Glioblastoma (GBM) is a devastating disease with an extremely poor prognosis. Immunotherapy via adoptive cell transfer (ACT), especially with T cells engineered to express chimeric antigen receptors ...(CAR), represents a particularly promising approach. Despite the recent success of CAR T cells for blood cancers, the question remains whether this powerful anticancer therapy will ultimately work for brain tumors, and whether the primary immunologic challenges in this disease, which include antigenic heterogeneity, immune suppression, and T-cell exhaustion, can be adequately addressed. Here, we contextualize these concepts by reviewing recent developments in ACT for GBM, with a special focus on pioneering clinical trials of CAR T-cell therapy.
Adoptive immunotherapy, or the infusion of lymphocytes, is a promising approach for the treatment of cancer and certain chronic viral infections. The application of the principles of synthetic ...biology to enhance T cell function has resulted in substantial increases in clinical efficacy. The primary challenge to the field is to identify tumor-specific targets to avoid off-tumor, on-target toxicity. Given recent advances in efficacy in numerous pilot trials, the next steps in clinical development will require multicenter trials to establish adoptive immunotherapy as a mainstream technology.
With the notable exception of B-cell malignancies, the efficacy of chimeric antigen receptor (CAR) T cells has been limited, and CAR T cells have not been shown to expand and persist in patients with ...nonlymphoid tumors. Here we demonstrate that redirection of primary human T cells with a CAR containing the inducible costimulator (ICOS) intracellular domain generates tumor-specific IL-17-producing effector cells that show enhanced persistence. Compared with CARs containing the CD3ζ chain alone, or in tandem with the CD28 or the 4-1BB intracellular domains, ICOS signaling increased IL-17A, IL-17F, and IL-22 following antigen recognition. In addition, T cells redirected with an ICOS-based CAR maintained a core molecular signature characteristic of TH17 cells and expressed higher levels of RORC, CD161, IL1R-1, and NCS1. Of note, ICOS signaling also induced the expression of IFN-γ and T-bet, consistent with a TH17/TH1 bipolarization. When transferred into mice with established tumors, TH17 cells that were redirected with ICOS-based CARs mediated efficient antitumor responses and showed enhanced persistence compared with CD28- or 4-1BB-based CAR T cells. Thus, redirection of TH17 cells with a CAR encoding the ICOS intracellular domain is a promising approach to augment the function and persistence of CAR T cells in hematologic malignancies.
•ICOS-based CARs program bipolar TH17/TH1 cells with augmented effector function and in vivo persistence.•The expression of selected CAR endodomains can program T cells for their subsequent differentiation fates and effector functions.
CAR T therapy has revolutionized the treatment of hematologic cancers. In their recent Nature Medicine paper, Mackensen et al. report the use of CAR T cells to treat systemic lupus erythematosus in ...five patients. This provides enthusiasm to further explore CAR T therapy beyond oncology.
CAR T therapy has revolutionized the treatment of hematologic cancers. In their recent Nature Medicine paper, Mackensen et al. report the use of CAR T cells to treat systemic lupus erythematosus in five patients. This provides enthusiasm to further explore CAR T therapy beyond oncology.
Poor tumor infiltration, development of exhaustion, and antigen insufficiency are common mechanisms that limit chimeric antigen receptor (CAR)-T cell efficacy. Delivery of pattern recognition ...receptor agonists is one strategy to improve immune function; however, targeting these agonists to immune cells is challenging, and off-target signaling in cancer cells can be detrimental. Here, we engineer CAR-T cells to deliver RN7SL1, an endogenous RNA that activates RIG-I/MDA5 signaling. RN7SL1 promotes expansion and effector-memory differentiation of CAR-T cells. Moreover, RN7SL1 is deployed in extracellular vesicles and selectively transferred to immune cells. Unlike other RNA agonists, transferred RN7SL1 restricts myeloid-derived suppressor cell (MDSC) development, decreases TGFB in myeloid cells, and fosters dendritic cell (DC) subsets with costimulatory features. Consequently, endogenous effector-memory and tumor-specific T cells also expand, allowing rejection of solid tumors with CAR antigen loss. Supported by improved endogenous immunity, CAR-T cells can now co-deploy peptide antigens with RN7SL1 to enhance efficacy, even when heterogenous CAR antigen tumors lack adequate neoantigens.
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•CAR-T cells deliver RN7SL1 in extracellular vesicles (EVs) and activate RIG-I•CAR-T cells expressing RN7SL1 show greater expansion and persistence and less exhaustion•Preferential uptake of RN7SL1 by DC/myeloid over tumor cells enhances endogenous immunity•CAR-T EVs can co-deliver antigen with RN7SL1 to reject tumors with CAR antigen loss
CAR-T cells expressing an immunostimulatory RNA achieve enhanced efficacy in solid tumor mouse models with CAR antigen loss by improving autonomous CAR-T cell function and promoting endogenous immunity through preferential uptake of RNA-containing extracellular vesicles in innate immune cells over tumor cells.
Pancreatic ductal adenocarcinoma (PDAC) is resistant to T-cell–mediated immunotherapy. We engineered T cells to transiently express a messenger RNA encoding a chimeric antigen receptor (CAR) specific ...for mesothelin, a protein that is overexpressed by PDAC cells. We performed a phase I study to evaluate the safety and efficacy of adoptive cell therapy with autologous mesothelin-specific CAR T cells (CARTmeso cells) in 6 patients with chemotherapy-refractory metastatic PDAC. Patients were given intravenous CARTmeso cells 3 times weekly for 3 weeks. None of the patients developed cytokine release syndrome or neurologic symptoms and there were no dose-limiting toxicities. Disease stabilized in 2 patients, with progression-free survival times of 3.8 and 5.4 months. We used 18F-2-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography/computed tomography imaging to monitor the metabolic active volume (MAV) of individual tumor lesions. The total MAV remained stable in 3 patients and decreased by 69.2% in 1 patient with biopsy-proven mesothelin expression; in this patient, all liver lesions had a complete reduction in FDG uptake at 1 month compared with baseline, although there was no effect on the primary PDAC. Transient CAR expression was detected in patients’ blood after infusion and led to expansion of new immunoglobulin G proteins. Our results provide evidence for the potential antitumor activity of messenger RNA CARTmeso cells, as well as PDAC resistance to the immune response.
Patients with diffuse large B-cell lymphoma or follicular lymphoma that is refractory to or that relapses after immunochemotherapy and transplantation have a poor prognosis. High response rates have ...been reported with the use of T cells modified by chimeric antigen receptor (CAR) that target CD19 in B-cell cancers, although data regarding B-cell lymphomas are limited.
We used autologous T cells that express a CD19-directed CAR (CTL019) to treat patients with diffuse large B-cell lymphoma or follicular lymphoma that had relapsed or was refractory to previous treatments. Patients were monitored for response to treatment, toxic effects, the expansion and persistence of CTL019 cells in vivo, and immune recovery.
A total of 28 adult patients with lymphoma received CTL019 cells, and 18 of 28 had a response (64%; 95% confidence interval CI, 44 to 81). Complete remission occurred in 6 of 14 patients with diffuse large B-cell lymphoma (43%; 95% CI, 18 to 71) and 10 of 14 patients with follicular lymphoma (71%; 95% CI, 42 to 92). CTL019 cells proliferated in vivo and were detectable in the blood and bone marrow of patients who had a response and patients who did not have a response. Sustained remissions were achieved, and at a median follow-up of 28.6 months, 86% of patients with diffuse large B-cell lymphoma who had a response (95% CI, 33 to 98) and 89% of patients with follicular lymphoma who had a response (95% CI, 43 to 98) had maintained the response. Severe cytokine-release syndrome occurred in 5 patients (18%). Serious encephalopathy occurred in 3 patients (11%); 2 cases were self-limiting and 1 case was fatal. All patients in complete remission by 6 months remained in remission at 7.7 to 37.9 months (median, 29.3 months) after induction, with a sustained reappearance of B cells in 8 of 16 patients and with improvement in levels of IgG in 4 of 10 patients and of IgM in 6 of 10 patients at 6 months or later and in levels of IgA in 3 of 10 patients at 18 months or later.
CTL019 cells can be effective in the treatment of relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. High rates of durable remission were observed, with recovery of B cells and immunoglobulins in some patients. Transient encephalopathy developed in approximately one in three patients and severe cytokine-release syndrome developed in one in five patients. (Funded by Novartis and others; ClinicalTrials.gov number, NCT02030834 .).
Boosting engineered T cells Singh, Nathan; June, Carl H
Science (American Association for the Advancement of Science),
07/2019, Letnik:
365, Številka:
6449
Journal Article
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Vaccines augment the antitumor activity of cellular therapy
After decades of work, researchers have finally begun to see broadly reproducible success of engineered T cells in the treatment of cancer. ...Chimeric antigen receptors (CARs) are synthetic molecules that combine the antigen specificity of monoclonal antibodies with the signaling of the T cell receptor (TCR) to direct patient-derived (autologous) T cells to seek out and destroy cancer cells. T cells engineered to express CARs targeting the B cell antigen CD19 can induce durable remissions in many patients with refractory B cell neoplasms (
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3
), and two CAR–T cell products have recently been approved by the U.S. Food and Drug Administration to treat B cell leukemia and lymphoma. Despite these successes in hematological cancers, CAR–T cell activity against solid tumors has been limited. On page 162, Ma
et al.
(
4
) describe a platform that uses a vaccine-boosting strategy to improve the efficacy of CAR–T cells to target solid tumors.
CAR T cells produced in vivo to treat cardiac injury Rurik, Joel G; Tombácz, István; Yadegari, Amir ...
Science (American Association for the Advancement of Science),
2022-Jan-07, 2022-01-07, 20220107, Letnik:
375, Številka:
6576
Journal Article
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Fibrosis affects millions of people with cardiac disease. We developed a therapeutic approach to generate transient antifibrotic chimeric antigen receptor (CAR) T cells in vivo by delivering modified ...messenger RNA (mRNA) in T cell–targeted lipid nanoparticles (LNPs). The efficacy of these in vivo–reprogrammed CAR T cells was evaluated by injecting CD5-targeted LNPs into a mouse model of heart failure. Efficient delivery of modified mRNA encoding the CAR to T lymphocytes was observed, which produced transient, effective CAR T cells in vivo. Antifibrotic CAR T cells exhibited trogocytosis and retained the target antigen as they accumulated in the spleen. Treatment with modified mRNA-targeted LNPs reduced fibrosis and restored cardiac function after injury. In vivo generation of CAR T cells may hold promise as a therapeutic platform to treat various diseases.
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