Overcoming Chimeric Antigen Receptor (CAR) Modified T-Cell Therapy Limitations in Multiple Myeloma.
García-Guerrero Estefanía,Sierro-Martínez Belén,Pérez-Simón Jose Antonio
Frontiers in immunology
Multiple myeloma (MM) remains an incurable disease regardless of recent advances in the field. Therefore, a substantial unmet need exists to treat patients with relapsed/refractory myeloma. The use of novel agents such as daratumumab, elotuzumab, carfilzomib, or pomalidomide, among others, usually cannot completely eradicate myeloma cells. Although these new drugs have had a significant impact on the prognosis of MM patients, the vast majority ultimately become refractory or can no longer be treated due to toxicity of prior treatment, and thus succumb to the disease. Cellular therapies represent a novel approach with a unique mechanism of action against myeloma with the potential to defeat drug resistance and achieve long-term remissions. Genetic modification of cells to express a novel receptor with tumor antigen specificity is currently being explored in myeloma. Chimeric antigen receptor gene-modified T-cells (CAR T-cells) have shown to be the most promising approach so far. CAR T-cells have shown to induce durable complete remissions in other advanced hematologic malignancies like acute lymphocytic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). With this background, significant efforts are underway to develop CAR-based therapies for MM. Currently, several antigen targets, including CD138, CD19, immunoglobulin kappa (Ig-Kappa) and B-cell maturation antigen (BCMA), are being used in clinical trials to treat myeloma patients. Some of these trials have shown promising results, especially in terms of response rates. However, the absence of a plateau is observed in most studies which correlates with the absence of durable remissions. Therefore, several potential limitations such as lack of effectiveness, off-tumor toxicities, and antigen loss or interference with soluble proteins could hamper the efficacy of CAR T-cells in myeloma. In this review, we will focus on clinical outcomes reported with CAR T-cells in myeloma, as well as on CAR T-cell limitations and how to overcome them with next generation of CAR T-cells.
CAR T cells targeting options in the fight against multiple myeloma.
Nicolini Fabio,Bravaccini Sara,Mazza Massimiliano,Gruszka Alicja M,Tazzari Marcella,MartÍn-Antonio Beatriz,Juan Manel,Ibrahim Toni,Maltoni Roberta,Martinelli Giovanni,Cerchione Claudio
INTRODUCTION:Multiple myeloma (MM) is a hematological malignancy in which patients present with bone marrow infiltration of clonal terminally-differentiated plasma cells. Monoclonal protein in the serum and/or urine is frequently detected. Over the past decade, important progress has been made in the comprehension of disease biology and treatment personalization. Much work has been put into the development of chimeric antigen receptor (CAR) gene-modified T-cell therapy thought to be a promising therapeutic option for pluritreated patients with refractory MM. EVIDENCE ACQUISITION:We performed an analysis of clinical trials registered at the international repository clinicaltrials.gov using "CAR" OR "CAR T" AND "multiple myeloma" as search terms to understand what were the antigens targeted by CAR T strategies and what was the trade-off of their exploitation. The search retrieved a list of 103 trials that was manually filtered to eliminate follow-up and observational or not-pertinent trials. EVIDENCE SYNTHESIS:Most studies employed anti-BCMA targeting either alone (62/94; 66%), or in combination with a second target (12/94; 13%). The second target most studied was SLAMF7 (CD319) explored by 4/94 (4%) clinical trials. Other antigens investigated and described here include: CD44v6, CD38, CD138, MUC1, CD56, CD19, Igk light chain, Lewis Y, CD229 and GPRC5D. CONCLUSIONS:Targeting an appropriate antigen(s) is the key to both safety and efficacy of CAR T approaches in MM as there is dearth of tumor-specific antigens. Most antigens tested are merely enriched on MM cells. Working with tumor-enriched antigens requires careful assessment of the balance between harm (toxicity) and benefit (disease eradication) to the patient. This review provides an up-to-date overview of the avenues that are being explored.
Treatment of Multiple Myeloma Using Chimeric Antigen Receptor T Cells with Dual Specificity.
Globerson Levin Anat,Rawet Slobodkin Moran,Waks Tova,Horn Galit,Ninio-Many Lihi,Deshet Unger Naamit,Ohayon Yaara,Suliman Shimrit,Cohen Yael,Tartakovsky Boris,Naparstek Ella,Avivi Irit,Eshhar Zelig
Cancer immunology research
Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable successes in fighting B-cell leukemias/lymphomas. Promising response rates are reported in patients treated with B-cell maturation antigen (BCMA) CAR T cells for multiple myeloma. However, responses appear to be nondurable, highlighting the need to expand the repertoire of multiple myeloma-specific targets for immunotherapy and to generate new CAR T cells. Here, we developed a "dual-CAR" targeting two multiple myeloma-associated antigens and explored its safety and efficacy. To reduce the "off-target" toxicity, we used the recognition of paired antigens that were coexpressed by the tumor to induce efficient CAR T-cell activation. The dual-CAR construct presented here was carefully designed to target the multiple myeloma-associated antigens, taking into consideration the distribution of both antigens on normal human tissues. Our results showed that the CD138/CD38-targeted dual CAR (dCAR138-38) elicited a potent anti-multiple myeloma response both and NSG mice transplanted with a multiple myeloma cell line and treated with dCAR138-38 showed median survival of 97 days compared with 31 days in the control group treated with mock-lymphocytes. The dCAR138-38 showed increased specificity toward cells expressing both targeted antigens compared with single-antigen-expressing cells and low activity toward primary cells from healthy tissues. Our findings indicated that the dCAR138-38 may provide a potent and safe alternative therapy for patients with multiple myeloma.
Recent updates on CAR T clinical trials for multiple myeloma.
Lin Quande,Zhao Juanjuan,Song Yongping,Liu Delong
Proteasome inhibitors, immunomodulatory agents and monoclonal antibodies have dramatically changed the natural history of multiple myeloma (MM). However, most patients eventually suffer a relapse and succumb to the disease. Chimeric antigen receptor (CAR) engineered T cells targeting B cell maturation antigen (BCMA), CD138, CS1 glycoprotein antigen (SLAMF7) and light chains are in active development for therapy of refractory /relapsed (RR) MM. CD19- targeted CAR T cells in conjunction with autologous stem cell transplantation also showed activity in RRMM. Dual- target CAR T cells are in clinical trials for RRMM. This review summarized the recent updates of ongoing CAR T clinical trials for multiple myeloma.
Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions.
Caraccio Chiara,Krishna Sachi,Phillips Darci J,Schürch Christian M
Frontiers in immunology
Multiple myeloma (MM) is a plasma cell malignancy and the second most common hematological neoplasm in adults, comprising 1.8% of all cancers. With an annual incidence of ~30,770 cases in the United States, MM has a high mortality rate, leading to 12,770 deaths per year. MM is a genetically complex, highly heterogeneous malignancy, with significant inter- and intra-patient clonal variability. Recent years have witnessed dramatic improvements in the diagnostics, classification, and treatment of MM. However, patients with high-risk disease have not yet benefited from therapeutic advances. High-risk patients are often primary refractory to treatment or relapse early, ultimately resulting in progression toward aggressive end-stage MM, with associated extramedullary disease or plasma cell leukemia. Therefore, novel treatment modalities are needed to improve the outcomes of these patients. Bispecific antibodies (BsAbs) are immunotherapeutics that simultaneously target and thereby redirect effector immune cells to tumor cells. BsAbs have shown high efficacy in B cell malignancies, including refractory/relapsed acute lymphoblastic leukemia. Various BsAbs targeting MM-specific antigens such as B cell maturation antigen (BCMA), CD38, and CD138 are currently in pre-clinical and clinical development, with promising results. In this review, we outline these advances, focusing on BsAb drugs, their targets, and their potential to improve survival, especially for high-risk MM patients. In combination with current treatment strategies, BsAbs may pave the way toward a cure for MM.
Dual Targeting to Overcome Current Challenges in Multiple Myeloma CAR T-Cell Treatment.
van der Schans Jort J,van de Donk Niels W C J,Mutis Tuna
Frontiers in oncology
In the era of highly promising novel targeted-immunotherapy strategies for multiple myeloma (MM), the first series of clinical trials with CAR T-cells targeting the plasma cell-specific B-cell maturation antigen (BCMA) have shown excellent response rates. In the long-term, however, MM appears to escape the therapy likely due to initial low and heterogeneous expression or downregulation of BCMA expression. Several other molecules targeted by CAR T-cells in MM are expressed at high levels on MM cells, but many of these attractive targets are also expressed on various, sometimes vital non-malignant cells, posing major risks for on-target, off-tumor side effects. CAR T-cell therapy for MM therefore faces two urgent challenges: (i) improving the efficacy of BCMA CAR T-cells and (ii) establishing a MM-selectivity even when CAR T-cells are directed against not entirely MM-specific target antigens. In this review, we will outline the current attempts to tackle these challenges, with a specific focus on how dual CAR targeting might be applied to tackle both issues.
B-cell maturation antigen-specific chimeric antigen receptor T cells for multiple myeloma: Clinical experience and future perspectives.
Sellner Leopold,Fan Fuli,Giesen Nicola,Schubert Maria-Luisa,Goldschmidt Hartmut,Müller-Tidow Carsten,Dreger Peter,Raab Marc S,Schmitt Michael
International journal of cancer
Despite major advances in the treatment of multiple myeloma (MM), it remains a largely incurable disease with long-term control often dependent on continuous therapy. More effective, better tolerated treatments are therefore required to achieve durable remissions and to improve the quality of life of MM patients. Adoptive immunotherapy employing T cells expressing chimeric antigen receptors (CAR) is currently among the most promising treatment approaches in cancer. Within the target portfolio for MM immunotherapy, B-cell maturation antigen (BCMA) is among the most widely studied target antigens. BCMA is consistently expressed on MM cells and, importantly, is not expressed in critical healthy tissue. For this reason, it is an ideal target for MM immunotherapy. Several clinical trials evaluating different BCMA-targeting CAR constructs have been initiated and early results are very promising. However, in this rapidly developing clinical landscape, the ultimate role of BCMA-specific CAR-T cell therapy remains unclear. In this review, we will summarize currently available clinical data on BCMA-directed CAR-T cells and discuss potential future perspective for this promising treatment approach in MM.
B-cell maturation antigen expression across hematologic cancers: a systematic literature review.
Dogan Ahmet,Siegel David,Tran Nguyet,Fu Alan,Fowler Jessica,Belani Rajesh,Landgren Ola
Blood cancer journal
B-cell maturation antigen (BCMA) plays a critical role in regulating B-cell proliferation and survival. There is evidence for BCMA expression in various hematologic malignancies, suggesting that BCMA may play an important role as a biomarker or therapeutic target in these diseases. Given advances in understanding the role of BCMA in B-cell development and the promise of BCMA as a therapeutic target, a systematic review is needed to rigorously assess the evidence for BCMA expression and identify areas of consensus and future research. The objective of this review was to summarize the evidence on BCMA protein and mRNA expression across hematologic malignancies. Using a PubMed database search up to 28 August 2019, a systematic literature review of publications reporting BCMA expression in patients with hematologic malignancies was conducted. Data from published congress abstracts presented at the American Society of Clinical Oncology and the American Society of Hematology were also searched. Studies that assessed BCMA expression (protein or mRNA) in patients of any age with hematologic malignancies were included. A total of 21 studies met inclusion criteria and were included in the review. BCMA was expressed in several hematologic malignancies, including multiple myeloma (MM), chronic lymphocytic leukemia, acute B-lymphoblastic leukemia, non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma. BCMA was expressed at uniformly high levels across all 13 MM studies and at low to moderate levels in acute myeloid leukemia and acute lymphoblastic leukemia. These results suggest that BCMA is a relevant target in MM as well as in a subset of B-cell leukemia. BCMA expression in Hodgkin lymphoma and NHL varied across studies, and further research is needed to determine the utility of BCMA as an antibody target and biomarker in these diseases. Differences in sample type, timing of sample collection, and laboratory technique used may have affected the reporting of BCMA levels.
Phase 1 study of the anti-BCMA antibody-drug conjugate AMG 224 in patients with relapsed/refractory multiple myeloma.
Lee Hans C,Raje Noopur S,Landgren Ola,Upreti Vijay V,Wang Jin,Avilion Ariel A,Hu Xuguang,Rasmussen Erik,Ngarmchamnanrith Gataree,Fujii Hisaki,Spencer Andrew
Chimeric antigen receptor T cell therapy comes to clinical practice.
Wall D A,Krueger J
Current oncology (Toronto, Ont.)
Adoptive cellular therapy with chimeric antigen receptor T cells (car-ts) has recently received approval from Health Canada and the U.S. Food and Drug Administration after remarkable and durable remissions were seen in children with recurrent or refractory leukemia and adults with non-Hodgkin lymphoma-responses that were so impressive that a shift in the paradigm of care has now occurred for children with acute lymphoblastic leukemia. The concept behind car-t immunotherapy is that modification of a patient's own T cells to facilitate their localization to the cancer cell, with subsequent activation of the T cell effector mechanism and proliferation, will result in targeted killing of cancer cells. The car-ts are a novel drug in that the starting material for the manufacture of the car-t product comes from the patient, whose viable T cells are then genetically modified. Thus, collaboration is needed between the pharmaceutical companies, which must meet good manufacturing standards for each patient's unique product, and the treating sites. For regulators and health authorities, this new class of drugs requires new paradigms for assessment and approval. Treatments with car-ts require that institutions address unique logistics requirements and management of novel toxicities. The Hospital for Sick Children has had early experience with both the licensing of clinical trials and the introduction of the first commercial product. Here, we provide an overview of basic concepts and treatment, with caveats drawn from what we have learned thus far in bringing this new therapy to the clinical front line.
Chimeric antigen receptor T cell therapy in multiple myeloma: promise and challenges.
Dhakal Binod,Hari Parameswaran N,Usmani Saad Z,Hamadani Mehdi
Bone marrow transplantation
Despite a sea change in the therapeutic landscape, multiple myeloma (MM), a cancer of antibody producing plasma cells, remains incurable requiring continued intervention for disease control. In this context, chimeric antigen receptor (CAR) T cell therapy has emerged as a promising immunotherapeutic approach with unprecedented results in heavily treated relapsed and/or refractory MM patients. Although B cell maturation antigen (BCMA) is the current lead target for CAR-T cell therapy in MM, several other antigenic targets are also being investigated. Relapses, however, are inevitable in spite of the promising early responses, and may be mediated by antigenic modulation, poor persistence and "immunostat" in tumor microenvironment. Akin to multi-agent chemotherapy, multi-targeted CAR-T antigens and combinatorial approaches are underway to overcome the resistance mechanisms. Further, CAR-T specific toxicity concerns such as cytokine release syndrome and neurotoxicity, as well as manufacturing time lag are other key challenges. Allogeneic CAR that offers "off-the-shelf" options, and mRNA transfected CAR are being developed to mitigate the access and safety issues. In this review we provide the comprehensive review of the most current clinical trial data for CAR-T in myeloma, challenges associated with this therapy and discuss its future in myeloma therapeutics.
Side-effect management of chimeric antigen receptor (CAR) T-cell therapy.
Schubert M-L,Schmitt M,Wang L,Ramos C A,Jordan K,Müller-Tidow C,Dreger P
Annals of oncology : official journal of the European Society for Medical Oncology
Chimeric antigen receptor (CAR) T cells directed against the B-cell marker CD19 are currently changing the landscape for treatment of patients with refractory and/or relapsed B-cell malignancies. Due to the nature of CAR T cells as living drugs, they display a unique toxicity profile. As CAR T-cell therapy is extending towards other diseases and being more broadly employed in hematology and oncology, optimal management strategies of side-effects associated with CAR T-cell therapy are of high relevance. Cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and cytopenias constitute challenges in the treatment of patients with CAR T cells. This review summarizes the current understanding of CAR T-cell toxicity and its management.
The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of multiple myeloma.
Shah Nina,Aiello Jack,Avigan David E,Berdeja Jesus G,Borrello Ivan M,Chari Ajai,Cohen Adam D,Ganapathi Karthik,Gray Lissa,Green Damian,Krishnan Amrita,Lin Yi,Manasanch Elisabet,Munshi Nikhil C,Nooka Ajay K,Rapoport Aaron P,Smith Eric L,Vij Ravi,Dhodapkar Madhav
Journal for immunotherapy of cancer
Outcomes in multiple myeloma (MM) have improved dramatically in the last two decades with the advent of novel therapies including immunomodulatory agents (IMiDs), proteasome inhibitors and monoclonal antibodies. In recent years, immunotherapy for the treatment of MM has advanced rapidly, with the approval of new targeted agents and monoclonal antibodies directed against myeloma cell-surface antigens, as well as maturing data from late stage trials of chimeric antigen receptor CAR T cells. Therapies that engage the immune system to treat myeloma offer significant clinical benefits with durable responses and manageable toxicity profiles, however, the appropriate use of these immunotherapy agents can present unique challenges for practicing physicians. Therefore, the Society for Immunotherapy of Cancer convened an expert panel, which met to consider the current role of approved and emerging immunotherapy agents in MM and provide guidance to the oncology community by developing consensus recommendations. As immunotherapy evolves as a therapeutic option for the treatment of MM, these guidelines will be updated.
CAR T-Cells in Multiple Myeloma: State of the Art and Future Directions.
Rodríguez-Lobato Luis Gerardo,Ganzetti Maya,Fernández de Larrea Carlos,Hudecek Michael,Einsele Hermann,Danhof Sophia
Frontiers in oncology
Despite recent therapeutic advances, the prognosis of multiple myeloma (MM) patients remains poor. Thus, new strategies to improve outcomes are imperative. Chimeric antigen receptor (CAR) T-cell therapy has changed the treatment landscape of B-cell malignancies, providing a potentially curative option for patients who are refractory to standard treatment. Long-term remissions achieved in patients with acute lymphoblastic leukemia and Non-Hodgkin Lymphoma encouraged its further development in MM. B-cell maturation antigen (BCMA)-targeted CAR T-cells have established outstanding results in heavily pre-treated patients. However, several other antigens such as SLAMF7 and CD44v6 are currently under investigation with promising results. Idecabtagene vicleucel is expected to be approved soon for clinical use. Unfortunately, relapses after CAR T-cell infusion have been reported. Hence, understanding the underlying mechanisms of resistance is essential to promote prevention strategies and to enhance CAR T-cell efficacy. In this review we provide an update of the most recent clinical and pre-clinical data and we elucidate both, the potential and the challenges of CAR T-cell therapy in the future.
CAR T cell therapy.
Chimeric antigen receptor (CAR) is generated by fusing a cancer-specific antibody's antigen recognition site with costimulatory molecules such as CD28 and CD3ζ. T cells transduced with CAR recognizes cancer-specific antigens and kill cancer cells. The effect of CD19-targeted CAR T cells on B-cell hematologic cancer is surprising and has already been approved in many countries including Japan. More targets for several kinds of cancers are being searched now. We have also shown that CAR T cells specific for activated integrin β7 are highly effective for multiple myeloma in pre-clinical tests.
Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data.
Roex Gils,Feys Tom,Beguin Yves,Kerre Tessa,Poiré Xavier,Lewalle Philippe,Vandenberghe Peter,Bron Dominique,Anguille Sébastien
Chimeric antigen receptor (CAR)-T-cell therapy is an innovative form of adoptive cell therapy that has revolutionized the treatment of certain hematological malignancies, including B-cell non-Hodgkin lymphoma (NHL) and B-cell acute lymphoblastic leukemia (ALL). The treatment is currently also being studied in other B-cell neoplasms, including multiple myeloma (MM) and chronic lymphocytic leukemia (CLL). CD19 and B-cell maturation antigen (BCMA) have been the most popular target antigens for CAR-T-cell immunotherapy of these malignancies. This review will discuss the efficacy and toxicity data from the pivotal clinical studies of CD19- and BCMA-targeted CAR-T-cell therapies in relapsed/refractory B-cell malignancies (NHL, ALL, CLL) and MM, respectively.
BCMA-targeting approaches for treatment of multiple myeloma.
Chen Yunxin,Nagarajan Chandramouli,Tan Melinda S,Martinelli Giovanni,Cerchione Claudio
Recent advances in treatment modalities have led to improved survival in patients with multiple myeloma (MM). However, despite these, MM remains an incurable disease. Many MM patients relapse through and become refractory to current treatment strategies or are intolerant due to toxicities arising from therapy. As such, novel strategies addressing new targets are crucial in improving care for MM patients. BCMA has emerged as a rationale therapeutic target for treatment of MM as it is preferentially expressed in mature B-lymphocytes and plasma cells with the overexpression and activation of BCMA via its ligands associated with the disease progression in multiple myeloma. Given the high expression of BCMA in malignant Plasma cells compared to those from normal healthy volunteers, targeting BCMA should reduce risks of on-target off-tumor toxicities. The main BCMA-targeting approaches currently used for treatment of MM include: 1) chimeric antigen receptor (CAR) T-cell therapy; 2) bi- and multi- specific antibodies; and 3) monoclonal antibodies and their drug conjugates. This review will outline these therapeutic agents and present their emerging clinical data.
Preclinical evaluation of CD8+ anti-BCMA mRNA CAR T cells for treatment of multiple myeloma.
Lin Liang,Cho Shih-Feng,Xing Lijie,Wen Kenneth,Li Yuyin,Yu Tengteng,Hsieh Phillip A,Chen Hailin,Kurtoglu Metin,Zhang Yi,Andrew Stewart C,Munshi Nikhil,Anderson Kenneth C,Tai Yu-Tzu
Chimeric antigen receptor (CAR) T-cell therapy remains limited to select centers that can carefully monitor adverse events. To broaden use of CAR T cells in community clinics and in a frontline setting, we developed a novel CD8+ CAR T-cell product, Descartes-08, with predictable pharmacokinetics for treatment of multiple myeloma. Descartes-08 is engineered by mRNA transfection to express anti-BCMA CAR for a defined length of time. Descartes-08 expresses anti-BCMA CAR for 1 week, limiting risk of uncontrolled proliferation; produce inflammatory cytokines in response to myeloma target cells; and are highly cytolytic against myeloma cells regardless of the presence of myeloma-protecting bone marrow stromal cells, exogenous a proliferation-inducing ligand, or drug resistance including IMiDs. The magnitude of cytolysis correlates with anti-BCMA CAR expression duration, indicating a temporal limit in activity. In the mouse model of aggressive disseminated human myeloma, Descartes-08 induces BCMA CAR-specific myeloma growth inhibition and significantly prolongs host survival (p < 0.0001). These preclinical data, coupled with an ongoing clinical trial of Descartes-08 in relapsed/refractory myeloma (NCT03448978) showing preliminary durable responses and a favorable therapeutic index, have provided the framework for a recently initiated trial of an optimized/humanized version of Descartes-08 (i.e., Descartes-11) in newly diagnosed myeloma patients with residual disease after induction therapy.
Allogeneic haematopoietic stem cell transplantation improves outcome of adults with relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia entering remission following CD19 chimeric antigen receptor T cells.
Gu Bin,Shi Bing-Yu,Zhang Xiang,Zhou Shi-Yuan,Chu Jian-Hong,Wu Xiao-Jin,Fu Cheng-Cheng,Qiu Hui-Ying,Han Yue,Chen Su-Ning,Yu Lei,Ma Xiao,Wu De-Pei
Bone marrow transplantation
Relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (r/r Ph+ ALL) has an extremely poor prognosis. Chimeric antigen receptor T-cell (CART) therapy has acquired unprecedented efficacy in B-cell malignancies, but its role in the long-term survival of r/r Ph+ ALL patients is unclear. We analyzed the effect of CART on 56 adults with r/r Ph+ ALL who accepted split doses of humanized CD19-targeted CART after lymphodepleting chemotherapy. 51/56 (91.1%) achieved complete remission (CR) or CR with inadequate count recovery (CRi), including 38 patients with negative minimal residual disease (MRD) tested by bone marrow BCR-ABL1 copies. Subsequently, 30/51 CR/CRi patients accepted consolidative allogeneic haematopoietic stem cell transplantation (alloHSCT). Their outcomes were compared with those of 21/51 contemporaneous patients without alloHSCT. The 2-year overall survival (OS) and leukemia-free survival (LFS) of CR/CRi patients with alloHSCT were significantly superior to those without alloHSCT (58.9%, CI 49.8-68.0% vs. 22.7%, CI 12.7-32.7%, p = 0.005; 53.2%, CI 43.6-62.8% vs. 18.8%, CI 9.2-28.4%, p = 0.000, respectively). Multivariate analysis revealed that alloHSCT and MRD-negative post-CART were the independent prognostic factors for OS and LFS. CART therapy is highly effective for r/r Ph+ ALL patients, and consolidative alloHSCT could prolong their OS and LFS.
Management of adults and children undergoing chimeric antigen receptor T-cell therapy: best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE).
Yakoub-Agha Ibrahim,Chabannon Christian,Bader Peter,Basak Grzegorz W,Bonig Halvard,Ciceri Fabio,Corbacioglu Selim,Duarte Rafael F,Einsele Hermann,Hudecek Michael,Kersten Marie José,Köhl Ulrike,Kuball Jürgen,Mielke Stephan,Mohty Mohamad,Murray John,Nagler Arnon,Robinson Stephen,Saccardi Riccardo,Sanchez-Guijo Fermin,Snowden John A,Srour Micha,Styczynski Jan,Urbano-Ispizua Alvaro,Hayden Patrick J,Kröger Nicolaus
Chimeric antigen receptor (CAR) T cells are a novel class of anti-cancer therapy in which autologous or allogeneic T cells are engineered to express a CAR targeting a membrane antigen. In Europe, tisagenlecleucel (Kymriah™) is approved for the treatment of refractory/relapsed acute lymphoblastic leukemia in children and young adults as well as relapsed/refractory diffuse large B-cell lymphoma, while axicabtagene ciloleucel (Yescarta™) is approved for the treatment of relapsed/refractory high-grade B-cell lymphoma and primary mediastinal B-cell lymphoma. Both agents are genetically engineered autologous T cells targeting CD19. These practical recommendations, prepared under the auspices of the European Society of Blood and Marrow Transplantation, relate to patient care and supply chain management under the following headings: patient eligibility, screening laboratory tests and imaging and work-up prior to leukapheresis, how to perform leukapheresis, bridging therapy, lymphodepleting conditioning, product receipt and thawing, infusion of CAR T cells, short-term complications including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, antibiotic prophylaxis, medium-term complications including cytopenias and B-cell aplasia, nursing and psychological support for patients, long-term follow-up, post-authorization safety surveillance, and regulatory issues. These recommendations are not prescriptive and are intended as guidance in the use of this novel therapeutic class.
Chimeric Antigen Receptor T Cell Therapy for Acute Lymphoblastic Leukemia.
Badar Talha,Shah Nirav N
Current treatment options in oncology
OPINION STATEMENT:Chimeric receptor antigen (CAR) T cells are an innovative cellular immunotherapeutic approach that involves genetic modification of T cells to express CAR targeting tumor antigen. Prior to the development of CAR-T, the only potential cure for patients with relapsed or refractory (RR) acute lymphoblastic leukemia (ALL) was allogeneic hematopoietic stem cell transplantation (HSCT). Several CAR-T cell products have been studied in prospective clinical trials which ultimately have resulted in the approval of one anti-CD19 CAR-T cell product in pediatric RR ALL: tisagenlecleucel (CD3ζ and 41BB). While some patients achieve durable responses with CAR-T, lack of response and relapse remains clinical challenges. Reasons for sub-optimal response include lack of CAR-T cell persistence and target antigen down-regulation. Future CARs are under development to improve long-term persistence and to be able to overcome resistance mechanisms associated with the disease and the hostile tumor microenvironment. With evolving understanding about CARs and new constructs under investigation, there is optimism that future products will improve the safety and efficacy from the current standard of care.
The incidence of cytokine release syndrome and neurotoxicity of CD19 chimeric antigen receptor-T cell therapy in the patient with acute lymphoblastic leukemia and lymphoma.
Cao Jun-Xia,Wang Hui,Gao Wei-Jian,You Jia,Wu Li-Hua,Wang Zheng-Xu
Our objective was to summarize the side effect of chimeric antigen receptor (CAR)-T cell therapy in patients with acute lymphocytic leukemia (ALL) and lymphoma. Two independent reviewers extracted relevant data. A total of 35 hematologic malignancy studies with CD19 CAR-T cell were included (1412 participants). Severe cytokine release syndrome (sCRS) proportion was experienced by 18.5% (95% confidence interval [CI], 0.128-0.259; P = 0.000) of 982 patients with the National Cancer Institute/Lee/common terminology criteria for adverse events grading system. The pooled neurotoxicity proportion was 21.7% (95% CI, 0.167-0.287; P = 0.000) of 747 patients with the same grading system. For all of the 25 clinical trials with the same grading system, subgroup analysis was performed. Based on the different disease type, a pooled prevalence of 35.7% was observed with event rate (ER) of 0.358 (95% CI, 0.289-0.434; P = 0.000) for ALL in 12 clinical trials. For lymphoma, a pooled prevalence of 13% was observed with ER of 0.073 (95% CI, 0.028-0.179; P = 0.000) in eight clinical trials. It was demonstrated that the patients who were older than 18 years of age have the lower sCRS incidence of 16.1% (95% CI, 0.110-0.250; P = 0.000) compared with 28.6% of the remaining population who were younger than 18 years of age (95% CI, 0.117-0.462: P = 0.023) in our analysis. Based on the different co-stimulatory domain, the sCRS of 16.5% was observed with ER of 0.175 (95% CI, 0.090-0.312; P = 0.000) for 4-1BB. The sCRS of 22.2% was observed with ER of 0.193 (95% CI, 0.107-0.322; P = 0.000) for CD28. For both the CD28 and 4-1BB, the sCRS of 17.3% was observed with ER of 0.170 (95% CI, 0.067-0.369; P = 0.003). Sub-analysis sCRS of the impact with cell dose and specific disease indication were also demonstrated. Limitations include heterogeneity of study populations, as well as high risk of bias of included studies. These results are helpful for physicians, patients and the other stakeholders to understand the adverse events and to further promote the improvement of CAR-T cell therapy in the future.
Identification of Neurotoxicity after Chimeric Antigen Receptor (CAR) T Cell Infusion without Deterioration in the Immune Effector Cell Encephalopathy (ICE) Score.
Herr Megan M,Chen George L,Ross Maureen,Jacobson Hillary,McKenzie Renee,Markel Laura,Balderman Sophia R,Ho Christine M,Hahn Theresa,McCarthy Philip L
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
A consensus grading schema for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) resulting from chimeric antigen receptor (CAR) T cell therapy was published in 2019. Although this consensus grading schema has been imperative in identifying and monitoring CRS and ICANS in our CAR T cell population, we observed patients exhibiting subtle neurotoxicity symptoms prior to a decrease in their immune effector cell (ICE) score, which is one component of ICANS. Because we treat grade 1 ICANS at our institution, identification of early neurotoxicity symptoms is important. Additionally, we found changes in personality, occupational confusion, or inability to answer dichotomous questions were early signs of neurotoxicity. Therefore, we developed a 3-step command tool to supplement the ICE evaluation. We present 2 examples of patients who exhibited early neurotoxicity symptoms and led us to develop this tool and 1 in whom it was effective. We propose that CAR T cell patients are consistently followed by a clinical care provider who is familiar with the patient to recognize early changes in personality, behavior, and cognition. Additionally, we propose that the multistep command tool be used in conjunction with the ICE score to detect early symptoms of ICANS. Early intervention has the potential to prevent irreversible neurotoxicity.
Treatment response, survival, safety, and predictive factors to chimeric antigen receptor T cell therapy in Chinese relapsed or refractory B cell acute lymphoblast leukemia patients.
Li Limin,Liu Jie,Xu Mengyuan,Yu Hongjuan,Lv Chengfang,Cao Fenglin,Wang Zhenkun,Fu Yueyue,Zhang Mingwen,Meng Hongbin,Zhang Xiaoqian,Kang Liqing,Zhang Zhuo,Li Jinmei,Feng Jiawei,Lian Xin,Yu Lei,Zhou Jin
Cell death & disease
This study aimed to evaluate treatment response, survival, safety profiles, and predictive factors to chimeric antigen receptor T cell (CAR-T) therapy in Chinese patients with relapsed or refractory B cell acute lymphoblast leukemia (R/R B-ALL). 39R/R B-ALL patients who underwent CAR-T therapy were included. Baseline data were collected from patients' electronic medical records. Patients' peripheral bloods, bone marrow aspirates, and biopsies were obtained for routine examination, and treatment response and survival profiles as well as adverse events were evaluated. The rates of complete remission (CR), CR with minimal residual disease (MRD) negative/positive, and bridging to hematopoietic stem-cell transplantation (HSCT) were 92.3%, 76.9%, 15.4%, and 43.6%, respectively. The median event-free survival (EFS) was 11.6 months (95% confidence interval (CI): 4.0-19.2 months) and median overall survival (OS) was 14.0 months (95% CI: 10.9-17.1 months). Bridging to HSCT independently predicted better EFS and OS, while high bone marrow blasts level independently predicted worse EFS. The incidence of cytokine release syndrome (CRS) was 97.4%, and refractory disease as well as decreased white blood cell independently predicted higher risk of severe CRS. Other common adverse events included hematologic toxicities (grade I: 5.1%, grade II: 7.7%, grade III: 17.9%, grade IV: 69.2%), neurotoxicity (28.2%), infection (38.5%), and admission for intensive care unit (10.3%). In conclusion, CAR-T therapy presents with promising treatment response, survival and safety profiles, and higher disease burden predicts worse survival as well as increased risk of severe CRS in Chinese R/R B-ALL patients.
CD4/CD8 T-Cell Selection Affects Chimeric Antigen Receptor (CAR) T-Cell Potency and Toxicity: Updated Results From a Phase I Anti-CD22 CAR T-Cell Trial.
Shah Nirali N,Highfill Steven L,Shalabi Haneen,Yates Bonnie,Jin Jianjian,Wolters Pamela L,Ombrello Amanda,Steinberg Seth M,Martin Staci,Delbrook Cindy,Hoffman Leah,Little Lauren,Ponduri Anusha,Qin Haiying,Qureshi Haris,Dulau-Florea Alina,Salem Dalia,Wang Hao-Wei,Yuan Constance,Stetler-Stevenson Maryalice,Panch Sandhya,Tran Minh,Mackall Crystal L,Stroncek David F,Fry Terry J
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE:Patients with B-cell acute lymphoblastic leukemia who experience relapse after or are resistant to CD19-targeted immunotherapies have limited treatment options. Targeting CD22, an alternative B-cell antigen, represents an alternate strategy. We report outcomes on the largest patient cohort treated with CD22 chimeric antigen receptor (CAR) T cells. PATIENTS AND METHODS:We conducted a single-center, phase I, 3 + 3 dose-escalation trial with a large expansion cohort that tested CD22-targeted CAR T cells for children and young adults with relapsed/refractory CD22 malignancies. Primary objectives were to assess the safety, toxicity, and feasibility. Secondary objectives included efficacy, CD22 CAR T-cell persistence, and cytokine profiling. RESULTS:Fifty-eight participants were infused; 51 (87.9%) after prior CD19-targeted therapy. Cytokine release syndrome occurred in 50 participants (86.2%) and was grade 1-2 in 45 (90%). Symptoms of neurotoxicity were minimal and transient. Hemophagocytic lymphohistiocytosis-like manifestations were seen in 19/58 (32.8%) of subjects, prompting utilization of anakinra. CD4/CD8 T-cell selection of the apheresis product improved CAR T-cell manufacturing feasibility as well as heightened inflammatory toxicities, leading to dose de-escalation. The complete remission rate was 70%. The median overall survival was 13.4 months (95% CI, 7.7 to 20.3 months). Among those who achieved a complete response, the median relapse-free survival was 6.0 months (95% CI, 4.1 to 6.5 months). Thirteen participants proceeded to stem-cell transplantation. CONCLUSION:In the largest experience of CD22 CAR T-cells to our knowledge, we provide novel information on the impact of manufacturing changes on clinical outcomes and report on unique CD22 CAR T-cell toxicities and toxicity mitigation strategies. The remission induction rate supports further development of CD22 CAR T cells as a therapeutic option in patients resistant to CD19-targeted immunotherapy.
Long-term follow-up of CD19 chimeric antigen receptor T-cell therapy for relapsed/refractory acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation.
Chen Yu-Hong,Zhang Xian,Cheng Yi-Fei,Chen Huan,Mo Xiao-Dong,Yan Chen-Hua,Chen Yao,Han Wei,Sun Yu-Qian,Wang Yu,Zhang Xiao-Hui,Xu Lan-Ping,Liu Kai-Yan,Yang Junfang,Zhang Jianping,Zhang Gai-Ling,Shi Yanze,Su Yun-Chao,Li Wen-Qian,Xu Li,Song Dan,Zhang Min,Lu Peihua,Huang Xiao-Jun
BACKGROUND AIMS:The efficacy of CD19-targeted chimeric antigen receptor T (CAR T) cells for treatment of relapsed B-cell malignancies after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the long-term outcomes of these patients remain inconclusive. METHODS:The authors focused on the survival of 35 patients with B-cell acute lymphoblastic leukemia who relapsed after allo-HSCT and received CAR T cells. RESULTS:Of the 34 eligible patients, 30 achieved minimal residual disease-negative complete remission (CR), with a total CR rate of 85.7% (79.8-91.6%). There were 14 patients who received various forms of additional therapy after achieving CR. After a median follow-up of 20.7 months, it was noted that 17 patients had relapsed at a median of 4.5 months (2-34 months). The cumulative recurrence rate (RR) at 18 months was 68.3% (57.6-79.0%). Additional treatment did not reduce the RR but seemed to delay the time to relapse (mean: 5.9 months vs 13.1 months; P = 0.046). Patients with a lower tumor burden (≤10%) had a lower RR (25.0% vs 78.6% at 12 months; P = 0.006). The overall survival (OS) rate for the CR patients was 30.0% (20.3-29.7%) at 18 months, with a median OS of 12.7 months. CONCLUSIONS:The authors' study indicated that for patients who relapsed after HSCT, although a high CR rate was achieved after CAR T therapy, the long-term efficacy was unsatisfactory. It is necessary to optimize additional treatment, including a second HSCT, to further improve long-term efficacy after CAR T infusion.
The long road to the first FDA-approved gene therapy: chimeric antigen receptor T cells targeting CD19.
Braendstrup Peter,Levine Bruce L,Ruella Marco
Thirty years after initial publications of the concept of a chimeric antigen receptor (CAR), the U.S. Food and Drug Administration (FDA) approved the first anti-CD19 CAR T-cell therapy. Unlike other immunotherapies, such as immune checkpoint inhibitors and bispecific antibodies, CAR T cells are unique as they are "living drugs," that is, gene-edited killer cells that can recognize and kill cancer. During these 30 years of development, the CAR construct, T-cell manufacturing process, and clinical patient management have gone through rounds of failures and successes that drove continuous improvement. Tisagenlecleucel was the first gene therapy to receive approval from the FDA for any indication. The initial approval was for relapsed or refractory (r/r) pediatric and young-adult B-cell acute lymphoblastic leukemia in August 2017 and in May 2018 for adult r/r diffuse large B-cell lymphoma. Here we review the preclinical and clinical development of what began as CART19 at the University of Pennsylvania and later developed into tisagenlecleucel.
Anti-CD19 chimeric antigen receptor T-cell therapy in acute lymphocytic leukaemia: a systematic review and meta-analysis.
Anagnostou Theodora,Riaz Irbaz B,Hashmi Shahrukh K,Murad Mohammad H,Kenderian Saad S
The Lancet. Haematology
BACKGROUND:Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable activity in patients with refractory or relapsed acute lymphocytic leukaemia. Various anti-CD19 CAR T-cell constructs have been trialled and responses vary widely among different studies. We aimed to systematically analyse the outcomes of patients with acute lymphocytic leukaemia treated with anti-CD19 CAR T cells and identify factors associated with differences in outcomes. METHODS:We did a systematic review and meta-analysis of published and unpublished clinical trials that reported data on the outcomes of adult or paediatric patients that were treated with anti-CD19 CAR T cells for relapsed or refractory B-cell acute lymphocytic leukaemia, reported between Jan 1, 2012, and April 14, 2020. Studies with two patients or fewer were excluded and summary data were extracted from the reports. The primary outcome was the number of patients who had complete remission at any time after anti-CD19 CAR T-cell infusion. This study is not registered in PROSPERO. FINDINGS:From 1160 studies, we identified 40 potentially appropriate studies, 35 (88%) of which met the eligibility criteria and were included in the final analysis (n=953 patients). The pooled complete remission was 80% (95% CI 75·5-84·8) and heterogeneity between studies was moderate (I=56·96%). In the prespecified subgroup analyses, 195 (75% [95% CI 66·9-82·9, I=35·22%]) of 263 patients in adult studies and 242 (81% [72·9-87·2, I=54·45%]) of 346 patients in paediatric studies achieved complete remission, p=0·24. The pooled complete remission did not significantly differ with anti-CD19 CAR T-cell construct type or single-chain variable fragment clone, but was higher with autologous T-cell origin (727 [83%, 78·5-86·5, I=44·34%] of 901 patients), compared with allogeneic T-cell origin (29 [55%, 30·6-79·0, I=62·64%] of 52 patients; p=0·018). 242 (26% [95% CI 18·5-34·1]) of 854 patients developed grade 3 or worse cytokine release syndrome and 97 (12% [6·6-19·2]) of 532 developed grade 3 or worse neurotoxicity. There was no difference in the proportion of patients who achieved complete remission or who had cytokine release syndrome or neurotoxicity between different anti-CD19 CAR T-cell constructs. The risk of bias was assessed as low in 17 studies and moderate in 18 studies. INTERPRETATION:The high response rates after anti-CD19 CAR T-cell therapy can be used to guide the use of therapy in patients with relapsed or refractory acute lymphocytic leukaemia. Comparison studies are required to further determine differences in efficacy between different anti-CD19 CAR T-cell constructs in the setting of relapsed or refractory acute lymphocytic leukaemia. FUNDING:National Cancer Institute, National Comprehensive Cancer Network, Mayo Clinic K2R Research Pipeline, and Mayo Clinic Center for Individualized Medicine.
Updates in Chimeric Antigen Receptor T-Cell (CAR-T) Therapy for Lymphoma and Leukemia from the Annual Meeting of American Society of Hematology 2019.
Bukhari Ali,Siglin Jonathan,Lutfi Forat,Kansagra Ankit J,Yared Jean,Rapoport Aaron P,Dahiya Saurabh
Critical reviews in oncology/hematology
Chimeric Antigen Receptor T-cell (CAR-T) therapy has revolutionized the field of hematologic malignancies and are potentially curative in patients with previously limited options. This review highlights key abstracts focusing on clinical studies in CAR-T therapy in leukemia and lymphoma presented at the 61 st annual meeting of the American Society of Hematology (December 2019, Orlando, FL). Selected studies discuss data on novel CAR-T constructs aimed at enhancing efficacy and durability of responses, improving toxicity mitigation strategies, challenging clinical scenarios in routine clinical practice for standard of care CAR-T therapy (role of bridging therapy, CNS involvement, and quality of life studies), and new technologies aiming to decrease production time to minimize delay in definitive therapy, all within the rapidly-evolving cellular immunotherapy landscape.
Complete remission in refractory acute lymphoblastic leukemia using blinatumomab after failure of response to CD-19 chimeric antigen receptor T-cell therapy.
Tambaro Francesco Paolo,Khazal Sajad,Nunez Cesar,Ragoonanan Dristhi,Tewari Priti,Petropoulos Demetrios,Kebriaei Partow,Wierda William George,Mahadeo Kris Michael
Clinical case reports
The T-cell engager monoclonal antibody, blinatumomab, is a potential therapeutic strategy for refractory B acute lymphoblastic leukemia after failure of CD 19 chimeric antigen receptor T-cell therapy.
Exploring the Dilemma of Allogeneic Hematopoietic Cell Transplantation after Chimeric Antigen Receptor T Cell Therapy: To Transplant or Not?
Bouziana Stella,Bouzianas Dimitrios
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
Patients with refractory or relapsed (R/R) B cell acute lymphoblastic leukemia (B-ALL) and highly aggressive B cell non-Hodgkin lymphoma (B-NHL) have a very dismal prognosis and limited treatment options. The advent of chimeric antigen receptor (CAR) T cell therapy constitutes a milestone in current cell and gene therapies, covering the unmet need of treatment of high-risk patients and bringing immunotherapies one step closer toward cancer therapeutics, including hematologic malignancies. CAR T cells targeting CD19 antigen have shown startling remission rates in heavily pretreated B-ALL and B-NHL patients, in whom CAR T cell therapy may sometimes be their last-resort treatment. However, a high proportion of these patients evade immune surveillance by CAR T cells losing their initial deep responses, which leads to disease recurrence as either CD19-positive or CD19-negative relapse. As a result, many investigators have questioned the need for consolidative allogeneic hematopoietic stem cell transplantation (allo-HCT) after CAR T cell therapy, once a patient has achieved remission. There remains much controversy regarding whether CAR T cells should be a bridge therapy to allo-HCT or a definitive treatment, owing to the paucity of strong evidence-based data. In this context, here we review the existing data regarding the necessity, safety, and outcomes of allo-HCT performed after autologous anti-CD19 CAR T cell therapy in B-ALL and B-NHL patients.
Advances in the development of chimeric antigen receptor-T-cell therapy in B-cell acute lymphoblastic leukemia.
Zhang Xian,Li Jing-Jing,Lu Pei-Hua
Chinese medical journal
CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy is effective in refractory/relapsed (R/R) B-cell acute lymphoblastic leukemia (B-ALL). This review focuses on achievements, current obstacles, and future directions in CAR-T research. A high complete remission rate of 68% to 93% could be achieved after anti-CD19 CAR-T treatment for B-ALL. Cytokine release syndrome and CAR-T-related neurotoxicity could be managed. In view of difficulties collecting autologous lymphocytes, universal CAR-T is a direction to explore. Regarding the high relapse rate after anti-CD19 CAR-T therapy, the main solutions have been developing new targets including CD22 CAR-T, or CD19/CD22 dual CAR-T. Additionally, some studies showed that bridging into transplant post-CAR-T could improve leukemia-free survival. Some patients who did not respond to CAR-T therapy were found to have an abnormal conformation of the CD19 exon or trogocytosis. Anti-CD19 CAR-T therapy for R/R B-ALL is effective. From individual to universal CAR-T, from one target to multi-targets, CAR-T-cell has a chance to be off the shelf in the future.
A brief review concerning Chimeric Antigen Receptors T cell therapy.
Li Ling-Lin,Yuan Hong-Ling,Yang Yu-Qiong,Wang Lin,Zou Ren-Chao
Journal of Cancer
The understanding concerning the function of immune system in cancer has achieved considerable advance with time passes by. Manipulating genetically engineered immune cells were investigated as a novel strategy for treating cancer. Chimeric antigen receptors (CARs) are recombinant protein molecules by merging the exquisite targeting the potent cytotoxicity of T cells and specificity of monoclonal antibodies and, which could trigger serial cascades of signal transduction and thereby activate T cells to directly destroy the tumor cells. Manufacturing CAR-modified T lymphocytes were successfully implemented in treating cancer derived from they could specifically retarget tumor-associated antigens, causing effective elimination of tumor cells, which spurred the optimization and development of new CAR-T cell technology. The advancement of synthetic biology methodologies of cell therapy in CAR-T would ultimately provide us with a much safer, reliable and efficient modality to against cancer. This review primarily described the emergence, development and application of cell therapy in CAR-T, then discuss the side effects and the potential factors of tumor reccurrence caused by CAR-T cell therapy, in addition to the corresponding countermeasure concerning complications.
Pre-clinical assessment of chimeric antigen receptor t cell therapy targeting CD19+ B cell malignancy.
Hu Sheng-I,Ko Ming-Chin,Dai Yi-Han,Lin Hsin-An,Chen Lih-Chyang,Huang Kuo-Yang,Pang Te-Ling,Kuo Cheng-Yi,Lin Hsin-Chung
Annals of translational medicine
Background:Autologous chimeric antigen receptor (CAR) T cell therapy is a promising therapeutic strategy for treating hematologic malignancies. A spectrum of serious complications caused by CAR-T cells has caught great attention. We developed a novel CAR against CD19 namely UWC19, consisting anti-CD19 single-chain variable fragment (scFv) hinged with 4-1BB and CD3z signaling domains. In this study, preclinical assessments of UWC19 were conducted to evaluate the safety and efficacy and . Methods:To evaluate the binding activity of UWC19 cells to CD19, we measured the saturation degree of CAR with human CD19 molecules using flow cytometry . The antitumor efficacy of UWC19 cells was determined by in vitro cytotoxicity assay against CD19 positive cells and in vivo using a xenograft mouse model. Cross tissue reactivity of UWC19 cells was examined by co-culturing with cell lines from difference human tissues. Tumorigenicity was determined by subcutaneously injecting UWC19 in immunodeficient mice. Persistence was analyzed using quantitative PCR. Results:We showed that UWC19 CAR T cells exerted highly specific binding affinity and cytotoxicity against CD19+ cells . , UWC19 CAR T cells are able to fully control disease progression in a Raji-xenografted immunodeficient mouse model. UWC19 exerted no obvious effects on the mean body mass and graft versus host disease were observed in surviving mice. We showed that UWC19 cells specifically recognized and eliminated CD19 positive cells, whereas CD19 negative cells were much less affected. No tumorigenicity of UWC19 in immunodeficient mice was observed. Conclusions:UWC19 treatment effectively eliminated CD19 positive tumor cells with favorable toxicity profile. The findings suggest encouraging clinical prospects for its use in patients with CD19 positive B cell malignancies. Our study presented an alternative evaluation strategy for CAR-T cell products.
Chimeric Antigen Receptor T Cell Therapy in Patients with Multiply Relapsed or Refractory Extramedullary Leukemia.
Rubinstein Jeremy D,Krupski Christa,Nelson Adam S,O'Brien Maureen M,Davies Stella M,Phillips Christine L
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
Autologous CD19-directed chimeric antigen receptor T lymphocyte (CAR-T) therapy is an approved and effective treatment for the management of patients with refractory and multiply relapsed B cell precursor acute lymphoblastic leukemia (B-ALL). Experience using this therapy in pediatric patients with extramedullary (EM) disease is limited, in part because these patients have frequently been excluded from clinical trials owing to concerns for an increased risk of immune effector cell-associated neurotoxicity syndrome (ICANS). We infused 7 patients with refractory or multiply relapsed B-ALL who presented with isolated EM relapse with tisagenlecleucel. Six patients had isolated central nervous system (CNS) leukemia, and 1 patient had an isolated testicular relapse. An initial complete response was seen in all patients, with 5 patients remaining in CAR-T-induced remission at a median of 18 months from first infusion. Reversible ICANS was seen in 1 patient with CNS leukemia. Durable B cell aplasia occurred in 3 patients, with a median time to B cell recovery of 6.5 months in the other patients. These data suggest that CAR-T therapy has promising safety and efficacy in treating EM leukemia, although definitive conclusions are limited by the small size of the cohort and limited follow-up period.
Chimeric antigen receptor T cell therapy for pediatric and young adult B cell acute lymphoblastic leukemia.
Myers Regina M,Dolan Joseph,Teachey David T
Expert review of clinical immunology
INTRODUCTION:Though 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 COVERED:This 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 OPINION:CD19-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.