Safety Of Chimeric Antigen Receptor Research Articles

CRISPR/Cas9-mediated Gene Knockout Followed by Negative Selection Leads to a Complete TCR Depletion in ortho CAR19 T Cells.

Genome-editing technologies, especially CRISPR (clustered regularly interspaced short palindrome repeats)/Cas9 (CRISPR-associated protein 9), endows researchers the ability to make efficient, simple , and precise genomic DNA changes in many eukaryotic cell types. CRISPR/Cas9-mediated efficient gene knockout holds huge potential to improve the efficacy and safety of chimeric antigen receptor (CAR) T cell-based immunotherapies. Here, we describe an optimized approach for a complete loss of endogenous T cell receptor (TCR) protein expression, by CRISPR/Cas9-mediated TCR α constant (TRAC) and TCR β constant (TRBC) gene knockout, followed by subsequent CD3 negative selection in engineered human ortho CAR19 T cells. We believe this method can be expanded beyond CAR T cell application, and target other cell surface receptors. Graphical abstract: Schematic overview of the two-step process of endogenous TCR depletion in engineered human ortho CAR19 T cells using (1) CRISPR/Cas9-mediated gene knockout followed by (2) CD3 negative selection.

Efficacy and Safety of Innovative Experimental Chimeric Antigen Receptor (CAR) T-cells versus Axicabtagene ciloleucel (Yescarta) for the Treatment of Relapsed/Refractory Large B-Cell Lymphoma (LBCL): Matching Adjusted Indirect Comparisons (MAICs) and Systematic Review.

Despite favorable results of CAR T-cell therapy for relapsed/refractory large B-cell lymphoma (R/R LBCL), several challenges remain, including incomplete response, immune-mediated toxicity, and antigen-loss relapse. We delineated the relative clinical benefit of the novel approaches compared to the currently approved CAR T-cell therapies. In the absence of head-to-head comparisons and randomized controlled trials, we performed Matching Adjusted Indirect Comparisons to quantify the relative efficacy and safety of experimental CARs against Axicabtagene ciloleucel (Yescarta), the first FDA-approved CAR. A total of 182R/R LBCL patients from 15 clinical trials with individual patient data (IPD) were pooled into eight populations by their CAR T-cell constructs and +/- ASCT status. The study endpoints were Progression-Free Survival (PFS), grade ≥ 3 cytokine release syndrome (CRS), and grade ≥ 3 neurotoxicity (NT). Tandem CD19.CD20.4-1BBζ CARs indicated favorable efficacy and safety, whereas the co-infusion of CD19 & CD20 with 4-1BBζ showed no clinical benefit compared to Yescarta. Third generation CD19. CD28. 4-1BBζ, and sequential administration of autologous stem cell transplantation (ASCT) and CD19. CARs presented statistically insignificant yet improved PFS and safety except for ASCT combined intervention which had suggestively higher NT risk than Yescarta. CARs with modified co-stimulatory domains to reduce toxicity (Hu19. CD8.28Zζ and CD19. BBz.86ζ) presented remarkable safety with no severe adverse events; however, both presented worse PFS than Yescarta. Third-generation CARs demonstrated statistically significantly lower NT than Yescarta. CD20. 4-1BBζ data suggested targeting CD20 antigen alone lacks clinical or safety benefit compared to Yescarta. Further comparisons with other FDA-approved CARs are needed.

Efficacy and Safety of Chimeric Antigen Receptor T Cell Therapy in Chronic Lymphocytic Leukemia: A Systematic Review

Background:Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults. Despite the advancements in drug therapies, CLL is largely incurable, and relapsed/refractory (R/R) patients have a very poor prognosis. Chimeric antigen receptor T (CART) cell therapy has shown promising results in B-cell malignancies. We conducted a systematic review to assess the efficacy and safety of CART cell therapy in patients with CLL.Methods:PRISMA guidelines were followed to perform the literature search and selection of articles for this systematic review. A search was performed using databases including PubMed, Cochrane, Web of Science, Embase, and clinicaltrials.gov. We used the following Mesh and Emtree terms, “Chronic lymphocytic leukemia” AND “Adoptive immunotherapy” from the inception of literature till 06/11/2021. Out of 1319 articles, we screened and included nine clinical studies (N=208) measuring the efficacy (i.e., complete response, partial response, etc.) and safety (adverse events ≥grade 3) in clinical terms. We excluded case reports, pre-clinical studies, review articles, and meta-analyses.Results:In 9 clinical studies, 158 patients with CLL were treated with anti-CD19 CART cell therapy. The range of age of the patients was 38-75 years. A high dose was used in 38 patients, and ibrutinib was added in 19 patients with CLL. The therapy was well tolerated with ≥grade 3 cytokine release syndrome (CRS) and neurological toxicity reported in 23/151 (15%) and 20/151 (13%) of the patients, respectively. Table 1. Complete response (CR), partial response (PR), and overall response (OR) were seen in 40% (54/134), 17% (22/126), and 56% (103/183). In the clinical study by Frey et al. (N=51)., progression-free survival (PFS) and ORR were significantly higher in the high dose (5x10 8 cells/kg) group as compared to the low dose (5x10 7 cells/kg) group (1.8 months vs. one month and 53% vs. 29%, respectively) without significantly increasing treatment-related adverse events (TRAE). In the clinical study by Gauthier et al. (N=38)., ORR was significantly high in the anti-CD19 CART cell therapy + ibrutinib group compared to the no ibrutinib group (83% vs. 56%). Neutropenia, infection, thrombocytopenia, leukemia, hypocalcemia, elevated ALT, and tumor lysis syndrome were common ≥grade 3 TRAEs reported in these patients (Table 1). More clinical trials are targeting CD-20, CD-137, CD-7, CD-28, ROR1, etc (Table 2).Conclusion:Anti-CD19 CART cell therapy was safe and effective in the treatment of CLL patients. A high dose of 5x10 8/kg CART cell therapy was well tolerated and had superior efficacy. Adding ibrutinib to CART cell therapy was safe and more effective than anti-CD19 CART cell therapy alone. More placebo-controlled randomized multicenter studies are needed to confirm these results. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Secondary Humanized CAR T Cells Salvage Therapy Improves Survival of R/R DLBCL Patients Failed to Murine CD19-CAR T Cells Therapy

Background: The Chimeric antigen receptor (CAR) T-cell therapy has shown very promising future in relapsed/refractory diffused large B cell lymphoma (R/R DLBCL) patients resisted to second-line chemotherapy and failed to auto hematopoietic cell transplantation. Trials with murine CD19-CAR T-cell therapy have shown only 40%-54% complete remission (CR) rate in patients with R/R DLBCL. However, 30%-60% of patients with previous CR relapse within 1 year. It is critical to develop new strategies to improve survival of R/R DLBCL patients failed to murine CD19-CAR T cells therapy. Forty-two R/R DLBCL patients failed to murine CD19-CAR T cells therapy who accepted secondary humanized CAR T cells salvage therapy in our center were recruited to this studyAim: 1. Investigate the effect and safety of Secondary humanized CAR T cells salvage therapy in R/R DLBCL patients failed to murine CD19-CAR T cells therapy. 2. Analyze the influence factor of curative effect of secondary humanized CAR T cells, to predict the outcome of treatment.Method: We retrospectively analyzed 42 cases treated with secondary humanized CAR T cells salvage therapy after failing to murine CD19-CAR T cells therapy in our center, enrolled from 05/01/2018 to 05/01/2020. According to the new result of tumor immunohistochemical analysis, five patients still chose to target CD19, twenty-one targeted CD20, and sixteen targeted CD22. Pretreatment regimen before infusion of CAR T cells were chemotherapy comprising fludarabine (three doses of 30 mg/m2 daily) and cyclophosphamide (three doses of 300mg/m2 daily). The T-cells with specific CAR expression in peripheral blood were dynamically detected by flow cytometry. After CAR T-cells infusion, PET-CT were performed every 3 months to evaluate the state of disease. Patients were followed up till 06/15/2021Results: The incidence of cytokine release syndrome (CRS) was 84%, of which 22% was severe CRS (≥grade 3), as the incidence of immune effector cells associated neurologic toxicity (ICANS) was 7.14%, of which 2.83% was severe ICANS. The incidence of target organ damage was 12%. The rate of treatment-related mortality was 7%. In 3 months, complete remission rate was 26.2%, partial remission rate (PR) was 33.3% and the overall response rate (ORR) was 59.5%. Ten patients (26.2%) remained in complete remission at the cutoff date. The median of progression-free survival (PFS) length was 4.42 months (95%CI: 1.87-6.02). The median of overall survival (OS) length was 9.24 months (95%CI: 4.44-~). The 1-year overall survival rate was 38.1%. We also found high level of LDH, heavy tumor burden, no less than 4 IPI score, and double expression of MYC and BCL2 were risk factors of OS, PFS and CR. The patients who had achieved CR or PR after murine CD19-CAR T cells therapy had a favorable OS and PFS. The longer the patients had PFS during murine CD19-CAR T cells therapy, the longer PFS and OS during humanized CAR T cells therapy.Conclusion: 1. Secondary humanized CAR T cells salvage therapy improves survival of R/R DLBCL patients failed to murine CD19-CAR T cells therapy. 2. The incidence of severe CRS and treatment-related causality were relatively low. 3. The patients who got better curative effect during murine CAR T cells therapy prone to a longer survival time.Keywords: Secondary humanized CAR T cells therapy, murine CAR T cells therapy, R/R DLBCL, CRS, ICANS. DisclosuresNo relevant conflicts of interest to declare.

Efficacy and Safety of Chimeric Antigen Receptor T Cells in Acute Lymphoblastic Leukemia With Post-Transplant Relapse.

Twenty patients with relapsed B-ALL after HSCT were treated with CAR T cell therapy and were evaluated for efficacy and safety. Twelve patients previously received haploidentical transplantation, while 8 patients received HLA-matched transplantation. The median relapse time was 12 months (range, 4 to 72). Thirteen patients received autologous CAR T cells, and 7 patients received allogeneic CAR T cells, which were derived from transplant donors. The median infusion dose was 2.9×106/kg (range, 0.33 to 12×106/kg). Nineteen patients were evaluated for efficacy, among which 17 patients (89.5%) achieved MRD negative. The CR rates in the HLA-matched transplantation group and haploidentical transplantation group were 100% (7/7) and 83.3% (10/12), respectively. The median follow-up time was 9.80 months (range, 2.40 to 64.97). Ten patients (50%) died of relapse, 3 patients (15%) died of infection, and 1 patient (5%) died of aGVHD. Fifteen patients (75%) developed CRS, including 3 (20%) grade 1 CRS, 6 (40%) grade 2 CRS, and 6 (40%) grade 3 CRS. Ten patients (50%) developed aGVHD, including 1 (10%) grade I aGVHD, 6 (60%) grade II aGVHD, and 3 (30%) grade III aGVHD. The log rank test showed that CAR T cell origin was correlated with aGVHD occurrence in the haploidentical transplantation group (P = 0.005). The authors’ study indicated that the initial efficacy and safety of CAR T cell therapy for patients with post-transplant relapse were satisfactory. However, aGVHD was a concern in patients with a history of haploidentical transplantation occupied with allogeneic CAR T cells, which warrants clinical attention.

Critical care management of chimeric antigen receptor T-cell therapy recipients.

Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapeutic treatment concept that is changing the treatment approach to hematologic malignancies. The development of CAR T-cell therapy represents a prime example for the successful bench-to-bedside translation of advances in immunology and cellular therapy into clinical practice. The currently available CAR T-cell products have shown high response rates and long-term remissions in patients with relapsed/refractory acute lymphoblastic leukemia and relapsed/refractory lymphoma. However, CAR T-cell therapy can induce severe life-threatening toxicities such as cytokine release syndrome, neurotoxicity, or infection, which require rapid and aggressive medical treatment in the intensive care unit setting. In this review, the authors provide an overview of the state-of-the-art in the clinical management of severe life-threatening events in CAR T-cell recipients. Furthermore, key challenges that have to be overcome to maximize the safety of CAR T cells are discussed.

CAR T\u2009cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B\u2009cell acute lymphoblastic leukemia: a phase 1 trial

Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially prevent this, but the clinical safety and efficacy of CAR T cells targeting both CD19 and CD22 remain unclear. We conducted a phase 1 trial in pediatric and young adult patients with relapsed or refractory B-ALL (n = 15) to test AUTO3, autologous transduced T cells expressing both anti-CD19 and anti-CD22 CARs (AMELIA trial, EUDRA CT 2016-004680-39). The primary endpoints were the incidence of grade 3–5 toxicity in the dose-limiting toxicity period and the frequency of dose-limiting toxicities. Secondary endpoints included the rate of morphological remission (complete response or complete response with incomplete bone marrow recovery) with minimal residual disease-negative response, as well as the frequency and severity of adverse events, expansion and persistence of AUTO3, duration of B cell aplasia, and overall and event-free survival. The study endpoints were met. AUTO3 showed a favorable safety profile, with no dose-limiting toxicities or cases of AUTO3-related severe cytokine release syndrome or neurotoxicity reported. At 1 month after treatment the remission rate (that is, complete response or complete response with incomplete bone marrow recovery) was 86% (13 of 15 patients). The 1 year overall and event-free survival rates were 60% and 32%, respectively. Relapses were probably due to limited long-term AUTO3 persistence. Strategies to improve CAR T cell persistence are needed to fully realize the potential of dual targeting CAR T cell therapy in B-ALL.

Dual-Switch CAR-T Cells: Orthogonal Molecular Switches to Control Activation and Elimination of CAR-T Cells to Target CD123+ Cancer

BackgroundImprovement of the efficacy and safety of chimeric antigen receptor (CAR)-T immunotherapies requires controlled activation and termination of the T cells when transfused into patients. Here we present two independently regulated molecular switches that can elicit specific and rapid induction of cellular responses upon exposure to their cognate ligands. T cell costimulation is controlled by the homodimerizer rimiducid that triggers signaling cascades downstream of MyD88 and CD40 via an engineered protein termed iMC. A rapamycin-controlled pro-apoptotic switch (iRC9) that induces dimerization of caspase-9 mitigates possible CAR-T cell toxicity. iRC9 is a chimeric protein comprisingan FKBP-rapamycin binding (FRB) domain in tandem with FKBP12 and caspase-9. This design permits rapamycin, a heterodimerizing ligand, to function as a homodimerizer. When combined with a first generation CD123-specific CAR, these molecular switches allow for controlled, robust expansion of engineered T cells to control acute myelogenous leukemia (AML) in vitro and in vivo combined with a rapid and efficient safety mechanism to block excessive cytokine release.Methods & ResultsT cells were activated and co-transduced with pSFG-iMC.2A.CD123CAR.ζ and pSFG-iRC9.2A.ΔCD19 vectors to generate Dual-switch (DS) CAR-T cells. Combined transduction of iRC9 and iMC-CAR vectors produced CD123-directed CAR-T cells that eliminated CD123+ THP1 and MOLM13 AML cells, but not CD123- HPAC tumor cells, in a co-culture assay. Cytokine secretion and target cell killing were dependent on the dose of rimiducid (EC50 < 0.5 nM) to activate iMC costimulation. When challenged in a THP1-eGFP Fluc tumor-bearing mouse xenograft model, activation of the on-switch by rimiducid (1 mg/kg) in DS CAR-T cells enhanced tumor killing measured by bioluminescence imaging and T-cell expansion determined by splenocyte flow cytometry and vector copy number analyses.Deployment of the off-switch induced fast (½ Vmax ~ 8 hours) and efficient T cell elimination of in a caspase-3 activation assay with real-time monitoring by Incucyte microscopy as well as Annexin V detection by flow cytometry (DS CAR-T = 77.6% versus untransduced = 2.2% Annexin V+ when treated with 1 nM rapamycin). In vivo assessment of the suicide switch was performed with eGFP Fluc -labeled CD123 DS CAR-T cells in NSG mice. Rapamycin, but not rimiducid, treatment efficiently eliminated DS CAR-T cells within 24 hours in NSG mice, which is similar to the clinically validated rimiducid-regulated iC9 switch. Importantly, the off-switch was insensitive to high rimiducid concentration, demonstrating that the on-switch regulator does not crosstalk with the safety switch.SummaryDual switch CAR-T, a novel platform comprising a first-generation CAR combined with regulated activation and apoptotic signaling elements, effectively controlled tumor growth and T cell expansion and elimination in vitro and in vivo . This dual switch technology provides a user-controlled system for managing persistence and safety of tumor antigen-specific CAR-T cells. [Display omitted] DisclosuresBayle:Bellicum Pharmaceuticals: Employment, Equity Ownership. Duong:Bellicum Pharmaceuticals: Employment, Equity Ownership. Lu:Bellicum Pharmaceuticals: Employment. Morschl:Bellicum Pharmaceuticals: Employment, Equity Ownership. Collinson-Pautz:Bellicum Pharmaceuticals: Employment, Equity Ownership. Sharp:Bellicum Pharmaceuticals: Employment, Equity Ownership. Szymanski:Bellicum Pharmaceuticals: Employment, Equity Ownership. Brandt:Bellicum Pharmaceuticals: Employment, Equity Ownership. Slawin:Bellicum Pharmaceuticals: Consultancy, Equity Ownership. Toler:Bellicum Pharmaceuticals: Employment, Equity Ownership. Yvon:Bellicum Pharmaceuticals: Equity Ownership. Foster:Bellicum Pharmaceuticals: Employment, Other: stockholders . Spencer:Bellicum Pharmaceuticals: Employment, Equity Ownership, Other: stockholders .

89723 CD105-targeted CAR T cells for the treatment of acute myeloid leukemia

ABSTRACT IMPACT: Our work might lead to a new treatment for patients with acute myeloid leukemia OBJECTIVES/GOALS: Acute myeloid leukemia (AML) is a devastating hematologic malignancy, with dismal 5-year survival. Chimeric antigen receptor (CAR) T cells have been approved for B cell malignancies but not for AML. The goal of this study is to explore the safety and efficacy of CAR T cells targeting CD105 (endoglin) to treat AML. METHODS/STUDY POPULATION: We have constructed human and murine CAR T cells targeting CD105. The CARs were created by sequencing the V(D)J regions of hybridomas and designing single chain variable fragments that target CD105 which were subsequently introduced in a CAR backbone via Gibson assembly. The CAR T cells were produced via transduction using retrovirus or lentivirus. Leukemia cell lines were assessed for CD105 expression with flow cytometry. Killing assays were performed via measurement of luminescence of target cells after co-culture with CAR T cells. Activation assays were performed with co-culture of CAR T cells and target cells and measurement of activation markers with flow cytometry. To assess in vivo efficacy and safety, murine CAR T cells were infused into C57BL/6J mice carrying B16 melanoma after lymphodepletion. RESULTS/ANTICIPATED RESULTS: All human leukemia cell lines assessed (Nalm6, MOLM-14, MV4-11, Kasumi-1, THP-1) expressed some degree of endoglin apart from the T cell leukemia Jurkat. Human CD105 CAR T cells were activated by co-culture with leukemia cell lines and effectively killed leukemia cells in vitro in a CD105-specific manner. Murine CAR T cells killed efficiently both murine solid tumors (B16 melanoma) and murine leukemias (C1498) in vitro. Murine CAR T cells did not exhibit any toxicity when infused after low-dose lymphodepletion (cyclophosphamide 100mg/kg) but caused significant morbidity after higher doses (cyclophosphamide 200mg/kg). Murine CAR T cells delayed the growth of B16 melanoma in immunocompetent mice. DISCUSSION/SIGNIFICANCE OF FINDINGS: We have constructed human and murine CD105 CAR T cells with excellent activity in vitro. The activity of human CD105 CAR T cells in xenografts and the biologic relevance of the toxicity of murine CD105 CAR T cells in humans needs to be further investigated. CD105 CAR T cells might prove an important therapeutic option for patients with AML.

Off-the-Shelf Chimeric Antigen Receptor T Cells: How Do We Get There?

Banked chimeric antigen receptor (CAR) T cells immediately available for off-the-shelf (OTS) application can solve key limitations of patient-specific CAR T-cell products while retaining their potency. The allogeneic nature of OTS cell therapies requires additional measures to minimize graft-versus-host disease and host-versus-graft immune rejection in immunocompetent recipients. In this review, we discuss engineering and manufacturing strategies aimed at minimizing unwanted interactions between allogeneic CAR T cells and the host. Overcoming these limitations will improve safety and antitumor potency of OTS CAR T cells and facilitate their wider use in cancer therapy.

Targeted multi-epitope switching enables straightforward positive/negative selection of CAR T cells

Chimeric antigen receptor (CAR) T cell technology has enabled successfully novel concepts to treat cancer patients, with substantial remission rates in lymphoid malignancies. This cell therapy is based on autologous T lymphocytes that are genetically modified to express a CAR that recognizes tumor-associated antigens and mediates the elimination of the respective tumor cells. Current limitations include laborious manufacturing procedures as well as severe immunological side effects upon administration of CAR T cells. To address these limitations, we integrated RQR8, a multi-epitope molecule harboring a CD34 epitope and two CD20 mimotopes, alongside a CD19-targeting CAR, into the CD52 locus. Using CRISPR-Cas9 and adeno-associated virus-based donor vectors, some 60% of genome-edited T cells were CAR+/CD20+/CD34+/CD52− without further selection. This could be increased to >95% purity after CD34 tag-based positive selection. These epitope-switched CAR T cells retained cell killing competence against CD19+ tumor cells, and were resistant to alemtuzumab (anti-CD52) but sensitive to rituximab (anti-CD20) in complement-dependent cytotoxicity assays. In conclusion, gene editing-based multiple epitope switching represents a promising development with the potential to improve both the manufacturing procedure as well as the clinical safety of CAR T cells.

Efficacy and safety of chimeric antigen receptor T cell immunotherapy in B-cell non-Hodgkin lymphoma: asystematic review and meta-analysis.

Aim: The aim was to evaluate the efficacy and safety of chimeric antigen receptor T (CAR-T) cell in B-cell non-Hodgkin lymphoma (B-NHL). Materials & methods: A meta-analysis was conducted using eligible clinical trials, which were obtained from electronic medical literature databases. Results: A total of 24 clinical trials with 590 patients were included. The best overall response rate was 66% and complete remission rate was 46%. The incidence rates of cytokine-release syndrome and neurotoxicity (grade≥3) were 9and 5%, respectively. The various clinical factors were analyzed. Autogenic CAR-T cell may lead to improved efficacy than allogeneic CAR-T cell. CD20 CAR-T cell may show increased efficacy than CD19 CAR-T cell. Conclusion: CAR-T immunotherapy has remarkable efficacy and low toxicity in relapsed/refractory B-NHL.

Comprehensive meta-analysis of anti-BCMA chimeric antigen receptor T-cell therapy in relapsed or refractory multiple myeloma

Background Chimeric antigen receptor (CAR) T-cell therapy shows impressive results in clinical trials. We conducted a meta-analysis based on the most recent data to systematically describe the efficacy and safety of anti-BCMA CAR T therapy for patients with relapsed or refractory multiple myeloma (R/R MM). Methods PubMed, Embase, Web of Science, Cochrane library, ClinicalTrials.gov, China Biology Medicine disc (CBM disc) and Wanfang Data were searched on 8 November 2020. Registration number of PROSPERO was CRD42020219127. Results From 763 articles, we identified 22 appropriate studies with 681 patients. The pooled overall response rate (ORR) was 85.2% (95%CI 0.797–0.910), complete response rate (CRR) was 47.0% (95%CI 0.378–0.583), and minimal residual disease (MRD) negativity rate was 97.8% (95%CI 0.935–1.022). The pooled incidence of grade 3–4 cytokine release syndrome was 6.6% (95%CI 0.036–0.096) and neurotoxicity was 2.2% (95%CI 0.006–0.038). The median progression-free survival (PFS) was 14.0 months and median overall survival (OS) was 24.0 months. Subgroup analysis showed dual epitope-binding CAR T cells achieved the best therapy outcomes and humanized CAR T cells had the best safety profile. Patients who were older, heavily pre-treated or received lower dose of CAR T cells had worse ORR. There was no significant difference in ORR, CRR and PFS between patients with and without high-risk cytogenetic features. The PFS and CRR of non-extramedullary disease (EMD) group was superior to those of EMD group. Conclusion Anti-BCMA CAR T therapy is effective and safe for patients with R/R MM. It can improve the prognosis of patients with high-risk cytogenetic features while the prognosis of patients with EMD remains poor. Moreover, patients are likely to benefit from an earlier use of CAR T therapy and human-derived CAR T cells have obvious advantages based on the existing data.

Efficacy and Safety of Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Immunoglobulin D Multiple Myeloma

Immunoglobulin D (IgD) multiple myeloma (MM) is a rare subtype of MM that carries a worse prognosis than non-IgD subtypes. Compared with non-IgD subtypes, IgD MM is associated with a shorter survival time. The application of chimeric antigen receptor (CAR) T-cell therapy for patients with relapsed or refractory multiple myeloma (R/R MM) has increasing evidence as an efficacious treatment. This study was designed to investigate efficacy and safety of chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory IgD MM (R/R IgD MM). In this single-arm, phase 2 trial, patients diagnosed with R/R IgD MM were infused with either a combination of anti-B-cell maturation antigen and anti-CD19 CAR T-cells or anti-CD19 CAR T-cells alone, with subsequent evaluation of therapeutic response and treatment-related toxicities. At the data cutoff date, 7 patients were enrolled in our study, and all patients achieved response based on the International Myeloma Working Group Uniform Response Criteria. Six patients achieved stringent complete remission (sCR) within 60 days after CAR T-cell infusion (median time 58 days, range 18 to 90 days), and 1 patient with extramedullary disease achieved minimal response (MR) at 30 days after infusion. Bone marrow minimal residual disease (MRD) negativity was achieved in all patients, and the median time to achieve MRD negativity was 22 days (range 14 to 60 days). The most common grade 3 to 4 treatment-related toxicities were hematological toxicities. All patients experienced cytokine release syndrome (CRS), although CAR T-cell-related neurotoxicity was not observed. In our study, CAR T-cell therapy showed encouraging efficacy in the patients with R/R IgD MM, achieving high rates of sCR and MRD negativity. Aside from CRS and prolonged hematologic toxicities, other adverse reactions were mild, suggesting that this is a well-tolerated treatment with a high therapeutic potential.

DNA scaffolds enable efficient and tunable functionalization of biomaterials for immune cell modulation.

Biomaterials can improve the safety and presentation of therapeutic agents for effective immunotherapy, and a high level of control over surface functionalization is essential for immune cell modulation. Here, we developed biocompatible immune cell engaging particles (ICEp) that use synthetic short DNA as scaffolds for efficient and tunable protein loading. To improve the safety of chimeric antigen receptor (CAR) T cell therapies, micron-sized ICEp were injected intratumorally to present a priming signal for systemically administered AND-gate CAR-T cells. Locally retained ICEp presenting a high density of priming antigens activated CAR-T cells, driving local tumor clearance while sparing uninjected tumors in immunodeficient mice. The ratiometric control of costimulatory ligands (anti-CD3 and anti-CD28 antibodies) and the surface presentation of a cytokine (IL-2) on ICEp were shown to significantly impact human primary T cell activation phenotypes. This modular and versatile biomaterial functionalization platform can provide new opportunities for immunotherapies.

ZUMA-19: A Phase 1/2 Multicenter Study of Lenzilumab Use With Axicabtagene Ciloleucel (Axi-Cel) in Patients (Pts) With Relapsed or Refractory Large B Cell Lymphoma (R/R LBCL)

ZUMA-19: A Phase 1/2 Multicenter Study of Lenzilumab Use With Axicabtagene Ciloleucel (Axi-Cel) in Patients (Pts) With Relapsed or Refractory Large B Cell Lymphoma (R/R LBCL)

A Phase I Study of FT819, a First-of-Kind, Off-the-Shelf, iPSC-Derived TCR-Less CD19 CAR T Cell Therapy for the Treatment of Relapsed/Refractory B-Cell Malignancies

A Phase I Study of FT819, a First-of-Kind, Off-the-Shelf, iPSC-Derived TCR-Less CD19 CAR T Cell Therapy for the Treatment of Relapsed/Refractory B-Cell Malignancies

Long-Term Survival and Gradual Recovery of B Cells in Patients with Refractory Large B Cell Lymphoma Treated with Axicabtagene Ciloleucel (Axi-Cel)

Long-Term Survival and Gradual Recovery of B Cells in Patients with Refractory Large B Cell Lymphoma Treated with Axicabtagene Ciloleucel (Axi-Cel)

Strategies for having a more effective and less toxic CAR T-cell therapy for acute lymphoblastic leukemia.

In the recent years, using genetically modified T cells has been known as a rapid developing therapeutic approach due to the heartwarming results of clinical trials with patients suffering from relapsed or refractory (R/R) hematologic malignancies such as R/R Acute Lymphoblastic Leukemia (R/R ALL). One of these renowned approaches is Chimeric antigen receptors (CARs). CARs are synthetic receptors with the ability to be expressed on the surface of T lymphocytes and are specifically designed to target a tumor-associated antigen (TAA) of interest. CAR-expressing T cells have the capability of proliferating and maintaining their immunological functionality in the recipient body but like any other therapeutic approach, the safety, effectiveness, and specificity enhancement of CAR T cells still lingers in the ambiguity arena. Genetic manipulation methods, expansion protocols, infusion dosage, and conditioning regimens are all among crucial factors which can affect the efficacy of CAR T cell-based cancer therapy. In this article, we discuss the studies that have focused on various aspects that affect the efficacy and persistence of CAR T-cell therapy for ALL treatment and provide a widespread overview regarding the practical approaches capable of elevating the effectiveness and lessening the relative toxicities attributed to it.

CAR T cells targeting options in the fight against multiple myeloma.

Multiple myeloma (MM) is a hematological malignancy in which patients present with bone marrow infiltration of clonal terminally-differentiated plasma cells. Monoclonal protein in the serum and/or urine is frequently detected. Over the past decade, important progress has been made in the comprehension of disease biology and treatment personalization. Much work has been put into the development of chimeric antigen receptor (CAR) gene-modified T-cell therapy thought to be a promising therapeutic option for pluritreated patients with refractory MM. We performed an analysis of clinical trials registered at the international repository clinicaltrials.gov using "CAR" OR "CAR T" AND "multiple myeloma" as search terms to understand what were the antigens targeted by CAR T strategies and what was the trade-off of their exploitation. The search retrieved a list of 103 trials that was manually filtered to eliminate follow-up and observational or not-pertinent trials. Most studies employed anti-BCMA targeting either alone (62/94; 66%), or in combination with a second target (12/94; 13%). The second target most studied was SLAMF7 (CD319) explored by 4/94 (4%) clinical trials. Other antigens investigated and described here include: CD44v6, CD38, CD138, MUC1, CD56, CD19, Igk light chain, Lewis Y, CD229 and GPRC5D. Targeting an appropriate antigen(s) is the key to both safety and efficacy of CAR T approaches in MM as there is dearth of tumor-specific antigens. Most antigens tested are merely enriched on MM cells. Working with tumor-enriched antigens requires careful assessment of the balance between harm (toxicity) and benefit (disease eradication) to the patient. This review provides an up-to-date overview of the avenues that are being explored.