Development and Evaluation of an Optimal Human Single-Chain Variable Fragment-Derived BCMA-Targeted CAR T Cell Vector.
Smith Eric L,Staehr Mette,Masakayan Reed,Tatake Ishan J,Purdon Terence J,Wang Xiuyan,Wang Pei,Liu Hong,Xu Yiyang,Garrett-Thomson Sarah C,Almo Steven C,Riviere Isabelle,Liu Cheng,Brentjens Renier J
Molecular therapy : the journal of the American Society of Gene Therapy
B cell maturation antigen (BCMA) has recently been identified as an important multiple myeloma (MM)-specific target for chimeric antigen receptor (CAR) T cell therapy. In CAR T cell therapy targeting CD19 for lymphoma, host immune anti-murine CAR responses limited the efficacy of repeat dosing and possibly long-term persistence. This clinically relevant concern can be addressed by generating a CAR incorporating a human single-chain variable fragment (scFv). We screened a human B cell-derived scFv phage display library and identified a panel of BCMA-specific clones from which human CARs were engineered. Despite a narrow range of affinity for BCMA, dramatic differences in CAR T cell expansion were observed between unique scFvs in a repeat antigen stimulation assay. These results were confirmed by screening in a MM xenograft model, where only the top preforming CARs from the repeat antigen stimulation assay eradicated disease and prolonged survival. The results of this screening identified a highly effective CAR T cell therapy with properties, including rapid in vivo expansion (>10,000-fold, day 6), eradication of large tumor burden, and durable protection to tumor re-challenge. We generated a bicistronic construct including a second-generation CAR and a truncated-epithelial growth factor receptor marker. CAR T cell vectors stemming from this work are under clinical investigation.
Anti-BCMA antibodies in the future management of multiple myeloma.
Gavriatopoulou Maria,Ntanasis-Stathopoulos Ioannis,Dimopoulos Meletios Athanasios,Terpos Evangelos
Expert review of anticancer therapy
INTRODUCTION:B-cell maturation antigen (BCMA) belongs to the tumor necrosis factor receptor family and is expressed on late B-cells and plasma cells. Serum BCMA is elevated in patients with multiple myeloma (MM) and chronic lymphocytic leukemia (CLL), and might represent a novel prognostic and monitoring tool. Serum BCMA levels can predict both progression free survival (PFS) and overall survival (OS). Several therapeutic strategies are currently under investigation including BCMA-directed monoclonal Abs (either naked or with drug conjugates, and bispecific Abs) and cellular T-cell therapies (chimeric antigen receptor T-cells) with impressive clinical results. Areas covered: This review aims to present the mechanisms of action and the available data on efficacy and safety of therapies targeting BCMA. Expert opinion: The preliminary preclinical and clinical results from the phase 1 and 2 studies have demonstrated significant activity of the anti-BCMA therapeutic strategies. The main toxicities induced include Cytokine Release Syndrome (CRS) and ocular toxicity. The management of these adverse events remains currently an issue of controversy.
A combination of humanised anti-CD19 and anti-BCMA CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, phase 2 trial.
Yan Zhiling,Cao Jiang,Cheng Hai,Qiao Jianlin,Zhang Huanxin,Wang Ying,Shi Ming,Lan Jianping,Fei Xiaoming,Jin Lai,Jing Guangjun,Sang Wei,Zhu Feng,Chen Wei,Wu Qingyun,Yao Yao,Wang Gang,Zhao Jing,Zheng Junnian,Li Zhenyu,Xu Kailin
The Lancet. Haematology
BACKGROUND:Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy has been shown to have activity in patients with relapsed or refractory multiple myeloma. Reports have suggested that a small subgroup of less differentiated myeloma clones express CD19 and anti-CD19 CAR T-cell therapy has shown activity in some of these patients. We aimed to assess the activity and safety of a combination of humanised anti-CD19 and anti-BCMA CAR T cells in patients with relapsed or refractory multiple myeloma. METHODS:We did a single-centre, single-arm, phase 2 trial at the Affiliated Hospital of Xuzhou Medical University in China. Patients were eligible if they were aged 18-69 years, had histologically confirmed multiple myeloma, a Karnofsky Performance Score of 50 points or more, and met the International Myeloma Working Group diagnostic criteria for relapsed or refractory disease. Fludarabine (three daily doses of 30mg/m) and cyclophosphamide (one daily dose of 750 mg/m) were used to deplete lymphocytes before infusion of humanised anti-CD19 CAR T cells (1 × 10 cells per kg) and murine anti-BCMA CAR T cells (1 × 10 cells per kg). The primary outcome was the proportion of patients who achieved an overall response. Responses were assessed according to the International Myeloma Working Group criteria. This study is registered with the Chinese Clinical Trial Registration Center, number ChiCTR-OIC-17011272. FINDINGS:From May 1, 2017, to Jan 20, 2019, 22 patients were enrolled and 21 received an infusion of CAR T cells and were evaluable for safety and activity analyses. At a median follow-up of 179 days (IQR 72-295), 20 (95%) of 21 patients had an overall response, including nine (43%) stringent complete responses, three (14%) complete responses, five (24%) very good partial responses, and three (14%) partial responses. The most common adverse events included cytokine release syndrome (19 [90%] of 21), including 18 patients (86%) with grade 1-2 cytokine release syndrome. The most common serious adverse events were haematological toxicities, which occurred in 20 (95%) of 21 patients. Common grade 3 or higher adverse events included neutropenia (18 [86%]), anaemia (13 [62%]), and thrombocytopenia (13 [62%]). One patient died due to cerebral hemorrhage, which was considered related to sustained thrombocytopenia. No deaths were judged to be treatment-related. INTERPRETATION:Our results confirm that combined infusion of humanised anti-CD19 and anti-BCMA CAR T cells is feasible in patients with relapsed or refractory multiple myeloma, and the preliminary activity observed warrants further investigation in randomised trials. This dual CAR-T cell combinations might be a promising treatment option for relapsed or refractory multiple myeloma. FUNDING:National Natural Science Foundation of China, Natural Science Foundation, Key Research and Development Plan of Jiangsu.
Long-term safety and activity of NY-ESO-1 SPEAR T cells after autologous stem cell transplant for myeloma.
Stadtmauer Edward A,Faitg Thomas H,Lowther Daniel E,Badros Ashraf Z,Chagin Karen,Dengel Karen,Iyengar Malini,Melchiori Luca,Navenot Jean-Marc,Norry Elliot,Trivedi Trupti,Wang Ruoxi,Binder Gwendolyn K,Amado Rafael,Rapoport Aaron P
This study in patients with relapsed, refractory, or high-risk multiple myeloma (MM) evaluated the safety and activity of autologous T cells engineered to express an affinity-enhanced T-cell receptor (TCR) that recognizes a peptide shared by cancer antigens New York esophageal squamous cell carcinoma-1 (NY-ESO-1) and L-antigen family member 1 (LAGE-1) and presented by HLA-A*02:01. T cells collected from 25 HLA-A*02:01-positive patients with MM expressing NY-ESO-1 and/or LAGE-1 were activated, transduced with self-inactivating lentiviral vector encoding the NY-ESO-1TCR, and expanded in culture. After myeloablation and autologous stem cell transplant (ASCT), all 25 patients received an infusion of up to 1 × 10 NY-ESO-1 specific peptide enhanced affinity receptor (SPEAR) T cells. Objective response rate (International Myeloma Working Group consensus criteria) was 80% at day 42 (95% confidence interval [CI], 0.59-0.93), 76% at day 100 (95% CI, 0.55-0.91), and 44% at 1 year (95% CI, 0.24-0.65). At year 1, 13/25 patients were disease progression-free (52%); 11 were responders (1 stringent complete response, 1 complete response, 8 very good partial response, 1 partial response). Three patients remained disease progression-free at 38.6, 59.2, and 60.6 months post-NY-ESO-1 SPEAR T-cell infusion. Median progression-free survival was 13.5 months (range, 3.2-60.6 months); median overall survival was 35.1 months (range, 6.4-66.7 months). Infusions were well tolerated; cytokine release syndrome was not reported. No fatal serious adverse events occurred during study conduct. NY-ESO-1 SPEAR T cells expanded in vivo, trafficked to bone marrow, demonstrated persistence, and exhibited tumor antigen-directed functionality. In this MM patient population, NY-ESO-1 SPEAR T-cell therapy in the context of ASCT was associated with antitumor activity. This trial was registered at www.clinicaltrials.gov as #NCT01352286.
The activated conformation of integrin β is a novel multiple myeloma-specific target for CAR T cell therapy.
Hosen Naoki,Matsunaga Yukiko,Hasegawa Kana,Matsuno Hiroshi,Nakamura Yuki,Makita Mio,Watanabe Kouki,Yoshida Mikako,Satoh Kei,Morimoto Soyoko,Fujiki Fumihiro,Nakajima Hiroko,Nakata Jun,Nishida Sumiyuki,Tsuboi Akihiro,Oka Yoshihiro,Manabe Masahiro,Ichihara Hiroyoshi,Aoyama Yasutaka,Mugitani Atsuko,Nakao Takafumi,Hino Masayuki,Uchibori Ryosuke,Ozawa Keiya,Baba Yoshihiro,Terakura Seitaro,Wada Naoki,Morii Eiichi,Nishimura Junichi,Takeda Kiyoshi,Oji Yusuke,Sugiyama Haruo,Takagi Junichi,Kumanogoh Atsushi
Cancer-specific cell-surface antigens are ideal targets for monoclonal antibody (mAb)-based immunotherapy but are likely to have previously been identified in transcriptome or proteome analyses. Here, we show that the active conformer of an integrin can serve as a specific therapeutic target for multiple myeloma (MM). We screened >10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb specifically recognizing a subset of integrin β molecules. The MMG49 epitope, in the N-terminal region of the β chain, is predicted to be inaccessible in the resting integrin conformer but exposed in the active conformation. Elevated expression and constitutive activation of integrin β conferred high MMG49 reactivity on MM cells, whereas MMG49 binding was scarcely detectable in other cell types including normal integrin β lymphocytes. T cells transduced with MMG49-derived chimeric antigen receptor (CAR) exerted anti-MM effects without damaging normal hematopoietic cells. Thus, MMG49 CAR T cell therapy is promising for MM, and a receptor protein with a rare but physiologically relevant conformation can serve as a cancer immunotherapy target.
Sending CAR T Cells After Multiple Myeloma.
Preliminary results from an ongoing phase I clinical trial in China suggest that chimeric antigen receptor T cells engineered to home in on a protein called BCMA may be a potent therapeutic option for multiple myeloma. The therapy was well tolerated and induced complete, durable responses in patients with relapsed/refractory disease.
Cellular immunotherapy in multiple myeloma.
Vo Manh-Cuong,Lakshmi Thangaraj Jaya,Jung Sung-Hoon,Cho Duck,Park Hye-Seong,Chu Tan-Huy,Lee Hyun-Ju,Kim Hyeoung-Joon,Kim Sang-Ki,Lee Je-Jung
The Korean journal of internal medicine
In multiple myeloma (MM), the impaired function of several types of immune cells favors the tumor's escape from immune surveillance and, therefore, its growth and survival. Tremendous improvements have been made in the treatment of MM over the past decade but cellular immunotherapy using dendritic cells, natural killer cells, and genetically engineered T-cells represent a new therapeutic era. The application of these treatments is growing rapidly, based on their capacity to eradicate MM. In this review, we summarize recent progress in cellular immunotherapy for MM and its future prospects.
Adoptive immunotherapy utilizing anti-CD19 chimeric antigen receptor T-cells for B-cell malignancies.
Oh Iekuni,Oh Yukiko,Ohmine Ken
[Rinsho ketsueki] The Japanese journal of clinical hematology
Genetically modified T-cells with forced expression of anti-CD19 chimeric antigen receptor (CD19 CAR) have demonstrated promising clinical results for relapsed and refractory B cell malignancies in early clinical trial settings. The first beneficial tumor regressions were identified among approximately half of CLL patients in 2011. Similarly, CD19 CAR T-cells achieved remissions in about 80% of aggressive B-cell lymphomas in 2012. Furthermore, in 2013 this cellular therapy showed an extremely high rate of efficacy against refractory CD19 positive acute lymphoid leukemia, which had been regarded as the most difficult to treat hematologic disease. Recently, despite the absence of CD19 expression by neoplastic plasma cells, patients with refractory multiple myeloma achieved stringent complete remission after this therapy coupled with high dose chemotherapy and autologous stem cell transplantation. However, there are significant toxicities. Cytokine releasing syndrome and neurotoxicity are recognized as life-threatening adverse events. Although phase I/II clinical trials have just started in Japan, given the exciting results obtained to date, this cellular therapy is expected to be a novel breakthrough immunotherapy for treating refractory B-cell malignancies.
CARs and other T cell therapies for MM: The clinical experience.
Danhof Sophia,Hudecek Michael,Smith Eric L
Best practice & research. Clinical haematology
Harnessing the endogenous immune system to eliminate malignant cells has long been an intriguing approach. After considerable success in the treatment of B-cell acute lymphoblastic leukemia, chimeric antigen receptor (CAR)-modified T cells have entered early clinical evaluation in the field of multiple myeloma (MM). The choice of suitable non-CD19 target antigens is challenging and a variety of myeloma-associated surface molecules have been under preclinical investigation. Most recent clinical protocols have focused on targeting B-cell maturation antigen (BCMA), and early results are promising. The trials differ in receptor constructs, patient selection, dosing strategies and conditioning chemotherapy and will thus pave the way to eventually define the optimal parameters. Other sources for autologous T-cell therapy of MM include affinity-enhanced T-cell receptor-modified cells and marrow infiltrating lymphocytes. In summary, adoptive T-cell transfer for the treatment of MM is still in its infancy, but if early response rates indicate durability, will be a paradigm changing therapeutic modality for the treatment of MM.
Quantification of B-cell maturation antigen, a target for novel chimeric antigen receptor T-cell therapy in Myeloma.
Salem Dalia A,Maric Irina,Yuan Constance M,Liewehr David J,Venzon David J,Kochenderfer James,Stetler-Stevenson Maryalice
B-cell maturation antigen (BCMA) is expressed by normal and malignant plasma cells and is targeted via anti-BCMA chimeric antigen receptor T-cell therapy (BCMA CAR T-cell therapy) in plasma cell myeloma (PCM) patients. Surface BCMA expression is required for CAR T-cell binding and killing. We determined the incidence and intensity of expression of BCMA in bone marrow PCM cells using flow cytometry (FC) and immunohistochemistry (IHC). PCM BCMA expression was assessed by FC in 70 patients and in 43 concurrent specimens by IHC. BCMA expression was detected in 94% of patients. FC could assess BCMA expression in all specimens and expression was quantifiable (QuantiBRITE system, BD Biosciences, San Jose, CA) in 89% of cases. Expression was highly variable and could be numerically classified into dim, moderate or bright levels of expression. In the 43 specimens assessed successfully by both IHC and FC, FC showed higher positivity rate (97%) than IHC (72%), indicating that FC is more useful than IHC in detection of BCMA (p = 0.002; McNemar's test). We conclude that FC is more sensitive than IHC and can be used to objectively quantify BCMA expression by myeloma cells. IHC is primarily useful when there is significant infiltration of the bone marrow by myeloma and is less sensitive with low numbers of myeloma cells. Furthermore, the ability of FC to differentiate between normal and abnormal plasma cells and to quantify BCMA on these cells, makes it a useful and sensitive tool in screening patients for CAR T-cell therapy and for follow-up post therapy.
Anti-BCMA CAR T-cell therapy in multiple myeloma: can we do better?
D'Agostino Mattia,Raje Noopur
Despite a substantial survival improvement and the availability of many new drugs in the last 2 decades, multiple myeloma (MM) remains largely incurable. Immunotherapeutic approaches are changing the current landscape in MM with B-cell maturation antigen (BCMA) as one of the most promising target antigens. Chimeric antigen receptor (CAR) T-cell therapy targeting BCMA produced unprecedented results in heavily pretreated relapsed and/or refractory MM. Data on more than 300 MM patients treated with anti-BCMA directed CAR T cells are available and these numbers are rapidly increasing. The response rate and the depth of responses induced by anti-BCMA CAR T cells are impressive; however, the majority of patients eventually relapse. Understanding the underlying mechanisms of response and resistance in treated MM patients will be critical to the rational development of this therapy. Moreover, the ideal place of this therapy in the treatment paradigm for MM is an important question that needs biological and clinical correlative data to help elucidate. T-cell-related, tumor-related and microenvironmental factors may play a role in the efficacy of anti-BCMA CAR T-cell therapy. In this review we summarize key clinical and correlative data on anti-BCMA CAR T-cell therapy. Based on available data we will try to highlight opportunities to further optimize this potential game-changing therapy for MM.
Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma.
Raje Noopur,Berdeja Jesus,Lin Yi,Siegel David,Jagannath Sundar,Madduri Deepu,Liedtke Michaela,Rosenblatt Jacalyn,Maus Marcela V,Turka Ashley,Lam Lyh-Ping,Morgan Richard A,Friedman Kevin,Massaro Monica,Wang Julie,Russotti Greg,Yang Zhihong,Campbell Timothy,Hege Kristen,Petrocca Fabio,Quigley M Travis,Munshi Nikhil,Kochenderfer James N
The New England journal of medicine
BACKGROUND:Preclinical studies suggest that bb2121, a chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA), has potential for the treatment of multiple myeloma. METHODS:In this phase 1 study involving patients with relapsed or refractory multiple myeloma, we administered bb2121 as a single infusion at doses of 50×10, 150×10, 450×10, or 800×10 CAR-positive (CAR+) T cells in the dose-escalation phase and 150×10 to 450×10 CAR+ T cells in the expansion phase. Patients had received at least three previous lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or were refractory to both drug classes. The primary end point was safety. RESULTS:Results for the first 33 consecutive patients who received a bb2121 infusion are reported. The data-cutoff date was 6.2 months after the last infusion date. Hematologic toxic effects were the most common events of grade 3 or higher, including neutropenia (in 85% of the patients), leukopenia (in 58%), anemia (in 45%), and thrombocytopenia (in 45%). A total of 25 patients (76%) had cytokine release syndrome, which was of grade 1 or 2 in 23 patients (70%) and grade 3 in 2 patients (6%). Neurologic toxic effects occurred in 14 patients (42%) and were of grade 1 or 2 in 13 patients (39%). One patient (3%) had a reversible grade 4 neurologic toxic effect. The objective response rate was 85%, including 15 patients (45%) with complete responses. Six of the 15 patients who had a complete response have had a relapse. The median progression-free survival was 11.8 months (95% confidence interval, 6.2 to 17.8). All 16 patients who had a response (partial response or better) and who could be evaluated for minimal residual disease (MRD) had MRD-negative status (≤10 nucleated cells). CAR T-cell expansion was associated with responses, and CAR T cells persisted up to 1 year after the infusion. CONCLUSIONS:We report the initial toxicity profile of a BCMA-directed cellular immunotherapy for patients with relapsed or refractory multiple myeloma. Antitumor activity was documented. (Funded by Bluebird Bio and Celgene; CRB-401 ClinicalTrials.gov number, NCT02658929.).
GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells.
Smith Eric L,Harrington Kim,Staehr Mette,Masakayan Reed,Jones Jon,Long Thomas J,Ng Khong Y,Ghoddusi Majid,Purdon Terence J,Wang Xiuyan,Do Trevor,Pham Minh Thu,Brown Jessica M,De Larrea Carlos Fernandez,Olson Eric,Peguero Elizabeth,Wang Pei,Liu Hong,Xu Yiyang,Garrett-Thomson Sarah C,Almo Steven C,Wendel Hans-Guido,Riviere Isabelle,Liu Cheng,Sather Blythe,Brentjens Renier J
Science translational medicine
Early clinical results of chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) for multiple myeloma (MM) appear promising, but relapses associated with residual low-to-negative BCMA-expressing MM cells have been reported, necessitating identification of additional targets. The orphan G protein-coupled receptor, class C group 5 member D (), normally expressed only in the hair follicle, was previously identified as expressed by mRNA in marrow aspirates from patients with MM, but confirmation of protein expression remained elusive. Using quantitative immunofluorescence, we determined that GPRC5D protein is expressed on CD138 MM cells from primary marrow samples with a distribution that was similar to, but independent of, BCMA. Panning a human B cell-derived phage display library identified seven GPRC5D-specific single-chain variable fragments (scFvs). Incorporation of these into multiple CAR formats yielded 42 different constructs, which were screened for antigen-specific and antigen-independent (tonic) signaling using a Nur77-based reporter system. Nur77 reporter screen results were confirmed in vivo using a marrow-tropic MM xenograft in mice. CAR T cells incorporating GPRC5D-targeted scFv clone 109 eradicated MM and enabled long-term survival, including in a BCMA antigen escape model. GPRC5D(109) is specific for GPRC5D and resulted in MM cell line and primary MM cytotoxicity, cytokine release, and in vivo activity comparable to anti-BCMA CAR T cells. Murine and cynomolgus cross-reactive CAR T cells did not cause alopecia or other signs of GPRC5D-mediated toxicity in these species. Thus, GPRC5D(109) CAR T cell therapy shows potential for the treatment of advanced MM irrespective of previous BCMA-targeted therapy.
T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma.
Ali Syed Abbas,Shi Victoria,Maric Irina,Wang Michael,Stroncek David F,Rose Jeremy J,Brudno Jennifer N,Stetler-Stevenson Maryalice,Feldman Steven A,Hansen Brenna G,Fellowes Vicki S,Hakim Frances T,Gress Ronald E,Kochenderfer James N
Therapies with novel mechanisms of action are needed for multiple myeloma (MM). B-cell maturation antigen (BCMA) is expressed in most cases of MM. We conducted the first-in-humans clinical trial of chimeric antigen receptor (CAR) T cells targeting BCMA. T cells expressing the CAR used in this work (CAR-BCMA) specifically recognized BCMA-expressing cells. Twelve patients received CAR-BCMA T cells in this dose-escalation trial. Among the 6 patients treated on the lowest 2 dose levels, limited antimyeloma activity and mild toxicity occurred. On the third dose level, 1 patient obtained a very good partial remission. Two patients were treated on the fourth dose level of 9 × 10(6) CAR(+) T cells/kg body weight. Before treatment, the first patient on the fourth dose level had chemotherapy-resistant MM, making up 90% of bone marrow cells. After treatment, bone marrow plasma cells became undetectable by flow cytometry, and the patient's MM entered a stringent complete remission that lasted for 17 weeks before relapse. The second patient on the fourth dose level had chemotherapy-resistant MM making up 80% of bone marrow cells before treatment. Twenty-eight weeks after this patient received CAR-BCMA T cells, bone marrow plasma cells were undetectable by flow cytometry, and the serum monoclonal protein had decreased by >95%. This patient is in an ongoing very good partial remission. Both patients treated on the fourth dose level had toxicity consistent with cytokine-release syndrome including fever, hypotension, and dyspnea. Both patients had prolonged cytopenias. Our findings demonstrate antimyeloma activity of CAR-BCMA T cells. This trial was registered to www.clinicaltrials.gov as #NCT02215967.
Chimeric antigen receptor T-cell therapy for multiple myeloma: a consensus statement from The European Myeloma Network.
Moreau Philippe,Sonneveld Pieter,Boccadoro Mario,Cook Gordon,Mateos Ma Victoria,Nahi Hareth,Goldschmidt Hartmut,Dimopoulos Meletios A,Lucio Paulo,Bladé Joan,Delforge Michel,Hajek Roman,Ludwig Heinz,Facon Thierry,Miguel Jesus F San,Einsele Hermann
Adoptive cellular therapy using chimeric antigen receptor T-cell (CART) therapy is currently being evaluated in patients with relapsed / refractory multiple myeloma (MM). The majority of CAR-T cell programs now being tested in clinical trials are targeting B-cell maturation antigen. Several recent phase I / II trials show promising preliminary results in patients with MM progressing on proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies targeting CD38. CAR-T cell therapy is a potentially life-threatening strategy that can only be administered in experienced centers. For the moment, CAR-T cell therapy for MM is still experimental, but once this strategy has been approved in relapsed/refractory MM, it will become one of the most important indications for this therapy in Europe and world-wide. This manuscript proposes practical considerations for the use of CAR-T cell therapy in MM, and discusses several important issues for its future development.
Targeting B Cell Maturation Antigen (BCMA) in Multiple Myeloma: Potential Uses of BCMA-Based Immunotherapy.
Cho Shih-Feng,Anderson Kenneth C,Tai Yu-Tzu
Frontiers in immunology
The approval of the first two monoclonal antibodies targeting CD38 (daratumumab) and SLAMF7 (elotuzumab) in late 2015 for treating relapsed and refractory multiple myeloma (RRMM) was a critical advance for immunotherapies for multiple myeloma (MM). Importantly, the outcome of patients continues to improve with the incorporation of this new class of agents with current MM therapies. However, both antigens are also expressed on other normal tissues including hematopoietic lineages and immune effector cells, which may limit their long-term clinical use. B cell maturation antigen (BCMA), a transmembrane glycoprotein in the tumor necrosis factor receptor superfamily 17 (TNFRSF17), is expressed at significantly higher levels in all patient MM cells but not on other normal tissues except normal plasma cells. Importantly, it is an antigen targeted by chimeric antigen receptor (CAR) T-cells, which have already shown significant clinical activities in patients with RRMM who have undergone at least three prior treatments, including a proteasome inhibitor and an immunomodulatory agent. Moreover, the first anti-BCMA antibody-drug conjugate also has achieved significant clinical responses in patients who failed at least three prior lines of therapy, including an anti-CD38 antibody, a proteasome inhibitor, and an immunomodulatory agent. Both BCMA targeting immunotherapies were granted breakthrough status for patients with RRMM by FDA in Nov 2017. Other promising BCMA-based immunotherapeutic macromolecules including bispecific T-cell engagers, bispecific molecules, bispecific or trispecific antibodies, as well as improved forms of next generation CAR T cells, also demonstrate high anti-MM activity in preclinical and even early clinical studies. Here, we focus on the biology of this promising MM target antigen and then highlight preclinical and clinical data of current BCMA-targeted immunotherapies with various mechanisms of action. These crucial studies will enhance selective anti-MM response, transform the treatment paradigm, and extend disease-free survival in MM.
Preclinical Evaluation of Allogeneic CAR T Cells Targeting BCMA for the Treatment of Multiple Myeloma.
Sommer Cesar,Boldajipour Bijan,Kuo Tracy C,Bentley Trevor,Sutton Janette,Chen Amy,Geng Tao,Dong Holly,Galetto Roman,Valton Julien,Pertel Thomas,Juillerat Alexandre,Gariboldi Annabelle,Pascua Edward,Brown Colleen,Chin Sherman M,Sai Tao,Ni Yajin,Duchateau Philippe,Smith Julianne,Rajpal Arvind,Van Blarcom Thomas,Chaparro-Riggers Javier,Sasu Barbra J
Molecular therapy : the journal of the American Society of Gene Therapy
Clinical success of autologous CD19-directed chimeric antigen receptor T cells (CAR Ts) in acute lymphoblastic leukemia and non-Hodgkin lymphoma suggests that CAR Ts may be a promising therapy for hematological malignancies, including multiple myeloma. However, autologous CAR T therapies have limitations that may impact clinical use, including lengthy vein-to-vein time and manufacturing constraints. Allogeneic CAR T (AlloCAR T) therapies may overcome these innate limitations of autologous CAR T therapies. Unlike autologous cell therapies, AlloCAR T therapies employ healthy donor T cells that are isolated in a manufacturing facility, engineered to express CARs with specificity for a tumor-associated antigen, and modified using gene-editing technology to limit T cell receptor (TCR)-mediated immune responses. Here, transcription activator-like effector nuclease (TALEN) gene editing of B cell maturation antigen (BCMA) CAR Ts was used to confer lymphodepletion resistance and reduced graft-versus-host disease (GvHD) potential. The safety profile of allogeneic BCMA CAR Ts was further enhanced by incorporating a CD20 mimotope-based intra-CAR off switch enabling effective CAR T elimination in the presence of rituximab. Allogeneic BCMA CAR Ts induced sustained antitumor responses in mice supplemented with human cytokines, and, most importantly, maintained their phenotype and potency after scale-up manufacturing. This novel off-the-shelf allogeneic BCMA CAR T product is a promising candidate for clinical evaluation.
B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma.
Cohen Adam D,Garfall Alfred L,Stadtmauer Edward A,Melenhorst J Joseph,Lacey Simon F,Lancaster Eric,Vogl Dan T,Weiss Brendan M,Dengel Karen,Nelson Annemarie,Plesa Gabriela,Chen Fang,Davis Megan M,Hwang Wei-Ting,Young Regina M,Brogdon Jennifer L,Isaacs Randi,Pruteanu-Malinici Iulian,Siegel Don L,Levine Bruce L,June Carl H,Milone Michael C
The Journal of clinical investigation
BACKGROUND:Chimeric antigen receptor (CAR) T cells are a promising therapy for hematologic malignancies. B-cell maturation antigen (BCMA) is a rational target in multiple myeloma (MM). METHODS:We conducted a phase I study of autologous T cells lentivirally-transduced with a fully-human, BCMA-specific CAR containing CD3ζ and 4-1BB signaling domains (CART-BCMA), in subjects with relapsed/refractory MM. Twenty-five subjects were treated in 3 cohorts: 1) 1-5 x 108 CART-BCMA cells alone; 2) Cyclophosphamide (Cy) 1.5 g/m2 + 1-5 x 107 CART-BCMA cells; and 3) Cy 1.5 g/m2 + 1-5 x 108 CART-BCMA cells. No pre-specified BCMA expression level was required. RESULTS:CART-BCMA cells were manufactured and expanded in all subjects. Toxicities included cytokine release syndrome and neurotoxicity, which were grade 3-4 in 8 (32%) and 3 (12%) subjects, respectively, and reversible. One subject died at day 24 from candidemia and progressive myeloma, following treatment for severe CRS and encephalopathy. Responses (based on treated subjects) were seen in 4/9 (44%) in cohort 1, 1/5 (20%) in cohort 2, and 7/11 (64%) in cohort 3, including 5 partial, 5 very good partial, and 2 complete responses, 3 of which were ongoing at 11, 14, and 32 months. Decreased BCMA expression on residual MM cells was noted in responders; expression increased at progression in most. Responses and CART-BCMA expansion were associated with CD4:CD8 T cell ratio and frequency of CD45RO-CD27+CD8+ T cells in the pre-manufacturing leukapheresis product. CONCLUSION:CART-BCMA infusions with or without lymphodepleting chemotherapy are clinically active in heavily-pretreated MM patients. TRIAL REGISTRATION:NCT02546167. FUNDING:University of Pennsylvania-Novartis Alliance and NIH.
Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma.
Xu Jie,Chen Li-Juan,Yang Shuang-Shuang,Sun Yan,Wu Wen,Liu Yuan-Fang,Xu Ji,Zhuang Yan,Zhang Wu,Weng Xiang-Qin,Wu Jing,Wang Yan,Wang Jin,Yan Hua,Xu Wen-Bin,Jiang Hua,Du Juan,Ding Xiao-Yi,Li Biao,Li Jun-Min,Fu Wei-Jun,Zhu Jiang,Zhu Li,Chen Zhu,Fan Xiao-Hu Frank,Hou Jian,Li Jian-Yong,Mi Jian-Qing,Chen Sai-Juan
Proceedings of the National Academy of Sciences of the United States of America
Relapsed and refractory (R/R) multiple myeloma (MM) patients have very poor prognosis. Chimeric antigen receptor modified T (CAR T) cells is an emerging approach in treating hematopoietic malignancies. Here we conducted the clinical trial of a biepitope-targeting CAR T against B cell maturation antigen (BCMA) (LCAR-B38M) in 17 R/R MM cases. CAR T cells were i.v. infused after lymphodepleting chemotherapy. Two delivery methods, three infusions versus one infusion of the total CAR T dose, were tested in, respectively, 8 and 9 cases. No response differences were noted among the two delivery subgroups. Together, after CAR T cell infusion, 10 cases experienced a mild cytokine release syndrome (CRS), 6 had severe but manageable CRS, and 1 died of a very severe toxic reaction. The abundance of BCMA and cytogenetic marker del(17p) and the elevation of IL-6 were the key indicators for severe CRS. Among 17 cases, the overall response rate was 88.2%, with 13 achieving stringent complete response (sCR) and 2 reaching very good partial response (VGPR), while 1 was a nonresponder. With a median follow-up of 417 days, 8 patients remained in sCR or VGPR, whereas 6 relapsed after sCR and 1 had progressive disease (PD) after VGPR. CAR T cells were high in most cases with stable response but low in 6 out of 7 relapse/PD cases. Notably, positive anti-CAR antibody constituted a high-risk factor for relapse/PD, and patients who received prior autologous hematopoietic stem cell transplantation had more durable response. Thus, biepitopic CAR T against BCMA represents a promising therapy for R/R MM, while most adverse effects are clinically manageable.
Chimeric antigen-receptor T-cell therapy for hematological malignancies and solid tumors: Clinical data to date, current limitations and perspectives.
Gauthier J,Yakoub-Agha I
Current research in translational medicine
Progress in our understanding of basic immunology along with the advent of bioengineering technologies have made possible the production of human T-cells expressing Chimeric Antigen Receptors (CAR T-cells). These CAR T-cells are designed to target specific antigens presented by cancer cells. Once CARs are bound to these antigens, CAR T-cells get activated and can initiate potent anti-tumor effects. We will here overview the bioengineering advances which made possible the clinical application of CAR T-cell therapy. We will review the data to date regarding anti-CD19 CAR T-cell therapy for acute lymphoblastic leukemia, non-Hodgkin lymphomas, and chronic lymphocytic leukemia. Besides CD19, CAR T-cells directed against the B-cell maturation antigen have also shown encouraging results to treat patients with refractory multiple myeloma. The more limited body of clinical research in the field of solid tumors will also be reviewed. Moreover, we will elaborate on the main toxicities of limitations of CAR T-cell therapy, namely cytokine release syndrome and neurotoxicity. While enjoying an undeniable hype, CAR T-cell therapy bears significant limitations. We will conclude by exposing the possible approaches to make CAR T-cells safer and more efficient beyond the CD19 target.
[Application of Chimeric Antigen Receptor-Modified NK Cells in Multiple Myeloma].
Wei Hua-Ping,Yang Nan,Gu Zhen-Yang,Zhao Sha-Sha,Wang Fei-Yan,Luo Lan,Guan Li-Xun,Gao Chun-Ji
Zhongguo shi yan xue ye xue za zhi
OBJECTIVE:To explore the killing effect of CAR (CD138-CD28-CD3ζ)-NK cells on myeloma cells through construction of CAR(CD138-CD28-CD3)-NK cells. METHODS:The antiCD138scFv-CD28-CD3 zeta plasmid pcDNA3.1 was constructed, which then together with 3 plasmid lentiviral packaging system were transfected into 293T cells, the virus was collected. Furthermore, in order to get the stably transfected cell line, the NK92MI cell line was infected by the virus, then the positive cells were screened by puromycin. The expression of the CARNK cells were verified by RT-PCR and Western blot. At last the ability of secreting cytokine CD107a was detected by flow cytometry, and the statistical analysis was carried out to verify the anti-myeloma effect of CAR-NK cells. RESULTS:Gene fragment of the CAR(antiCD138scFv-CD28-CD3ζ) was constructed successfully by gene engineering technique in vitro, and the gene sequence was verified to be correct by sequencing. By virus packaging technology, the virus expressing the protein of the CAR was obtained. PCR and Western blot verified the expression of CAR fusion protein on the sufurce of NK cells. The cell killing experiment confirmed that the CAR-NK cells possessed the ability to secrete cytokine CD107a superior to control cells and showed the obvious killing effect on multiple myeloma cells. CONCLUSION:The CAR can be constructed in vitro, and express on NK92 cells. The CAR-NK cells can kill the multiple myeloma cells expressing CD138 antigen, thereby plays an antimyeloma effect.
Chimeric Antigen Receptor (CAR) therapy for multiple myeloma.
Atanackovic Djordje,Radhakrishnan Sabarinath V,Bhardwaj Neelam,Luetkens Tim
British journal of haematology
The introduction of chimeric antigen receptor (CAR)-modified T cells has revolutionized immunotherapy and cancer treatment as a whole. However, so far, clinical efficacy has only been demonstrated for CD19-positive B cell lymphomas. For Multiple Myeloma (MM), the second most common haematological malignancy, there are currently no clinical results supporting the usefulness of the adoptive transfer of CAR-modified T cells. This might be related to the fact that an ideal surface target has not yet been identified or the presence of strong local immunosuppression in the tumour microenvironment, which is a hallmark of MM. In this review, we provide a comprehensive overview of promising target molecules for CAR T cell approaches in MM and we outline a number of ways in which the local immunosuppression in MM can be overcome. By providing a strategy for the design of CAR T cell treatments for MM we hope to transform this new therapeutic approach into a valuable tool within the therapeutic armamentarium for MM.
Development of chimeric antigen receptors for multiple myeloma.
Martínez-Cingolani Carolina,Bories Jean Christophe
Biochemical Society transactions
Multiple myeloma (MM) is a haematologic malignancy characterized by the expansion of monoclonal plasma cells in the bone marrow. It is associated with serum or urine monoclonal protein and organ damage including renal failure, anaemia, hypercalcaemia and bone lesions. Despite recent improvements MM still remains an incurable disease. Previous studies have shown that the adoptive transfer of autologous T-cells modified to express chimeric antigen receptors (CAR) is effective in cases of acute and chronic lymphoid leukaemia. However, the adjustment of CAR-T-cell therapy to MM is hindered by the scarcity of antigens specific to the tumour plasma cells. Most candidate targets are shared by healthy tissues, and entail high risks of toxicity. Therefore several strategies have been proposed to regulate CAR-T-cell function as well as to enhance CAR-T-cell specificity against tumour cells. In this article we summarize the surface markers that have been investigated as targets to eliminate MM plasma cells and the MM-specific CARs that have been developed to date. Then we describe the different CAR-T-cell designs that could be applied in the case of MM to circumvent current problems of toxicity.
Chimeric antigen receptor T cell immunotherapy for multiple myeloma: A review of current data and potential clinical applications.
Susanibar Adaniya Sandra P,Cohen Adam D,Garfall Alfred L
American journal of hematology
Multiple myeloma (MM) is a malignant plasma cell disorder that remains incurable for most patients despite significant improvements achieved with modern therapy. Tumor evasion is a key process in the pathogenesis of MM and a compromised immune system is associated with more aggressive forms of the disease. In contrast, the emergence of myeloma-specific immune responses after both autologous and allogeneic stem cell transplantation is associated with better prognosis. Adoptive T cell therapies may improve specific anti-myeloma immunity resulting in long-lasting remissions. CAR T cell therapies for MM are at an early stage of clinical development. To date, anti-BCMA CAR T cells have shown the greatest results in early-phase clinical trials. Toxicities have included cytokine release syndrome (CRS) and neurotoxicity. Current areas of research in CAR T cell therapies include the use of gene-editing to enhance their effectiveness and safety, the integration of CAR T cells with other therapies (immunomodulatory drugs, checkpoint inhibitors) and CAR T cells to target multiple antigens.
Chimeric antigen receptor T-cell therapies for multiple myeloma.
Mikkilineni Lekha,Kochenderfer James N
Multiple myeloma (MM) is a nearly always incurable malignancy of plasma cells, so new approaches to treatment are needed. T-cell therapies are a promising approach for treating MM, with a mechanism of action different than those of standard MM treatments. Chimeric antigen receptors (CARs) are fusion proteins incorporating antigen-recognition domains and T-cell signaling domains. T cells genetically engineered to express CARs can specifically recognize antigens. Success of CAR-T cells (CAR-Ts) against leukemia and lymphoma has encouraged development of CAR-T therapies for MM. Target antigens for CARs must be expressed on malignant cells, but expression on normal cells must be absent or limited. B-cell maturation antigen is expressed by normal and malignant plasma cells. CAR-Ts targeting B-cell maturation antigen have demonstrated significant antimyeloma activity in early clinical trials. Toxicities in these trials, including cytokine release syndrome, have been similar to toxicities observed in CAR-T trials for leukemia. Targeting postulated CD19 myeloma stem cells with anti-CD19 CAR-Ts is a novel approach to MM therapy. MM antigens including CD138, CD38, signaling lymphocyte-activating molecule 7, and κ light chain are under investigation as CAR targets. MM is genetically and phenotypically heterogeneous, so targeting of >1 antigen might often be required for effective treatment of MM with CAR-Ts. Integration of CAR-Ts with other myeloma therapies is an important area of future research. CAR-T therapies for MM are at an early stage of development but have great promise to improve MM treatment.
Effective Targeting of Multiple B-Cell Maturation Antigen-Expressing Hematological Malignances by Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor T Cells.
Friedman Kevin M,Garrett Tracy E,Evans John W,Horton Holly M,Latimer Howard J,Seidel Stacie L,Horvath Christopher J,Morgan Richard A
Human gene therapy
B-cell maturation antigen (BCMA) expression has been proposed as a marker for the identification of malignant plasma cells in patients with multiple myeloma (MM). Nearly all MM tumor cells express BCMA, while normal tissue expression is restricted to plasma cells and a subset of mature B cells. Consistent BCMA expression was confirmed on MM biopsies (29/29 BCMA+), and it was further demonstrated that BCMA is expressed in a substantial number of lymphoma samples, as well as primary chronic lymphocytic leukemia B cells. To target BCMA using redirected autologous T cells, lentiviral vectors (LVV) encoding chimeric antigen receptors (CARs) were constructed with four unique anti-BCMA single-chain variable fragments, fused to the CD137 (4-1BB) co-stimulatory and CD3ζ signaling domains. One LVV, BB2121, was studied in detail, and BB2121 CAR-transduced T cells (bb2121) exhibited a high frequency of CAR + T cells and robust in vitro activity against MM cell lines, lymphoma cell lines, and primary chronic lymphocytic leukemia peripheral blood. Based on receptor quantification, bb2121 recognized tumor cells expressing as little as 222 BCMA molecules per cell. The in vivo pharmacology of anti-BCMA CAR T cells was studied in NSG mouse models of human MM, Burkitt lymphoma, and mantle cell lymphoma, where mice received a single intravenous administration of vehicle, control vector-transduced T cells, or anti-BCMA CAR-transduced T cells. In all models, the vehicle and control CAR T cells failed to inhibit tumor growth. In contrast, treatment with bb2121 resulted in rapid and sustained elimination of the tumors and 100% survival in all treatment models. Together, these data support the further development of anti-BCMA CAR T cells as a potential treatment for not only MM but also some lymphomas.
[Chimeric antigen receptor T-cell therapy for multiple myeloma].
[Rinsho ketsueki] The Japanese journal of clinical hematology
CAR T-cell therapy is a novel cancer immunotherapy targeting cancer-specific cell-surface antigen. CD19-CAR T cells have been demonstrated to be highly efficacious in treating B-cell leukemia/lymphoma. Currently, several researchers are developing CAR T cells for multiple myeloma. In some early-phase clinical trials, CAR T cells targeting B-cell maturation antigen have exhibited promising efficacy. Recently, we reported that CAR T cells targeting the activated integrin 7 can selectively eradicate MM cells including CD19 clonotypic B cells; a clinical trial for further assessment regarding this study is in process.
[New Research Advances on Chimeric Antigen Receptor T Cells in the Treatment of Relapsed and Refractory Multiple Myeloma-Review].
Zhang Fang-Rong,Li Xin,Liu Jing
Zhongguo shi yan xue ye xue za zhi
Abstract Chimeric antigen receptor-T cell(CAR-T) is a kind of genetically engineered T cells that can express tumor antigen-specific receptors on its surface, and the modified T cells can be used for cancer therapy through targeting malignant tumor cells with its specific receptor and killing tumor cells with its cytotoxicity. CAR-T has been successfully applied to treat various hematological malignancies, such as ALL, CLL, NHL and MM. It is a feasible treatment for relapsed and refractory multiple myeloma (RRMM). The achievements of CAR-T in clinical trials have been widely reported, which is expected to be a therapy to prolong patients survival. In this review, the clinical application of CAR-T in the treatment of RRMM from the following aspects：different types of CAR-T and its curative efficacy, adverse effects, opportunities and challenges are summarized beriefly.
Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma.
Drent Esther,Groen Richard W J,Noort Willy A,Themeli Maria,Lammerts van Bueren Jeroen J,Parren Paul W H I,Kuball Jürgen,Sebestyen Zsolt,Yuan Huipin,de Bruijn Joost,van de Donk Niels W C J,Martens Anton C M,Lokhorst Henk M,Mutis Tuna
Adoptive transfer of chimeric antigen receptor-transduced T cells is a promising strategy for cancer immunotherapy. The CD38 molecule, with its high expression on multiple myeloma cells, appears a suitable target for antibody therapy. Prompted by this, we used three different CD38 antibody sequences to generate second-generation retroviral CD38-chimeric antigen receptor constructs with which we transduced T cells from healthy donors and multiple myeloma patients. We then evaluated the preclinical efficacy and safety of the transduced T cells. Irrespective of the donor and antibody sequence, CD38-chimeric antigen receptor-transduced T cells proliferated, produced inflammatory cytokines and effectively lysed malignant cell lines and primary malignant cells from patients with acute myeloid leukemia and multi-drug resistant multiple myeloma in a cell-dose, and CD38-dependent manner, despite becoming CD38-negative during culture. CD38-chimeric antigen receptor-transduced T cells also displayed significant anti-tumor effects in a xenotransplant model, in which multiple myeloma tumors were grown in a human bone marrow-like microenvironment. CD38-chimeric antigen receptor-transduced T cells also appeared to lyse the CD38(+) fractions of CD34(+) hematopoietic progenitor cells, monocytes, natural killer cells, and to a lesser extent T and B cells but did not inhibit the outgrowth of progenitor cells into various myeloid lineages and, furthermore, were effectively controllable with a caspase-9-based suicide gene. These results signify the potential importance of CD38-chimeric antigen receptor-transduced T cells as therapeutic tools for CD38(+) malignancies and warrant further efforts to diminish the undesired effects of this immunotherapy using appropriate strategies.
Anti-B-cell Maturation Antigen Chimeric Antigen Receptor T cell Function against Multiple Myeloma Is Enhanced in the Presence of Lenalidomide.
Works Melissa,Soni Neha,Hauskins Collin,Sierra Catherine,Baturevych Alex,Jones Jon C,Curtis Wendy,Carlson Patrick,Johnstone Timothy G,Kugler David,Hause Ronald J,Jiang Yue,Wimberly Lindsey,Clouser Christopher R,Jessup Heidi K,Sather Blythe,Salmon Ruth A,Ports Michael O
Molecular cancer therapeutics
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells have shown promising clinical responses in patients with relapsed/refractory multiple myeloma. Lenalidomide, an immunomodulatory drug, potentiates T cell functionality, drives antimyeloma activity, and alters the suppressive microenvironment; these properties may effectively combine with anti-BCMA CAR T cells to enhance function. Using an anti-BCMA CAR T, we demonstrated that lenalidomide enhances CAR T cell function in a concentration-dependent manner. Lenalidomide increased CAR T effector cytokine production, particularly under low CAR stimulation or in the presence of inhibitory ligand programmed cell death 1 ligand 1. Notably, lenalidomide also enhanced CAR T cytokine production, cytolytic activity, and activation profile relative to untreated CAR T cells in chronic stimulation assays. This unique potentiation of both short-term CAR T activity and long-term functionality during chronic stimulation prompted investigation of the molecular profile of lenalidomide-treated CAR T cells. Signatures from RNA sequencing and assay for transposase-accessible chromatin using sequencing indicated that pathways associated with T-helper 1 response, cytokine production, T cell activation, cell-cycle control, and cytoskeletal remodeling were altered with lenalidomide. Finally, study of lenalidomide and anti-BCMA CAR T cells in a murine, disseminated, multiple myeloma model indicated that lenalidomide increased CAR T cell counts in blood and significantly prolonged animal survival. In summary, preclinical studies demonstrated that lenalidomide potentiated CAR T activity in low-antigen or suppressive environments and delayed onset of functional exhaustion. These results support further investigation of lenalidomide and anti-BCMA CAR T cells in the clinic.
An APRIL-based chimeric antigen receptor for dual targeting of BCMA and TACI in multiple myeloma.
Lee Lydia,Draper Benjamin,Chaplin Neil,Philip Brian,Chin Melody,Galas-Filipowicz Daria,Onuoha Shimobi,Thomas Simon,Baldan Vania,Bughda Reyisa,Maciocia Paul,Kokalaki Eva,Neves Margarida P,Patel Dominic,Rodriguez-Justo Manuel,Francis James,Yong Kwee,Pule Martin
B-cell maturation antigen (BCMA) is a promising therapeutic target for multiple myeloma (MM), but expression is variable, and early reports of BCMA targeting chimeric antigen receptors (CARs) suggest antigen downregulation at relapse. Dual-antigen targeting increases targetable tumor antigens and reduces the risk of antigen-negative disease escape. "A proliferation-inducing ligand" (APRIL) is a natural high-affinity ligand for BCMA and transmembrane activator and calcium-modulator and cyclophilin ligand (TACI). We quantified surface tumor expression of BCMA and TACI on primary MM cells (n = 50). All cases tested expressed BCMA, and 39 (78%) of them also expressed TACI. We engineered a third-generation APRIL-based CAR (ACAR), which killed targets expressing either BCMA or TACI ( < .01 and < .05, respectively, cf. control, effector-to-target [E:T] ratio 16:1). We confirmed cytolysis at antigen levels similar to those on primary MM, at low E:T ratios (56.2% ± 3.9% killing of MM.1s at 48 h, E:T ratio 1:32; < .01) and of primary MM cells (72.9% ± 12.2% killing at 3 days, E:T ratio 1:1; < .05, n = 5). Demonstrating tumor control in the absence of BCMA, we maintained cytolysis of primary tumor expressing both BCMA and TACI in the presence of a BCMA-targeting antibody. Furthermore, using an intramedullary myeloma model, ACAR T cells caused regression of an established tumor within 2 days. Finally, in an in vivo model of tumor escape, there was complete ACAR-mediated tumor clearance of BCMATACI and BCMATACI cells, and a single-chain variable fragment CAR targeting BCMA alone resulted in outgrowth of a BCMA-negative tumor. These results support the clinical potential of this approach.
A compound chimeric antigen receptor strategy for targeting multiple myeloma.
Chen K H,Wada M,Pinz K G,Liu H,Shuai X,Chen X,Yan L E,Petrov J C,Salman H,Senzel L,Leung E L H,Jiang X,Ma Y
Current clinical outcomes using chimeric-antigen receptors (CARs) against multiple myeloma show promise in the eradication of bulk disease. However, these anti-BCMA (CD269) CARs observe relapse as a common phenomenon after treatment due to the reemergence of either antigen-positive or -negative cells. Hence, the development of improvements in CAR design to target antigen loss and increase effector cell persistency represents a critical need. Here, we report on the anti-tumor activity of a CAR T-cell possessing two complete and independent CAR receptors against the multiple myeloma antigens BCMA and CS1. We determined that the resulting compound CAR (cCAR) T-cell possesses consistent, potent and directed cytotoxicity against each target antigen population. Using multiple mouse models of myeloma and mixed cell populations, we are further able to show superior in vivo survival by directed cytotoxicity against multiple populations compared to a single-expressing CAR T-cell. These findings indicate that compound targeting of BCMA and CS1 on myeloma cells can potentially be an effective strategy for augmenting the response against myeloma bulk disease and for initiation of broader coverage CAR therapy.
SOHO State of the Art Updates and Next Questions: T-Cell-Directed Immune Therapies for Multiple Myeloma: Chimeric Antigen Receptor-Modified T Cells and Bispecific T-Cell-Engaging Agents.
Madduri Deepu,Dhodapkar Madhav V,Lonial Sagar,Jagannath Sundar,Cho Hearn Jay
Clinical lymphoma, myeloma & leukemia
Therapeutic monoclonal antibodies targeting SLAMF7 and CD38 are the first classes of targeted immunotherapies approved for multiple myeloma, a cancer of plasma cells. These agents are effective, particularly in combination with the immunomodulatory drugs lenalidomide and pomalidomide. The next generation of myeloma immunotherapy under investigation consists of T-cell-directed strategies designed to promote cytotoxic activity against myeloma cells, as embodied by chimeric antigen receptor-modified T cells (CAR-T) and bispecific T-cell-engaging agents. Early clinical trial results with these classes of therapies are promising, with high response rates reported. These strategies appear to be strong activators of immunoresponse, and adverse effects, particularly cytokine release syndrome and cytokine-related encephalopathic syndrome, are common. Ongoing research explores the optimal disease setting and combination therapies for these agents. These studies provide an unprecedented opportunity to understand the mechanisms of action and their relations to adverse effects and resistance to therapy.
T Cells Genetically Modified to Express an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma.
Brudno Jennifer N,Maric Irina,Hartman Steven D,Rose Jeremy J,Wang Michael,Lam Norris,Stetler-Stevenson Maryalice,Salem Dalia,Yuan Constance,Pavletic Steven,Kanakry Jennifer A,Ali Syed Abbas,Mikkilineni Lekha,Feldman Steven A,Stroncek David F,Hansen Brenna G,Lawrence Judith,Patel Rashmika,Hakim Frances,Gress Ronald E,Kochenderfer James N
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Purpose Therapies with novel mechanisms of action are needed for multiple myeloma (MM). T cells can be genetically modified to express chimeric antigen receptors (CARs), which are artificial proteins that target T cells to antigens. B-cell maturation antigen (BCMA) is expressed by normal and malignant plasma cells but not normal essential cells. We conducted the first-in-humans clinical trial, to our knowledge, of T cells expressing a CAR targeting BCMA (CAR-BCMA). Patients and Methods Sixteen patients received 9 × 10 CAR-BCMA T cells/kg at the highest dose level of the trial; we are reporting results of these 16 patients. The patients had a median of 9.5 prior lines of MM therapy. Sixty-three percent of patients had MM refractory to the last treatment regimen before protocol enrollment. T cells were transduced with a γ-retroviral vector encoding CAR-BCMA. Patients received CAR-BCMA T cells after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. Results The overall response rate was 81%, with 63% very good partial response or complete response. Median event-free survival was 31 weeks. Responses included eradication of extensive bone marrow myeloma and resolution of soft-tissue plasmacytomas. All 11 patients who obtained an anti-MM response of partial response or better and had MM evaluable for minimal residual disease obtained bone marrow minimal residual disease-negative status. High peak blood CAR cell levels were associated with anti-MM responses. Cytokine-release syndrome toxicities were severe in some cases but were reversible. Blood CAR-BCMA T cells were predominantly highly differentiated CD8 T cells 6 to 9 days after infusion. BCMA antigen loss from MM was observed. Conclusion CAR-BCMA T cells had substantial activity against heavily treated relapsed/refractory MM. Our results should encourage additional development of CAR T-cell therapies for MM.
Chimeric Antigen Receptor-Modified T Cell Therapy in Multiple Myeloma: Beyond B Cell Maturation Antigen.
Timmers Marijke,Roex Gils,Wang Yuedi,Campillo-Davo Diana,Van Tendeloo Viggo F I,Chu Yiwei,Berneman Zwi N,Luo Feifei,Van Acker Heleen H,Anguille Sébastien
Frontiers in immunology
Chimeric antigen receptor (CAR)-modified T cell therapy is a rapidly emerging immunotherapeutic approach that is revolutionizing cancer treatment. The impressive clinical results obtained with CAR-T cell therapy in patients with acute lymphoblastic leukemia and lymphoma have fueled the development of CAR-T cells targeting other malignancies, including multiple myeloma (MM). The field of CAR-T cell therapy for MM is still in its infancy, but remains promising. To date, most studies have been performed with B cell maturation antigen (BCMA)-targeted CARs, for which high response rates have been obtained in early-phase clinical trials. However, responses are usually temporary, and relapses have frequently been observed. One of the major reasons for relapse is the loss or downregulation of BCMA expression following CAR-T therapy. This has fostered a search for alternative target antigens that are expressed on the MM cell surface. In this review, we provide an overview of myeloma target antigens other than BCMA that are currently being evaluated in pre-clinical and clinical studies.
Chimeric antigen receptor T cell therapies for multiple myeloma.
Wu Chao,Zhang Lina,Brockman Qierra R,Zhan Fenghuang,Chen Lijuan
Journal of hematology & oncology
Multiple myeloma (MM) is the second most common hematologic malignancy and remains incurable despite the advent of numerous new drugs such as proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and monoclonal antibodies. There is an unmet need to develop novel therapies for refractory/relapsed MM. In the past few years, chimeric antigen receptor (CAR)-modified T cell therapy for MM has shown promising efficacy in preclinical and clinical studies. Furthermore, the toxicities of CAR-T cell therapy are manageable. This article summarizes recent developments of CAR-T therapy in MM, focusing on promising targets, new technologies, and new research areas. Additionally, a comprehensive overview of antigen selection is presented along with preliminary results and future directions of CAR-T therapy development.
Chimeric antigen receptor T cell targeting B cell maturation antigen immunotherapy is promising for multiple myeloma.
Ma Tiantian,Shi Jing,Liu Huasheng
Annals of hematology
Multiple myeloma (MM) remains an incurable plasma cells malignancy because of its complex genetic heterogeneity and high relapse rate post immunotherapy. The encouraging results of chimeric antigen receptor T cell (CAR-T) targeting B cell maturation antigen (BCMA) immunotherapy clinical trials have shed light on curing MM in recent years. However, many therapeutic side effects limit the promotion and clinical use of this novel effective approach such as cytokine release syndrome, antigen escape, and neurotoxicity. We should make every effort to do further study about this immunotherapy to make it safer and effective. This review focusing on this topic clarifies the following contents: present status of MM treatment, effectiveness of CAR-T cells, features of BCMA, preclinical and clinical trials of BCMA CAR-T cells therapy, and existing problems and strategies. Hoping to provide a reference for the subsequent correlative clinical and research.
Multiple Myeloma, Targeting B-Cell Maturation Antigen With Chimeric Antigen Receptor T-Cells.
Shah Urvi A,Smith Eric L
Cancer journal (Sudbury, Mass.)
Multiple myeloma is still an incurable malignancy despite the many new therapies approved over the last decade and therefore represents a significant unmet medical need. To address this need, adoptive cellular therapies using chimeric antigen receptor (CAR) T-cells are being explored in clinical investigations. The number of CAR T-cell trials for multiple myeloma has increased exponentially over the past few years. Although the data are preliminary at this time, the results have garnered much enthusiasm in the field. Immune therapies targeting B-cell maturation antigen have been the most widely developed, and much of these early data were presented at the recent American Society of Hematology 2018 meeting. Here we review the available data for anti-B-cell maturation antigen CAR T-cell therapies and discuss next steps as the field progresses forward.
The promise of chimeric antigen receptor (CAR) T cell therapy in multiple myeloma.
Feinberg Daniel,Paul Barry,Kang Yubin
A cure for multiple myeloma (MM), a malignancy of plasma cells, remains elusive. Nearly all myeloma patients will eventually relapse and develop resistance to currently available treatments. There is an unmet medical need to develop novel and effective therapies that can induce sustained responses. Early phase clinical trials using chimeric antigen receptor (CAR) T cell therapy have shown great promise in the treatment of relapsed and/or refractory MM. In this review article, we provide an overview of the CAR constructs, the gene transfer vector systems, and approaches for T cell activation and expansion. We then summarize the outcomes of several early phase clinical trials of CAR T cell therapy in MM and the novel CAR T targets that are under development. Finally, we explore the potential mechanisms that result in disease relapse after CAR T therapy and propose future directions in CAR T therapy in MM.