Despite impressive progress, more than 50% of patients treated with CD19-targeting chimeric antigen receptor T cells (CAR19) experience progressive disease. Ten of 16 patients with large B cell ...lymphoma (LBCL) with progressive disease after CAR19 treatment had absent or low CD19. Lower surface CD19 density pretreatment was associated with progressive disease. To prevent relapse with CD19
or CD19
disease, we tested a bispecific CAR targeting CD19 and/or CD22 (CD19-22.BB.z-CAR) in a phase I clinical trial ( NCT03233854 ) of adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and LBCL. The primary end points were manufacturing feasibility and safety with a secondary efficacy end point. Primary end points were met; 97% of products met protocol-specified dose and no dose-limiting toxicities occurred during dose escalation. In B-ALL (n = 17), 100% of patients responded with 88% minimal residual disease-negative complete remission (CR); in LBCL (n = 21), 62% of patients responded with 29% CR. Relapses were CD19
in 50% (5 out of 10) of patients with B-ALL and 29% (4 out of 14) of patients with LBCL but were not associated with CD22
disease. CD19/22-CAR products demonstrated reduced cytokine production when stimulated with CD22 versus CD19. Our results further implicate antigen loss as a major cause of CAR T cell resistance, highlight the challenge of engineering multi-specific CAR T cells with equivalent potency across targets and identify cytokine production as an important quality indicator for CAR T cell potency.
Metastasis is the leading cause of cancer-related deaths, and greater knowledge of the metastatic microenvironment is necessary to effectively target this process. Microenvironmental changes occur at ...distant sites prior to clinically detectable metastatic disease; however, the key niche regulatory signals during metastatic progression remain poorly characterized. Here, we identify a core immune suppression gene signature in pre-metastatic niche formation that is expressed predominantly by myeloid cells. We target this immune suppression program by utilizing genetically engineered myeloid cells (GEMys) to deliver IL-12 to modulate the metastatic microenvironment. Our data demonstrate that IL12-GEMy treatment reverses immune suppression in the pre-metastatic niche by activating antigen presentation and T cell activation, resulting in reduced metastatic and primary tumor burden and improved survival of tumor-bearing mice. We demonstrate that IL12-GEMys can functionally modulate the core program of immune suppression in the pre-metastatic niche to successfully rebalance the dysregulated metastatic microenvironment in cancer.
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•A myeloid-rich, T-cell-poor immunosuppressive microenvironment promotes metastasis•Genetically engineered myeloid cells (GEMys) deliver IL-12 to metastatic sites•IL12-GEMys reverse immune suppression and activate anti-tumor immunity•Chemotherapy with IL12-GEMy treatment achieves durable cures in pre-clinical models
Genetically engineered myeloid cells expressing IL-12 can reverse the immunosuppressive environment developed during metastatic progression by augmenting T cell responses and reducing metastatic burden in preclinical models.
Long-lived, self-renewing, multipotent T memory stem cells (TSCM) can trigger profound and sustained tumor regression but their rareness poses a major hurdle to their clinical application. Presently, ...clinically compliant procedures to generate relevant numbers of this T-cell population are undefined. Here, we provide a strategy for deriving large numbers of clinical-grade tumor-redirected TSCM starting from naive precursors. CD8+CD62L+CD45RA+ naive T cells enriched by streptamer-based serial-positive selection were activated by CD3/CD28 engagement in the presence of interleukin-7 (IL-7), IL-21, and the glycogen synthase-3β inhibitor TWS119, and genetically engineered to express a CD19-specific chimeric antigen receptor (CD19-CAR). These conditions enabled the generation of CD19-CAR–modified CD8+ TSCM that were phenotypically, functionally, and transcriptomically equivalent to their naturally occurring counterpart. Compared with CD8+ T cells generated with clinical protocols currently under investigation, CD19-CAR–modified CD8+ TSCM exhibited enhanced metabolic fitness and mediated robust, long-lasting antitumor responses against systemic acute lymphoblastic leukemia xenografts. This clinical-grade platform provides the basis for a phase 1 trial evaluating the activity of CD19-CAR–modified CD8+ TSCM in patients with B-cell malignancies refractory to prior allogeneic hematopoietic stem cell transplantation.
•A platform for the generation of clinical-grade CD19-CAR–modified TSCM.•CD19-CAR–modified TSCM mediate superior antitumor responses compared with CD19-CAR T cells currently used in clinical trials.
Adoptive immunotherapy using chimeric antigen receptor (CAR) expressing T cells targeting the CD19 B lineage receptor has demonstrated marked success in relapsed pre-B-cell acute lymphoblastic ...leukaemia (ALL). Persisting CAR-T cells generate sustained pressure against CD19 that may drive unique mechanisms of resistance. Pre-B ALL originates from a committed pre-B cell or an earlier progenitor, with potential to reprogram into other hematopoietic lineages. Here we report changes in lineage markers including myeloid conversion in patients following CD19 CAR therapy. Using murine ALL models we study the long-term effects of CD19 CAR-T cells and demonstrate partial or complete lineage switch as a consistent mechanism of CAR resistance depending on the underlying genetic oncogenic driver. Deletion of Pax5 or Ebf1 recapitulates lineage reprogramming occurring during CD19 CAR pressure. Our findings establish lineage switch as a mechanism of CAR resistance exposing inherent plasticity in genetic subtypes of pre-B-cell ALL.
► Single-component device has number of advantages compared with the conventional three-component device. ► Better catalyst functions for both H2 and O2 which can realize good device performance. ► ...Faster kinetic processes because of removal of anode/electrolyte and electrolyte/cathode two interfaces. ► Better device performances, higher power outputs more than 700mWcm-2 achieved at 550oC. ► Faster electrochemical response processes.
Single-component and three-component fuel cell devices have been studied using mixed ionic and electronic conductor. The three-component fuel cell means a conventional fuel cell which is the configuration consists of anode, electrolyte and cathode; while the single-component fuel cell uses only one component that can function as the electrodes and electrolyte simultaneously. The single-component fuel cell showed the same or even better performance compared to conventional three-component fuel cell. A maximum power density of 700mWcm−2 has been achieved by the single-component fuel cell at 550°C.
Despite high remission rates following CAR-T cell therapy in B-ALL, relapse due to loss of the targeted antigen is increasingly recognized as a mechanism of immune escape. We hypothesized that ...simultaneous targeting of CD19 and CD22 may reduce the likelihood of antigen loss, thus improving sustained remission rates. A systematic approach to the generation of CAR constructs incorporating two target-binding domains led to several novel CD19/CD22 bivalent CAR constructs. Importantly, we demonstrate the challenges associated with the construction of a bivalent CAR format that preserves bifunctionality against both CD19 and CD22. Using the most active bivalent CAR constructs, we found similar transduction efficiency compared to that of either CD19 or CD22 single CARs alone. When expressed on human T cells, the optimized CD19/CD22 CAR construct induced comparable interferon γ and interleukin-2 in vitro compared to single CARs against dual-antigen-expressing as well as single-antigen-expressing cell lines. Finally, the T cells expressing CD19/CD22 CAR eradicated ALL cell line xenografts and patient-derived xenografts (PDX), including a PDX generated from a patient with CD19− relapse following CD19-directed CAR therapy. The CD19/CD22 bivalent CAR provides an opportunity to test whether simultaneous targeting may reduce risk of antigen loss.
Chimeric antigen receptor (CAR) T cell therapies targeting single antigens have performed poorly in clinical trials for solid tumors due to heterogenous expression of tumor-associated antigens ...(TAAs), limited T cell persistence, and T cell exhaustion. Here, we aimed to identify optimal CARs against glypican 2 (GPC2) or CD276 (B7-H3), which were highly but heterogeneously expressed in neuroblastoma (NB), a lethal extracranial solid tumor of childhood. First, we examined CAR T cell expansion in the presence of targets by digital droplet PCR. Next, using pooled competitive optimization of CAR by cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq), termed P-COCC, we simultaneously analyzed protein and transcriptome expression of CAR T cells to identify high-activity CARs. Finally, we performed cytotoxicity assays to identify the most effective CAR against each target and combined the CARs into a bicistronic "OR" CAR (BiCisCAR). BiCisCAR T cells effectively eliminated tumor cells expressing GPC2 or CD276. Furthermore, the BiCisCAR T cells demonstrated prolonged persistence and resistance to exhaustion when compared with CARs targeting a single antigen. This study illustrated that targeting multiple TAAs with BiCisCAR may overcome heterogenous expression of target antigens in solid tumors and identified a potent, clinically relevant CAR against NB. Moreover, our multimodal approach integrating competitive expansion, P-COCC, and cytotoxicity assays is an effective strategy to identify potent CARs among a pool of candidates.
A fuel cell device is realized by using a single component of lithium nickel oxide and gadolinium doped ceria (LiNiO
2-GDC) composite material, a mixture of electronic and ionic conductors, when ...nickel foam and silver paste are attached to each surface of the single component pellet as current collectors. This simple fuel cell construction with only one component showed the same or even better performances compared to conventional three-component MEA (membrane electrolyte assembly) fuel cell using GDC as electrolyte. The maximum power density of 450
mW/cm
2 has been achieved at 550
°C for the single component fuel cell.
•Highly flexible and light-weight MnO2/carbon fiber cloth electrode.•Through a direct reduction of permanganate.•Excellent mechanical flexibility and high-rate capability.
Self-standing MnO2 ...electrodes have been fabricated through the redox reaction between carbon fiber and potassium permanganate. The porous film of birnessite-type MnO2 deposited tightly onto surfaces of the carbon fibers to form manganese dioxide/carbon fiber cloth electrode. The electrodes have not only excellent capacitive performances, but also superior electrochemical stability. Owing to the formation of thin-film morphology, porous structure and the intimate contact between the electroactive material and the current collector, the MnO2 film provides an enhancement of the kinetics by short transport/diffusion path lengths, timely accompanying of electrolyte and large specific surface areas, thus both high energy density and high power density are achieved. In addition to the effective release of stress resulting from charge/discharge, the porous structure also facilitates accompanying electrolyte at high rate operation and avoiding dramatic capacitance fade in cycling. The specific capacitance still retains at least about 84% after continuous 5000 charge/discharge cycles.
► Ceria–carbonate composite electrolyte showed excellent performance, 800
mW
cm
−2. ► It exhibits high co-ionic (H
+/O
2−) conductivity at 550
°C even with very low activation energy of 0.238
eV. ► ...Nanocomposite co-doped ceria–carbonate is a promising electrolyte for LTSOFC. ► General mixing rule verified that the enhanced conductivity is due to interfaces between ceria and carbonates.
A co-doped ceria–carbonate (Ce
0.8Sm
0.2−
x
Ca
x
O
2−
δ
–Na
2CO
3) has been synthesized by a co-precipitation method. The detailed electrochemical characterizations (e.g. impedance spectra, polarization curve and IV curves) of this composite material are reported and discussed. The two phase nanocomposite electrolytes with carbonate coated on the co-doped ceria displays dual (H
+/O
2−) ion conduction at low temperature (300–600
°C) in solid oxide fuel cell. The observed remarkable temperature-dependent of conductivity is attributed to the softening/melting of carbonate phase as the physical state of carbonate phase transforms from solid to molten state. Coexistence of various charge carriers, oxide phase composition, and the oxide–carbonate interfacial area are investigated by Raman spectra. The enhancement of conductivity is also discussed by the general mixing rule/percolation theory of composite interfaces. The co-doping with 2nd phase gives a good approach to realize challenges for solid oxide fuel cell.
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