scholarly journals Efficacy and Safety of Fully Human Bcma Targeting CAR T Cell Therapy in Relapsed/Refractory Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 929-929 ◽  
Author(s):  
Chunrui Li ◽  
Jue Wang ◽  
Di Wang ◽  
Guang Hu ◽  
Yongkun Yang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Residual Disease ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cells ◽  
Car T ◽  
Post Infusion ◽  
Minimal Residual

Background: Previous studies indicate that patients with relapsed/refractory multiple myeloma (RRMM) who receive BCMA-targeting CAR-T cells may achieve better remission but have a higher relapse rate. Persistence of CAR T cells post-infusion may be one determinant of the duration of response. Moreover, once the disease progresses again, the re-infusion of CAR-T cells is not effective. To solve this dilemma, we have developed a novel BCMA-targeting CAR-T (CT103A) with a lentiviral vector containing a CAR structure with a fully human scFv, CD8a hinger, and transmembrane, 4-1BB co-stimulatory and CD3z activation domains. Methods: ChiCTR1800018137 is a single-center and single-arm trial of CT103A in patients with RRMM (≥ 3 prior lines, including a proteasome inhibitor and an IMiD, or double refractory). The primary objectives are the incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). The secondary objectives are the duration of clinical response, evaluation of minimal residual disease (MRD), progression-free and overall survival, and CAR-T cell persistence in blood. Between September 21, 2018, and August 1st, 2019, sixteen patients (including 4 patients having relapsed after being given a murine BCMA CAR-T and 5 patients having extramedullary disease and/or plasma cell leukemia) received CT103A in 3+3 dose-escalation trial (four doses at 1, 3, 6, 8 ×106/kg) after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. Median follow-up after CT103A infusion was 195 days (23 to 314 days) and all 16 patients were evaluable for initial (14 days) clinical response. Results: As of August 1st, 2019, the objective response rate was 100%, 6/16 patients achieved CR/sCR within two weeks post-infusion and all 8 patients surpassing 6 months achieved VGPR/CR/sCR. CR/sCR was 75%, and VGPR was 25% for these 8 patients, according to the IMWG Uniform Response Criteria for MM. In 4 patients who have participated in a prior CAR-T trial, three have achieved sCR, and 1 achieved VGPR. All 15 patients who could be evaluated for minimal residual disease (MRD) had MRD-negative status (≤10-4 nucleated cells by flow). The circulating CT103A cells were detected in the blood by flow and digital polymerase chain reaction, peaking at 14 days (ranging from 9 to 25), and remaining detectable in 12/16 patients, at the time of their last evaluation. Patient #1 (the first patient treated) has now exceeded 314 days of CART persistence, post-infusion. All sixteen patients developed cytokine release syndrome (according to ASBMT Consensus Grading for Cytokine Release Syndrome and Neurological Toxicity Associated with Immune Effector Cells: 10 Grade 1-2, 5 Grade 3,1 Grade 4). A grade 4 CRS appeared at the 6×106 /kg dose level and was considered as a dose-limiting toxicity DLT. No neurotoxicity was observed in all dose groups. One patient died of a lung infection 19 days post-infusion. Conclusions: Data from this early-stage clinical study showed the unparalleled safety and efficacy of CT103A in heavily pretreated R/R multiple myeloma patients. Highly active (ORR 100%) and rapid response within two weeks, suggests CT103A could be developed as a competitive therapy to treat patients with RRMM. Disclosures Hu: Nanjing Iaso Biotherapeutics Co. Ltd..: Employment. Yang:Nanjing Iaso Biotherapeutics Co.: Employment. Zhou:Nanjing Iaso Biotherapeutics Co. Ltd.: Other: Chairman of Advisory Committee of Science and Medicine .

scholarly journals Development of CAR-T Cell Constructs with Broad Anti-Tumor Tropism

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 24-24
Author(s):  
Ameet K. Mishra ◽  
Iris Kemler ◽  
David Dingli
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cells ◽  
Car T Cell ◽  
Nsg Mice ◽  
Human T Cells ◽  
Car T

Chimeric antigen receptor T (CAR-T) cell therapy is a transformative approach to cancer eradication. CAR-T is expensive in part due to the restricted use of each CAR construct for a specific set of tumors such as B cell lymphoma targeted with CD19 and multiple myeloma targeted with BCMA. A CAR construct with broad anti-tumor activity can be advantageous due to wide applicability and scalability of production. We show that CD126, the IL-6 receptor alpha, is an antigen that is expressed by many hematologic and solid malignancies including multiple myeloma, non-Hodgkin lymphoma, acute myeloid leukemia, pancreatic and prostate adenocarcinoma, non-small cell lung cancer and malignant melanoma amongst others. High CD126 expression is a negative prognostic marker in many malignancies. The two CD126 targeting CAR-T cell constructs contain the CD28 anchoring domain followed by 4-1BB and CD3 zeta signaling domain. Lentiviral vectors were generated with triple plasmid (CAR, psPAX2 and pMD2.G) transfection of 293T cells and the vector concentrated by ultracentrifugation and used to transduce human T cells. T cells were isolated from leuko-reduction cones using negative selection with magnetic beads. The transduction efficiency was around 60%. The T cells were activated with anti-CD3/CD28 beads and expanded for two weeks before using for downstream experiments. CD126 CAR-T cells are able to kill many tumor cells in an antigen specific manner and with an efficiency that is directly proportional to the cell surface expression of CD126 expression (rho = 0.6, p = 0.0019). The presence of soluble CD126 in the culture media did not interfere with CAR-T cell killing. The CAR-T constructs bind murine CD126. However, injection of CD126 targeting CAR-T cells in NSG mice did not lead to any evidence of hepatotoxicity and weight loss despite possible expression of this antigen on hepatocytes. In vivo studies in NSG mice with multiple myeloma (RPMI-8226) and prostate adenocarcinoma (DU-145) xenograft models (n=10 tumors per group) showed that the intravenously injected CD126 targeted CAR-T cells (107) infiltrated the tumors, expanded, produced human interferon gamma and killed the tumor cells (p<0.001). Bioluminescence imaging showed control of tumor growth in the actively treated tumors compared to the controls (p<0.05). At post mortem, mice injected with CD126 targeted CAR-T cells had smaller residual tumors compared to controls injected with non-engineered human T cells from the same donor. Binding of sIL-6R by CAR-T cells could mitigate cytokine release syndrome. In support of this, murine SAA-3 levels (the equivalent of human CRP) were lower in mice injected with CD126 CAR-T compared to controls (p<0.05), suggesting that binding of sIL-6R by CAR-T cells could mitigate cytokine release syndrome. CD126 provides a novel therapeutic for CAR-T cells in a broad variety of tumors with low risk of toxicity. Disclosures Dingli: Apellis: Consultancy; Millenium: Consultancy; Janssen: Consultancy; Bristol Myers Squibb: Research Funding; Sanofi-Genzyme: Consultancy; Alexion: Consultancy; Rigel: Consultancy; Karyopharm Therapeutics: Research Funding.

scholarly journals Preclinical development of CD126 CAR-T cells with broad antitumor activity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ameet K. Mishra ◽  
Iris Kemler ◽  
David Dingli
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Tumor Cells ◽  
Prostate Adenocarcinoma ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cells ◽  
Car T

AbstractChimeric antigen receptor T (CAR-T) cell therapy is a transformative approach to cancer eradication. CAR-T is expensive partly due to the restricted use of each CAR construct for specific tumors. Thus, a CAR construct with broad antitumor activity can be advantageous. We identified that CD126 is expressed by many hematologic and solid tumors, including multiple myeloma, lymphoma, acute myeloid leukemia, pancreatic and prostate adenocarcinoma, non-small cell lung cancer, and malignant melanoma among others. CAR-T cells targeting CD126 were generated and shown to kill many tumor cells in an antigen-specific manner and with efficiency directly proportional to CD126 expression. Soluble CD126 did not interfere with CAR-T cell killing. The CAR-T constructs bind murine CD126 but caused no weight loss or hepatotoxicity in mice. In multiple myeloma and prostate adenocarcinoma xenograft models, intravenously injected CD126 CAR-T cells infiltrated within, expanded, and killed tumor cells without toxicity. Binding of soluble interleukin-6 receptor (sIL-6R) by CAR-T cells could mitigate cytokine release syndrome. Murine SAA-3 levels were lower in mice injected with CD126 CAR-T compared to controls, suggesting that binding of sIL-6R by CAR-T cells could mitigate cytokine release syndrome. CD126 provides a novel therapeutic target for CAR-T cells for many tumors with a low risk of toxicity.

scholarly journals Development of molecular and pharmacological switches for chimeric antigen receptor T cells

2019 ◽  
Vol 8 (1) ◽  
Author(s):  
Bill X. Wu ◽  
No-Joon Song ◽  
Brian P. Riesenberg ◽  
Zihai Li
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Intervention Strategy ◽  
Antigen Receptor ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Abstract The use of chimeric antigen receptor (CAR) T cell technology as a therapeutic strategy for the treatment blood-born human cancers has delivered outstanding clinical efficacy. However, this treatment modality can also be associated with serious adverse events in the form of cytokine release syndrome. While several avenues are being pursued to limit the off-target effects, it is critically important that any intervention strategy has minimal consequences on long term efficacy. A recent study published in Science Translational Medicine by Dr. Hudecek’s group proved that dasatinib, a tyrosine kinase inhibitor, can serve as an on/off switch for CD19-CAR-T cells in preclinical models by limiting toxicities while maintaining therapeutic efficacy. In this editorial, we discuss the recent strategies for generating safer CAR-T cells, and also important questions surrounding the use of dasatinib for emergency intervention of CAR-T cell mediated cytokine release syndrome.

Latest in Clinical Application of CAR Cell Therapy for B-cell Malignancy and Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. SCI-24-SCI-24
Author(s):  
Crystal L. Mackall
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
B Cell ◽  
Graft Failure ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cells ◽  
Car T

Unparalleled remission rates in patients with chemorefractory B-ALL treated with CD19-CAR T cells illustrate the potential for immunotherapy to eradicate chemoresistant cancer. CD19-CAR therapy is poised to fundamentally alter the clinical approach to relapsed B-ALL and ultimately may be incorporated into frontline therapy. Despite these successes, as clinical experience with this novel modality has increased, so has understanding of factors that limit success of CD19-CAR T cells for leukemia. These insights have implications for the future of cell based immunotherapy for leukemia and provide a glimpse of more global challenges likely to face the emerging field of cancer immunotherapy. Five challenges limiting the overall effectiveness of CD19-CAR therapy will be discussed: 1) T cell exhaustion is a differentiation pathway that occurs in T cells subjected to excessive T cell receptor signaling. A progressive functional decline occurs, manifest first by diminished proliferative potential and cytokine production, following by diminished cytolytic function and ultimately cell death. High leukemic burdens predispose CD19-CAR T cells to exhaustion as does the presence of a CD28 costimulatory signal, while a 4-1BB costimulatory signal diminishes the susceptibility to exhaustion. This biology is likely responsible for limited CD19-CAR persistence observed in clinical trials using a CD19-zeta-28 CAR compared to that observed using a CD19-zeta-BB CAR. 2) Leukemia resistance occurs in approximately 20% of patients treated with CD19-CAR and is associated with selection of B-ALL cells lacking CD19 targeted by the chimeric receptor. Emerging data demonstrates two distinct biologies associated with CD19-epitope loss. Isoform switch is characterized by an increase in CD19 isoforms specifically lacking exon 2, which binds the scFvs incorporated into CD19-CARs currently in clinical trials. Lineage switch is characterized by a global change in leukemia cell phenotype, and is associated with dedifferentiation toward a more stem-like, or myeloid leukemia in the setting of CD19-CAR for B-ALL. These insights raise the prospect that effectiveness of immunotherapy for leukemia may be significantly enhanced by targeting of more than one leukemia antigen. 3) CAR immunogenicity describes immune responses induced in the host that can lead to rejection of the CD19-CAR transduced T cells. Anti-CAR immune responses have been observed by several groups, and mapping is underway to identify the most immunogenic regions of the CAR, as a first step toward preventing this complication. 4) The most common toxicities associated with CD19-CAR therapy are cytokine release syndrome, neurotoxicity and B cell aplasia. Cytokine release syndrome is primarily observed in the setting of high disease burdens and efforts are underway to standardize grading and treatment algorithms to diminish morbidity. Increased information is needed to better understand the neurotoxicity observed in the context of this therapy. Although clinical data is limited, B cell aplasia appears to be adequately treated with IVIG replacement therapy. 5) Technical graft failure (e.g. inadequate expansion/transduction) is a challenge that has received limited attention, primarily since many trials have not reported the percentage of patients in whom adequate products could not be generated. We have observed that technical graft failure is often associated with a high frequency of contaminating myeloid populations in the lymphocyte product and selection approaches designed to eradicate myeloid populations have resulted in improved T cell expansion and transduction. These results suggest that optimization of lymphocyte selection may diminish the incidence of technical graft failure. Disclosures Mackall: Juno: Patents & Royalties: CD22-CAR. Off Label Use: cyclophosphamide.

Pre-Emptive Donor Lymphocyte Infusion with CD19-Directed, CAR-Modified T Cells Infused after Allogeneic Hematopoietic Cell Transplantation for Patients with Advanced CD19+ Malignancies

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 862-862 ◽  
Author(s):  
Partow Kebriaei ◽  
Stefan O. Ciurea ◽  
Mary Helen Huls ◽  
Harjeet Singh ◽  
Simon Olivares ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hematopoietic Cell Transplantation ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Lymphoid Malignancies ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Equity Ownership

Background: Allogeneic hematopoietic cell transplantation (HCT) can be curative in a subset of patients with advanced lymphoid malignancies but relapse remains a major reason for treatment failure. Donor-derived, non-specific lymphocyte infusions (DLI) can confer an immune anti-malignancy effect but can be complicated by graft-versus-host-disease (GVHD). Chimeric antigen receptor (CAR)-modified T cells directed toward CD19 have demonstrated dramatic efficacy in patients with refractory ALL and NHL. However, responses are often associated with life-threatening cytokine release syndrome. Aim: We hypothesized that infusing CAR-modified, CD19-specific T-cells after HCT as a directed DLI would be associated with a low rate of GVHD, better disease control, and a less severe cytokine release syndrome since administered in a minimal disease state. Methods: We employed a non-viral gene transfer using the Sleeping Beauty (SB) transposon/transposase system to stably express a CD19-specific CAR (designated CD19RCD28 that activates via CD3z & CD28) in donor-derived T cells for patients with advanced CD19+ lymphoid malignancies. T-cells were electroporated using a Nucleofector device to synchronously introduce two DNA plasmids coding for SB transposon (CD19RCD28) and hyperactive SB transposase (SB11). T-cells stably expressing the CAR were retrieved over 28 days of co-culture by recursive additions of g-irradiated activating and propagating cells (AaPC) in presence of soluble recombinant interleukin (IL)-2 and IL-21. The AaPC were derived from K562 cells and genetically modified to co-express CD19 as well as the co-stimulatory molecules CD86, CD137L, and a membrane-bound version of IL-15. Results: To date, we have successfully treated 21 patients with median age 36 years (range 21-62) with advanced CD19+ ALL (n=18) or NHL (n=3); 10 patients had active disease at time of HCT. Donor-derived CAR+ T cells (HLA-matched sibling n=10; 1 Ag mismatched sibling n=1; haplo family n=8; cord blood n=2) were infused at a median 64 days (range 42-91 days) following HCT to prevent disease progression. Transplant preparative regimens were myeloablative, busulfan-based (n=10) or reduced intensity, fludarabine-based (n=11). All patients were maintained on GVHD prophylaxis at time of CAR T-cell infusion with tacrolimus, plus mycophenolate mofeteil for cord, plus post-HCT cyclophosphamide for haplo donors. The starting CAR+ T-cell dose was 106 (n=7), escalated to 107 (n=6), 5x107 (n=5), and currently at 108 (n=3) modified T cells/m2 (based on recipient body surface area). Patients have not demonstrated any acute or late toxicity to CAR+ T cell infusions. Three patients developed acute grades 2-4 GVHD (liver n=1, upper GI n=1, skin=1) which was within the expected range after allogeneic HCT alone. Of note, the rate of CMV reactivation after CAR T cell infusion was 24% vs. 41 % previously reported for our patients without CAR T cell infusion (Wilhelm et al. J Oncol Parm Practice, 2014, 20:257). Nineteen patients have had at least 30 days follow-up post CAR T-cell infusion and are evaluable for disease progression. Forty-eight percent of patients (n=10) remain alive and in complete remission (CR) at median 5.2 months (range 0-21.3 months) following CAR T cell infusion. Importantly, among 8 patients who received haplo-HCT and CAR, 7 remain in remission at median 4.2 months. Conclusion: We demonstrate that infusing donor-derived CD19-specific CAR+ T cells, using the SB and AaPC platform, in the adjuvant HCT setting as pre-emptive DLI may provide an effective and safe approach for maintaining remission in patients at high risk for relapse. Graft-vs-host disease did not appear increased by administration of the donor derived CAR-T cells. Furthermore, the add-back of allogeneic T cells appears to have contributed to immune reconstitution and control of opportunistic viral infection. Disclosures Huls: Intrexon and Ziopharm: Employment, Equity Ownership. Singh:Intrexon and Ziopharm: Equity Ownership, Patents & Royalties. Olivares:Intrexon and Ziopharm: Equity Ownership, Patents & Royalties. Su:Ziopharm and Intrexon: Employment. Figliola:Intrexon and Ziopharm: Equity Ownership, Patents & Royalties. Kumar:Ziopharm and Intrexon: Equity Ownership. Jena:Ziopharm Oncology: Equity Ownership, Patents & Royalties: Potential roylaties (Patent submitted); Intrexon: Equity Ownership, Patents & Royalties: Potential royalties (Patent submitted). Ang:Intrexon and Ziopharm: Equity Ownership. Lee:Intrexon: Equity Ownership; Cyto-Sen: Equity Ownership; Ziopharm: Equity Ownership.

T Cells Expressing a Novel Fully-Human Anti-CD19 Chimeric Antigen Receptor Induce Remissions of Advanced Lymphoma in a First-in-Humans Clinical Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 999-999 ◽  
Author(s):  
Jennifer N. Brudno ◽  
Victoria Shi ◽  
David Stroncek ◽  
Stefania Pittaluga ◽  
Jennifer A. Kanakry ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Low Dose ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cells ◽  
Car T ◽  
Low Dose Chemotherapy ◽  
Cd19 Expression

Abstract Background: Chimeric antigen receptors (CARs) are fusion proteins that combine antigen-recognition domains and T-cell signaling domains. T cells genetically modified to express CARs directed against the B-cell antigen CD19 can cause remissions of B-cell malignancies. Most CARs in clinical use contain components derived from murine antibodies. Immune responses have been reported to eliminate CAR T cells in clinical trials, especially after second infusions of CAR T cells (C. Turtle et al., Journal of Clinical Investigation, 2016). These immune responses could be directed at the murine components of CARs. Such immune responses might limit the persistence of the CAR T cells, and anti-CAR immune responses might be an especially important problem if multiple infusions of CAR T cells are administered. Development of fully-human CARs could reduce recipient immune responses against CAR T cells. Methods: We designed the first fully-human anti-CD19 CAR (HuCAR-19). The CAR is encoded by a lentiviral vector. This CAR has a fully-human single-chain variable fragment, hinge and transmembrane regions from CD8-alpha, a CD28 costimulatory domain, and a CD3-zeta T-cell activation domain. We conducted a phase I dose-escalation trial with a primary objective of investigating the safety of HuCAR-19 T cells and a secondary objective of assessing anti-lymphoma efficacy. Low-dose chemotherapy was administered before HuCAR-19 T-cell infusions to enhance CAR T-cell activity. The low-dose chemotherapy consisted of cyclophosphamide 300 mg/m2 daily for 3 days and fludarabine 30 mg/m2 daily for 3 days on the same days as cyclophosphamide. HuCAR-19 T cells were infused 2 days after the end of the chemotherapy regimen. Patients with residual lymphoma after a first treatment were potentially eligible for repeat treatments if dose-limiting toxicities did not occur with the first treatment. Repeat infusions were given at the same dose level as the first infusion or 1 dose level higher than the first infusion. Findings: A total of 11 HuCAR-19 T-cell infusions have been administered to 9 patients; 2 patients received 2 infusions each. So far, there is an 86% overall response rate (Table). Grade 3 adverse events (AEs) included expected cytokine-release syndrome toxicities such as fever, tachycardia, and hypotension. Corticosteroids were used to treat toxicity in Patient 3. The interleukin-(IL)-6 receptor antagonist tocilizumab was used to treat toxicity in Patient 4, and both tocilizumab and corticosteroids were used to treat toxicity in Patient 8. Only 1 of 8 evaluable patients, Patient 3, has experienced significant neurological toxicity to date. This patient experienced encephalopathy that was associated with a cerebrospinal fluid (CSF) white blood cell count of 165/mm3. Almost all of the CSF white cells were CAR T cells, and the CSF IL-6 level was elevated. All toxicities have resolved fully in all patients. In Patient 1, tumor biopsies revealed a complete loss of CD19 expression by lymphoma cells after 2 HuCAR-19 T-cell infusions, which to our knowledge is the first documented complete loss of CD19 expression by lymphoma after anti-CD19 CAR T-cell therapy. This loss of CD19 expression was associated with lymphoma progression. After first CAR-19 T-cell infusions, HuCAR-19 cells were detectable in the blood of every patient. The median peak number of blood CAR+ cells was 26/microliter (range 3 to 1005 cells/microliter). Blood HuCAR-19 cells were detected after second infusions in the blood of both patients who received second infusions. Patient 1 obtained a partial response after a second infusion after only obtaining stable disease after a first infusion. We detected elevations of inflammatory cytokines including IL-6, interferon gamma, and IL-8 in the serum of patients experiencing clinical toxicities consistent with cytokine-release syndrome. Interpretation: T cells expressing HuCAR-19 have substantial activity against advanced lymphoma, and infusions of HuCAR-19 T cells caused reversible toxicities attributable to cytokine-release syndrome. Disclosures Kochenderfer: Kite Pharma: Patents & Royalties, Research Funding; bluebird bio: Patents & Royalties, Research Funding.

Chimeric Antigen Receptor T-Cell Therapies for Aggressive B-Cell Lymphomas: Current and Future State of the Art

2019 ◽  
pp. 446-453 ◽  
Author(s):  
Jeremy S. Abramson ◽  
Matthew Lunning ◽  
M. Lia Palomba
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Chimeric Antigen Receptor ◽  
Refractory Disease ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Aggressive B-cell lymphomas that are primary refractory to, or relapse after, frontline chemoimmunotherapy have a low cure rate with conventional therapies. Although high-dose chemotherapy remains the standard of care at first relapse for sufficiently young and fit patients, fewer than one-quarter of patients with relapsed/refractory disease are cured with this approach. Anti-CD19 chimeric antigen receptor (CAR) T cells have emerged as an effective therapy in patients with multiple relapsed/refractory disease, capable of inducing durable remissions in patients with chemotherapy-refractory disease. Three anti-CD19 CAR T cells for aggressive B-cell lymphoma (axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene ciloleucel) are either U.S. Food and Drug Administration approved or in late-stage development. All three CAR T cells produce durable remissions in 33%–40% of treated patients. Differences among these products include the specific CAR constructs, costimulatory domains, manufacturing process, dose, and eligibility criteria for their pivotal trials. Notable toxicities include cytokine release syndrome and neurologic toxicities, which are usually treatable and reversible, as well as cytopenias and hypogammaglobulinemia. Incidences of cytokine release syndrome and neurotoxicity differ across CAR T-cell products, related in part to the type of costimulatory domain. Potential mechanisms of resistance include CAR T-cell exhaustion and immune evasion, CD19 antigen loss, and a lack of persistence. Rational combination strategies with CAR T cells are under evaluation, including immune checkpoint inhibitors, immunomodulators, and tyrosine kinase inhibitors. Novel cell products are also being developed and include CAR T cells that target multiple tumor antigens, cytokine-secreting CAR T cells, and gene-edited CAR T cells, among others.

scholarly journals T Cells Expressing Anti B-Cell Maturation Antigen Chimeric Antigen Receptors for Plasma Cell Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1013-1013 ◽  
Author(s):  
Chunrui Li ◽  
Qiuxiang Wang ◽  
Hui Zhu ◽  
Xia Mao ◽  
Ying Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Plasma Cell ◽  
Response Rate ◽  
Disease Free Survival ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cells ◽  
Car T ◽  
Expression Rate

Abstract Introduction: Chimeric antigen receptor (CAR) modified T cells targeting B-cell maturation antigen (BCMA) have shown activity in a case series of patients with relapsed or refractory Multiple Myeloma (MM), but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define the duration of disease, number of treatment lines, treatment course, extramedullary plasma cell tumor, hematopoietic stem cell transplantation, FISH abnormal gene number, risk (combined FISH and second-generation sequencing analysis) ,feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in patients with malignant plasma cell disease treated with BCMA-CAR T cells. This trial is registered with ChiCTR, number ChiCTR-OPC-16009113. Methods: Between March 10, 2017, and March 27, 2018, 28 patients (including 26 patients with relapsed or refractory MM, 1 patient with Plasma cell leukemia and 1 patient with POEMS) were enrolled and infused with BCMA-CAR T cells. The CAR-BCMA chimeric antigen receptor was encoded by the lentiviral vector and contained a murine anti-BCMA single-chain variable fragment, a CD8a hinge, the CD28 transmembrane regions and intracellular domain and CD3-ζ T-cell activation domain. Peripheral blood mononuclear cells were collected from the patient by leukapheresis, and whole peripheral blood mononuclear cells were cultured and transduced. Patients received a target dose of 5.4 ~ 25.0×106 anti-BCMA CAR T cells per kilogram of body weight after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. MM response assessment was conducted according to the International Uniform Response Criteria for MM. Cytokine-release syndrome (CRS) was graded as Lee DW et al. described (Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188-195.) Results: Twenty-six of 28 treated patients obtained remission. According to the expression rate of BCMA on the surface of plasma cells, all patients were divided into BCMA strong expression group (22 cases, BCMA expression rate ≥ 50%) and BCMA weak expression group (6 cases, BCMA expression rate <50%). The overall response rate for BCMA strong expression group was 87%, with 73% complete response. The overall response rate for the BCMA weak expression group was 100%, with 33% very good partial response or complete response (Figure a-d). The overall survival of the two groups was undefined (a strong group) and 206.5 days (a weak group) respectively (P=0.0468). The median disease-free survival of the two groups was 296 days (strong group, 20 responded cases) and 64 days (weak group,6 cases) respectively (P=0.0069) (Figure e, f). Patients with longer duration have shorter overall survival time. Patients with soft-tissue plasmacytomas have short disease-free survival (155 days vs. 327 days) (Figure g, h). All toxicities were fully reversible, with the most severe being grade 3 cytokine release syndrome that occurred in four of 28 patients. High peak blood CAR+ cell levels were associated with anti-MM responses. Blood CAR-BCMA T cells were predominantly highly differentiated CD8+ T cells after infusion. Conclusions: BCMA-CAR T cell therapy is feasible, safe, and mediates potent anti-tumor activity in relapsed/refractory Multiple Myeloma. All toxicities were reversible Our results should encourage additional development of CAR T-cell therapies for other plasma cell malignancies such as plasma cell leukemia and POEMS. Figure Figure. Disclosures No relevant conflicts of interest to declare.

scholarly journals The BCMA-Targeted Fourth-Generation CAR-T Cells Secreting IL-7 and CCL19 for Therapy of Refractory/Recurrent Multiple Myeloma

2021 ◽  
Vol 12 ◽  
Author(s):  
Deming Duan ◽  
Keke Wang ◽  
Cheng Wei ◽  
Dudu Feng ◽  
Yonghua Liu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Fourth Generation ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Human Clinical Trial ◽  
Safety And Efficacy ◽  
Car T Cells ◽  
Car T ◽  
Hematological Tumors

Chimeric antigen receptor (CAR) technology has revolutionized cancer treatment, particularly in malignant hematological tumors. Currently, the BCMA-targeted second-generation CAR-T cells have showed impressive efficacy in the treatment of refractory/relapsed multiple myeloma (R/R MM), but up to 50% relapse remains to be addressed urgently. Here we constructed the BCMA-targeted fourth-generation CAR-T cells expressing IL-7 and CCL19 (i.e., BCMA-7 × 19 CAR-T cells), and demonstrated that BCMA-7 × 19 CAR-T cells exhibited superior expansion, differentiation, migration and cytotoxicity. Furthermore, we have been carrying out the first-in-human clinical trial for therapy of R/R MM by use of BCMA-7 × 19 CAR-T cells (ClinicalTrials.gov Identifier: NCT03778346), which preliminarily showed promising safety and efficacy in first two enrolled patients. The two patients achieved a CR and VGPR with Grade 1 cytokine release syndrome only 1 month after one dose of CAR-T cell infusion, and the responses lasted more than 12-month. Taken together, BCMA-7 × 19 CAR-T cells were safe and effective against refractory/relapsed multiple myeloma and thus warranted further clinical study.

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