for refractory/ relapsed B-cell acute lymphomalastic leukemia.
Zhang Yan,Chen Huiren,Song Yanzhi,Tan Xiyou,Zhao Yongqiang,Liu Xiaodong,Li Zhihui,Yang Fan,Jiang Min,Gao Zhiyong,Wu Tong
British journal of haematology
Although chimeric antigen receptor T cells (CAR-T) targeted at CD19 or CD22 have achieved high complete remission (CR) in refractory/relapsed B-cell acute lymphoblastic leukaemia (B-ALL), it is uncertain if allogeneic haematopoietic stem cell transplantation (allo-HSCT) should be performed after CAR-T therapy to accomplish a sustainable remission. Fifty-two cases with relapsed/refractory B-ALL who underwent allo-HSCT after CR by CD19 or CD22 CAR-T were enrolled. The median time from CAR-T infusion to allo-HSCT was 50 (34-98) days. Myeloablative reduced-intensity conditioning (RIC) with total body irradiation/fludarabine-based or busulfan/fludarabine-based regimens was used. Incidences of grade II-IV acute graft-versus-host disease (aGVHD) and severe aGVHD were 23·1% and 5·8% respectively. Of 48 evaluable cases, 16 developed chronic GVHD (cGVHD) and in three of them the pattern was extensive. With a median follow-up of 334 (41-479) days, one-year overall survival and event-free survival (EFS) were 87·7% and 73·0%. One-year relapse rate and transplant-related mortality (TRM) were 24·7% and 2·2% respectively. With quick bridge to allo-HSCT after CAR-T therapy, high EFS for refractory/relapsed B-ALL has been achieved in this relatively large cohort. Our myeloablative RIC regimens have resulted in low incidences of aGVHD, cGVHD, viral reactivation and very low TRM even majority of transplants from haploidentical donors. Long-term follow-up is warranted.
What is the Role of Hematopoietic Cell Transplantation (HCT) for Pediatric Acute Lymphoblastic Leukemia (ALL) in the Age of Chimeric Antigen Receptor T-Cell (CART) Therapy?
Taraseviciute Agne,Broglie Larisa,Phelan Rachel,Bhatt Neel S,Becktell Kerri,Burke Michael J
Journal of pediatric hematology/oncology
CD19 chimeric antigen receptor T-cell (CART) therapy has revolutionized the treatment of patients with relapsed/refractory hematologic malignancies, especially B-cell acute lymphoblastic leukemia. As CART immunotherapy expands from clinical trials to FDA-approved treatments, a consensus among oncologists and hematopoietic cell transplant (HCT) physicians is needed to identify which patients may benefit from consolidative HCT post-CART therapy. Here, we review CD19 CART therapy and the outcomes of published clinical trials, highlighting the use of post-CART HCT and the pattern of relapse after CD19 CART. At this time, the limited available long-term data from clinical trials precludes us from making definitive HCT recommendations. However, based on currently available data, we propose that consolidative HCT post-CART therapy be considered for all HCT-eligible patients and especially for pediatric patients with KMT2A-rearranged B-cell acute lymphoblastic leukemia.
Chimeric Antigen Receptor T Cells: A Race to Revolutionize Cancer Therapy.
Subklewe Marion,von Bergwelt-Baildon Michael,Humpe Andreas
Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie
For years, cancer treatment was dominated by chemotherapy, radiation therapy, and stem cell transplantation. New insights into genetic characteristics of leukemic cells have initiated the development of the chimeric antigen receptor (CAR) T-cell therapy. This type of adoptive cell immunotherapy has been a breakthrough in the treatment of aggressive B-cell lymphoma and B-cell precursor acute lymphoblastic leukemia. In August 2018, the European Commission has approved the first CAR T-cell products - tisagenlecleucel (Kymriah®, Novartis) and axicabtagene ciloleucel (Yescarta®, Gilead) - for hematological neoplasms in Europe. As CAR T cells are a living drug, its benefits can last for many years. The administration of CAR T cells is a complex and costly endeavor involving cell manufacture, shipping of apheresis products, and management of novel and severe adverse reactions. The most common toxicities observed after CAR T-cell therapy are cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Current research focuses on improved safety and efficacy in hematological malignancies as well as the translation of CAR T-cell therapy to solid tumors. This review covers the development and current status of CAR T-cell therapy in a clinical setting with focus on challenges and future opportunities.
T-cell receptor and chimeric antigen receptor in solid cancers: current landscape, preclinical data and insight into future developments.
Azizi Alexander A,Pillai Manon,Thistlethwaite Fiona C
Current opinion in oncology
PURPOSE OF REVIEW:The remarkable and durable clinical responses seen in certain solid tumours using checkpoint inhibitors and in haematological malignancies using chimeric antigen receptor (CAR) T therapy have led to great interest in the possibility of using engineered T-cell receptor (TCR) and CAR T therapies to treat solid tumours. RECENT FINDINGS:In this article, we focus on the published clinical data for engineered TCR and CAR T therapy in solid tumours and recent preclinical work to explore how these therapies may develop and improve. We discuss recent approaches in target selection, encouraging epitope spreading and replicative capacity, CAR activation, T-cell trafficking, survival in the immunosuppressive microenvironment, universal T-cell therapies, manufacturing processes and managing toxicity. SUMMARY:In haematological malignancies, CAR T treatments have shown remarkable clinical responses. Engineered TCR and CAR therapies demonstrate responses in numerous preclinical models of solid tumours and have shown objective clinical responses in select solid tumour types. It is anticipated that the integration of efficacious changes to the T-cell products from disparate preclinical experiments will increase the ability of T-cell therapies to overcome the challenges of treating solid tumours and note that healthcare facilities will need to adapt to deliver these treatments.
Chimeric antigen receptor T cell therapy and other therapeutics for malignancies: Combination and opportunity.
Wang Luyao,Yao Ruixue,Zhang Lifa,Fan Chuanbo,Ma Leina,Liu Jia
Chimeric antigen receptor T (CAR-T) cell therapy provides possibility for the treatment of malignancies since clinical trials have shown that CAR-T therapy has a significant anti-tumor effect. Although many efforts have been made to improve the efficacy and reduce the side effects of CAR-T therapy, there are still many problems to solve. With the rapid development of this field, combination immunotherapy has been proved to improve the efficacy of CAR-T therapy. Studies have shown that radiotherapy, chemotherapy, oncolytic virotherapy, BTK inhibitors and immune checkpoint blockade-based therapy may further enhance the efficacy of CAR-T therapy while CRISPR/Cas9 technology and IL-1 blockade may improve the safety. In this review, we summarized the advantages and the mechanisms of the combination immunotherapy based on CAR-T cell therapy.
The journey to CAR T cell therapy: the pediatric and young adult experience with relapsed or refractory B-ALL.
Hucks George,Rheingold Susan R
Blood cancer journal
Outcomes of pediatric and young adult patients diagnosed with acute lymphoblastic leukemia (ALL) have improved significantly in the past few decades. Treatment advances have provided 5-year survival rates ranging from 78 to 91% depending on the age at diagnosis. However, approximately 2-3% of patients will present with refractory disease that is unresponsive to chemotherapy, and 10-15% of patients will relapse. Outcomes post-relapse show significantly reduced 5-year survival rates that continue to decrease with each subsequent relapse. Despite our increased understanding of risk factors and disease predictors, treatment strategies for patients with relapsed or refractory (r/r) disease, including variations of chemotherapy and stem cell transplant, remain ineffective for many patients. To improve outcomes of patients with r/r disease, immunotherapies targeting specific B cell antigens are being developed. Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy recently approved by the US Food and Drug Administration for patients with refractory leukemia or those with second or later relapse. In this treatment strategy, a patient's own T cells are transduced to express an anti-CD19 CAR that, when reintroduced into the patient, directs specific binding and killing of CD19+ B cells. In a phase 2, single-arm, multicenter, global study, tisagenlecleucel resulted in a remission rate of 81% in pediatric and adolescent patients with r/r B cell ALL. This review article summarizes four typical cases of pediatric and adolescent r/r B-cell ALL, focusing on the patient's journey from initial diagnosis to treatment with CAR T cell therapy.
Chimeric Antigen Receptor T-Cell Therapy Clinical Results in Pediatric and Young Adult B-ALL.
DiNofia Amanda M,Maude Shannon L
Chimeric antigen receptor (CAR)-modified T-cell therapy has revolutionized the care of patients with relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL). Results from clinical trials across multiple institutions report remarkable remission rates with CD19-directed CAR-modified T-cell therapy. These remissions are also proving to be durable in many patients with a relapse-free survival (RFS) of approximately 50% to 60% at 1 year across several trials and institutions in this population that has been historically very difficult to treat. In addition, new products are being developed to enhance upon the original CAR T-cell products, which include a humanized CAR, allogeneic CARs, and both CD22 and biallelic CD19 and CD22 constructs. Toxicity after CAR-modified T-cell therapy is characterized by cytokine release syndrome (CRS) and neurotoxicity in the acute post-infusion period and B-cell aplasia as a long-term consequence of treatment. This review will summarize the published data thus far on the use of CAR-modified T-cell therapy in pediatric B-ALL and outline the various CAR products now being developed for this population. Delivery of this therapy and the decision to pursue hematopoietic stem cell transplant (HSCT) after treatment will be discussed.
Utilization of CAR T Cell Therapy in Pediatric Patients.
Szenes Victoria,Curran Kevin J
Seminars in oncology nursing
OBJECTIVE:To provide an overview of chimeric antigen receptor (CAR) T cell therapy for pediatric patients with relapsed or refractory malignancy and the associated toxicities. DATA SOURCES:Research articles, reviews, clinical trial information. CONCLUSION:The key to the successful application of CAR T cell immunotherapy is (1) identifying patients with malignancies that are eligible for immunotherapy, (2) coordinating T-cell collection, (3) safe infusion of CAR T cells, and (4) managing/preventing toxicities following infusion. IMPLICATIONS FOR NURSING PRACTICE:As the use of targeted therapy with tumor-specific T cells becomes more prevalent, it is essential that the nursing staff stay abreast of these current therapies.
Recent advances in the treatment of acute lymphoblastic leukemia.
Rafei Hind,Kantarjian Hagop M,Jabbour Elias J
Leukemia & lymphoma
Acute lymphoblastic leukemia (ALL) is a heterogeneous disease with a bimodal distribution. The progresses made in understanding its biology led to the development of targeted therapies. In this review, we summarize the current and future approaches in management of adult ALL. Tyrosine kinase inhibitors (TKI) targeting BCR-ABL1 tyrosine kinase, monoclonal antibodies targeting cell surface antigens (CD19, CD20, and CD22), bispecific antibodies, and chimeric antigen receptor (CAR)-T therapy are breakthrough treatments. They resulted in FDA approvals of blinatumomab in 2014, inotuzumab ozagamicin in 2017, and tisagenlecleucel in 2017 for relapsed/refractory ALL. Currently, long-term survival is achieved in more than 50% of patients with precursor B-ALL (50-70% in patients with Philadelphia chromosome (Ph)-positive ALL), 50-60% T-ALL, and 80% mature B-ALL. Ongoing efforts exist to optimize therapeutic options in both the relapsed/refractory as well as the frontline settings. In the era of precision medicine, the future lies in using less cytotoxic and more targeted agents.
CD19 chimeric antigen receptor-T cells in B-cell leukemia and lymphoma: current status and perspectives.
Mohty Mohamad,Gautier Jordan,Malard Florent,Aljurf Mahmoud,Bazarbachi Ali,Chabannon Christian,Kharfan-Dabaja Mohamed A,Savani Bipin N,Huang He,Kenderian Saad,Nagler Arnon,Perales Miguel-Angel
The approval of tisagenlecleucel and axicabtagene ciloleucel represents a breakthrough in the field of immune and cellular therapy for hematologic malignancies. These anti-CD19 chimeric antigen receptor-T cells (CAR) proved to be highly effective in the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) and specific histologic subtypes of B-cell non-Hodgkin lymphomas. This expert review aims to summarize the current available research evidence in this field, with a special focus on the different challenges faced by treating physicians, and we also provide future perspectives.
Adult Acute Lymphoblastic Leukemia: Treatment and Management Updates.
Seminars in oncology nursing
OBJECTIVE:To present an overview of novel therapies for the treatment of adult acute lymphoblastic leukemia and to discuss nursing implications for these new therapies. DATA SOURCES:Published manuscripts, Web sites, and pharmaceutical package inserts. CONCLUSION:Several promising therapies have emerged in the treatment of relapsed/refractory and minimal residual disease acute lymphoblastic leukemia. IMPLICATIONS FOR NURSING PRACTICE:With the changing paradigm for hematologic malignancies, nurses must remain current in their knowledge regarding novel therapies, including their administration, toxicity profile, and management of adverse events. This article addresses the clinical benefits of novel agents and nursing implications for those agents.
Advances of CD19-directed chimeric antigen receptor-modified T cells in refractory/relapsed acute lymphoblastic leukemia.
Wei Guoqing,Ding Lijuan,Wang Jiasheng,Hu Yongxian,Huang He
Experimental hematology & oncology
Refractory/relapsed B-cell acute lymphoblastic leukemia remains to be a significant cause of cancer-associated morbidity and mortality for children and adults. Developing novel and effective molecular-targeted approaches is thus a major priority. Chimeric antigen receptor-modified T cell (CAR-T) therapy, as one of the most promising targeted immunotherapies, has drawn extensive attention and resulted in multiple applications. According to published studies, CD19-directed CAR-T cells (CD19 CAR-T) can reach a complete remission rate of 94% in both children and adults with refractory/relapsed ALL, much higher than that of chemotherapy. However, the encouraging outcomes are often associated with complications such as cytokine release syndrome (CRS), serious neurotoxicity, and on-target off-tumor effect, which seriously impeded further clinical application of CAR-T cells. Moreover, CAR-T therapy is typically associated with high relapse rate. This article briefly reviews the manufacture technologies, the conditioning regimens, the cell infusion doses, as well as the prevention and treatment strategies of complications for CAR-T cell therapy.
Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy for Acute Lymphoblastic Leukemia.
Fitzgerald Julie C,Weiss Scott L,Maude Shannon L,Barrett David M,Lacey Simon F,Melenhorst J Joseph,Shaw Pamela,Berg Robert A,June Carl H,Porter David L,Frey Noelle V,Grupp Stephan A,Teachey David T
Critical care medicine
OBJECTIVE:Initial 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. DESIGN:Retrospective cohort study. SETTING:Academic children's hospital. PATIENTS:Thirty-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). INTERVENTIONS:All 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 RESULTS:Eighteen 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. CONCLUSIONS:Grade 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.
Mechanisms and Management of Chimeric Antigen Receptor T-Cell Therapy-Related Toxicities.
Dholaria Bhagirathbhai R,Bachmeier Christina A,Locke Frederick
BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy
Chimeric antigen receptor T-cell (CAR-T) therapy has proven to be a very effective cancer immunotherapy. Axicabtagene ciloleucel and tisagenlecleucel are the first-in-class anti-CD19 CAR-T currently available for relapsed/refractory adult large B-cell lymphoma. Tisagenlecleucel is also available for pediatric and young adult (up to age 25 years) patients with relapsed/refractory B-acute lymphoblastic leukemia. Cytokine release syndrome (CRS) and CAR-T-associated encephalopathy syndrome (neurotoxicity) are the most common adverse effects associated with CAR-T therapy. They can lead to significant morbidity and preclude widespread use of this treatment modality. Treatment-related deaths from severe CRS and cerebral edema have been reported. There is a significant heterogeneity in the side-effect profile of different CAR-T products under investigation and there is a need to develop standardized guidelines for toxicity grading and management. Here, we summarize the current literature on pathogenesis, clinical presentation, and management of CRS and neurotoxicity. The different grading systems of CRS and management protocols used in different trials have made it difficult to compare the outcomes of different CAR-T therapies. Several prevention strategies such as predictive biomarkers of CRS and neurotoxicity and modified CAR-T with 'built-in' safety mechanisms are being studied, with the potential to greatly expand the safety and applicability of CAR-T treatment across various malignancies.
Current approaches in the grading and management of cytokine release syndrome after chimeric antigen receptor T-cell therapy.
Riegler Lara L,Jones Gavin P,Lee Daniel W
Therapeutics and clinical risk management
With immunotherapy innovations for cancer treatment, in particular chimeric antigen receptor (CAR) T cells, becoming more successful and prevalent, strategies to mitigate and manage their toxicities are required. Anti-CD19 CAR T-cell therapy has revolutionized the treatment of relapsed/refractory pediatric and adult acute lymphoblastic leukemia and refractory adult non-Hodgkin lymphoma, resulting in the expanded use of CAR T cells in multicenter trials and as US FDA-approved products. Cytokine release syndrome (CRS) and CAR-associated neurotoxicity, which can occur independently or concurrently with CRS, are two potentially life-threatening toxicities of CAR T-cell therapy. In this review, we will focus on describing the pathophysiology behind CRS, the proposed definitions of and grading systems for CRS, and innovative options for treating this potentially lethal systemic inflammatory condition.
Management of cytokine release syndrome and neurotoxicity in chimeric antigen receptor (CAR) T cell therapy.
Acharya Utkarsh H,Dhawale Tejaswini,Yun Seongseok,Jacobson Caron A,Chavez Julio C,Ramos Jorge D,Appelbaum Jacob,Maloney David G
Expert review of hematology
INTRODUCTION:Chimeric antigen receptor (CAR) T cell immunotherapy has demonstrated remarkable anti-tumor activity in B-cell malignancies and is under investigation in other hematologic malignancies and solid tumors. While highly efficacious, post-infusion T cell activity often results in massive cytokine release precipitating cytokine release syndrome (CRS), the signature toxicity of CAR T cells. This toxicity is characterized by systemic immune activation resulting in fever, hypotension, respiratory insufficiency and capillary leak. Either in conjunction with or in the absence of CRS, a subset of patients may also develop mild to severe neurotoxicity. Although the precise pathogenesis of CRS and neurotoxicity aren't fully elucidated, risk factors and mitigation strategies have been reported. Areas covered: This manuscript provides an in-depth overview of the pathogenesis, clinical characteristics, current toxicity management strategies, and future perspectives pertaining to CRS and neurotoxicity. Expert Opinion: As CAR T cell based therapies gain popularity in the management of various malignancies, the complimentary toxicities of CRS and neurotoxicity pose a clinical challenge in practice. Risk adaptive modeling incorporating disease profile, patient demographics, lymphodepletion, cell dosing, CAR T construct, and potentially cytokine gene polymorphisms may be instructive to assess individualized risk and optimal CRS/neurotoxicity management.
Evolution of chimeric antigen receptor (CAR) T cell therapy: current status and future perspectives.
Lee Young-Ho,Kim Chan Hyuk
Archives of pharmacal research
Engineering T cells with a chimeric antigen receptor (CAR) that reprograms their antigen selectivity and signaling has recently emerged as one of the most promising therapeutic approaches for treating cancers. For example, two CD19-specific CAR T cell (CAR-T) therapies have shown remarkable responses in patients with relapsed/refractory B-cell cancers, and were approved by the US Food and Drug Administration in 2017. This initial clinical success has spurred an explosion of interests in this novel therapy from both academia and industry, and results from basic and clinical research have enabled the rapid evolution of the CAR-T field. In this review, we describe the basic structure of the CAR and discuss how each of its domains affect the efficacy and safety of CAR-T therapies. In addition, we discuss some of the novel concepts and other considerations that are essential for ensuring the future success of CAR-T therapy.
[Chimeric antigen receptor T-cell therapy].
Müller Klaus,Ifversen Marianne,Kielsen Katrine,Petersen Søren Lykke,Met Özcan,Svane Inge Marie
Ugeskrift for laeger
Although treatment of haematological cancer has improved significantly during the latest decades, the prognosis is poor in case of relapse or refractory disease. This review describes the chimeric antigen receptor (CAR) T-cell therapy, which has emerged as a new promising treatment principle, in which the patient's own T-cells are genetically modified to recognise cancer cells. The possible side effects are usually only transient. A commercial CD19 CAR T-cell product has recently been approved as treatment for acute lympho-blastic leukaemia in children and young adults in Denmark, and a non-commercial CAR T-cell production is being established.
Anti-CD19 chimeric antigen receptor-modified T-cell therapy bridging to allogeneic hematopoietic stem cell transplantation for relapsed/refractory B-cell acute lymphoblastic leukemia: An open-label pragmatic clinical trial.
Jiang Huiwen,Li Chenggong,Yin Ping,Guo Tao,Liu Lin,Xia Linghui,Wu Yaohui,Zhou Fen,Ai Lisha,Shi Wei,Lu Xuan,Wang Huafang,Tang Lu,Wei Qiuzhe,Deng Jun,Jin Runming,Xiong Wei,Dong Jian,Mei Heng,Hu Yu
American journal of hematology
Chimeric antigen receptor-modified T-cell (CAR-T) therapy is effective and safe for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL), but its value has been limited in terms of long-term leukemia-free survival. New strategies that can help CAR-T therapy achieve lasting effect are urgently warranted. This non-randomized interventional pragmatic clinical trial had a particular aim. It explored whether consolidative allogeneic hematopoietic stem cell transplantation (allo-HSCT) could improve the long-term prognosis of the minimal residual disease-negative complete remission (MRD CR) patients after CAR-T therapy. In the first stage, 58 r/r B-ALL patients received split doses of CAR-T cells after lymphodepleting chemotherapy, and 51 (87.9%) achieved CR. In the second stage, 21/47 MRD CR patients without previous allo-HSCT and contraindications or other restrictions, on their own accord, received consolidative allo-HSCT within three months after CAR-T therapy. There was no difference in overall survival (OS) between the MRD CR patients who received allo-HSCT and those who did not. However, event-free survival (EFS) and relapse-free survival (RFS) were significantly prolonged by allo-HSCT in the subgroups. This was with either high (≥5%) pre-infusion bone marrow MRD assessed by flow cytometry (BM-FCM-MRD) or poor prognostic markers (P < .05). However, no difference was found in EFS and RFS for patients with pre-infusion BM-FCM-MRD <5% and without poor prognostic markers (P > .05). To conclude, CAR-T therapy bridging to allo-HSCT is a safe and effective therapeutic strategy for r/r B-ALL patients, and may prolong their EFS and RFS, especially when they have high pre-infusion BM-FCM-MRD or poor prognostic markers.
Mechanisms of failure of chimeric antigen receptor T-cell therapy.
Li Xiaoqing,Chen Weihong
Current opinion in hematology
PURPOSE OF REVIEW:Although chimeric antigen receptor T (CART)-cell therapy is best recognized for its antitumor effect in relapsed/refractory B-cell hematological cancers, it is still associated with a high relapse rate. RECENT FINDINGS:We firstly analyzed internal immunological and genetic reasons of CD19+ relapse after treatment for R/R B-cell hematological cancers with CART19 cells. The reasons: murine-derived scFv may limit expansion of CART cells. Repeated antigen exposure leads to T-cell exhaustion. Activation of T cells can cause T-cell senescence and high expression of inhibitive receptors, PD-1, CTLA4, TIGIT, LAG-3, CD244, CD160, TIM3, which might be solved by some external pharmacological intervention methods [for instance, the use of FC (Fludarabine, Cyclophosphamide) lymphodepletion regimen, lenalidomide, PD-1 inhibitor, ibrutinib and humanized CD19-CART cells. Secondly, mechanism of CD19 relapse can be attributed to the preexisting of CD19 subclone, the loss or alternative RNA splicing on exon 2 of chromosome 16 on which CD19 gene is located, B-cell transcript factors - paired-box 5 (PAX5) and early B-cell factor 1 (EBF1) are down-regulated to cause lineage-switch from lymphoid to myeloid. SUMMARY:Although different preparation techniques generates various entities of CART 19 cells, these problems could be conquered by novel agents and novel CAR system. VIDEO ABSTRACT:Although Chimeric Antigen Receptor T (CART) cell therapy is best recognized for its antitumor effect in Relapsed/Refractory B-cell hematological cancers, it still shows a high relapse rate. We review mechanisms of failure of CART therapy. http://links.lww.com/COH/A18.
[Cell therapy's poster child: Chimeric antigen receptor T cell therapy].
Qian Liling,Chen Jiangqing,Wu Xiaoyan,Jing Ruirui,Sun Jie
Sheng wu gong cheng xue bao = Chinese journal of biotechnology
Chimeric antigen receptor T (CAR-T) cell therapy, which adoptively transfers engineered T cells expressing synthetic receptors to target specific antigens, has achieved great clinical success in treating hematological malignancies. Though FDA has approved two CAR-T products, CAR-T therapy can cause some side effects, such as cytokine release syndrome (CRS), neurotoxicity and B cell aplasia. Meanwhile, lacking tumor specific antigen and the suppressive tumor environment limit the efficacy of CAR-T therapy in solid tumor. This review focuses on the structural components, clinical applications and synthetic biology approaches on CAR-T cell design, and summarizes the challenges and perspectives of CAR-T therapy as a revolutionary cancer immunotherapy.
Cytokine release syndrome and neurologic toxicities associated with chimeric antigen receptor T-cell therapy: A comprehensive review of emerging grading models.
Chavez Julio C,Jain Michael D,Kharfan-Dabaja Mohamed A
Hematology/oncology and stem cell therapy
Advances in the fields of immuno-oncology and T-cell engineering have brought autologous chimeric antigen receptor T-cell (CART) therapies from the bench to the bedside. At present, two CART products that target CD19 are commercially available: tisagenlecleucel and axicabtagene ciloleucel. They have demonstrated remarkable efficacy for their particular indications. One challenge is to compare the safety among commercially available and clinical trial CART treatments due to the use of different grading models to assess the severity of cytokine release syndrome and neurotoxicity. An unmet need exists to harmonize current grading models in order to develop uniform treatment strategies to manage these toxicities. Here, we attempt to summarize the evolution of the various grading systems for cytokine release syndrome and neurotoxicity and also highlight the major differences among them, whenever applicable.
Optimizing Chimeric Antigen Receptor T-Cell Therapy for Adults With Acute Lymphoblastic Leukemia.
Frey Noelle V,Shaw Pamela A,Hexner Elizabeth O,Pequignot Edward,Gill Saar,Luger Selina M,Mangan James K,Loren Alison W,Perl Alexander E,Maude Shannon L,Grupp Stephan A,Shah Nirav N,Gilmore Joan,Lacey Simon F,Melenhorst Jos J,Levine Bruce L,June Carl H,Porter David L
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE:The 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. METHODS:Adults 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. RESULTS:Thirty-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%). CONCLUSION:Fractionated dosing of CTL019 with intrapatient dose modification optimizes safety without compromising efficacy in adults with r/r ALL.