Efficacy-enhanced anti-CD7 universal chimeric antigen receptor-T cell therapy for relapsed/refractory CD7-positive hematological malignancies: A phase I clinical study
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE192453 | GEO | 2022/09/08
REPOSITORIES: GEO
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Project description:Chimeric antigen receptor-T (CAR-T) therapy remains to be investigated in T-cell malignancies. CD7 is an ideal target for T-cell malignancies but is also expressed on normal T cells, which may cause CAR-T cell fratricide. Donor-derived anti-CD7 CAR-T cells using endoplasmic reticulum retention have shown efficacy in patients with T-cell acute lymphoblastic leukemia (ALL). Here we launched a phase I trial to explore differences between autologous and allogeneic anti-CD7 CAR-T therapies in T-cell ALL and lymphoma. Ten patients were treated and 5 received autologous CAR-T therapies. No dose-limiting toxicity or neurotoxicity was observed. Grade 1-2 cytokine release syndrome occurred in 7 patients, and grade 3 in 1 patient. Grade 1-2 graft-versus-host diseases were observed in 2 patients. Seven patients had bone marrow infiltration, and 100% of them achieved complete remission with negative minimal residual disease within one month. Two-fifths of patients achieved extramedullary or extranodular remission. The median follow-up was 6 (range, 2.7- 14) months and bridging transplantation was not administrated. Patients treated with allogeneic CAR-T cells had higher remission rate, less recurrence and more durable CAR-T survival than those receiving autologous products. Allogeneic CAR-T cells appeared to be a better option for patients with T-cell malignancies.
2023-03-25 | GSE227828 | GEO
Project description:The direct integration of chimeric-antigen-receptor (CAR) T cell with allogeneic hematopoietic cell transplantation (allo-HCT) carries the risk of graft-versus-host disease (GVHD) induction by allogeneic CAR-T cells. Based on our past experiments, it has been shown that post-transplantation cyclophosphamide (PTCy) prevents GVHD induction by other cell infusions after T-cell-replete MHC-haploidentical murine allo-HCT models. In this study, we investigated whether CAR-T cells, given in a similar manner in the same MHC-haploidentical murine allo-HCT model, could safely exert anti-tumor effects. We showed that anti-CD19 CAR-T cells administered early after (day +5 of transplant) or prior to (day 0 of transplant) PTCy for allo-HCT cleared leukemia without toxicity or GVHD exacerbation. Using next generation single-cell RNA sequencing approaches, we demonstrated that in comparison to CAR-T cells infused early after PTCy (day +5), CAR-T cells infused prior to PTCy (day 0) exhibited transcriptional changes consistent with increased CD4+ T-cell activation and CD8+ T-cell cytotoxicity.
2022-10-09 | GSE214788 | GEO
Project description:Adoptive transfer of chimeric antigen receptor (CAR)-T cells is expected to become the first line of treatment for multiple malignancies, following the enormous success of anti-CD19 therapies. However, their mechanism of action is not fully understood, and clear guidelines for the design of safe and efficient receptors are missing. We hereby describe a systematic analysis of the CAR “signalosome” in human primary T cells. Two CAR designs were compared: a second-generation (PSCA2) and a third-generation (PSCA3) anti-PSCA CAR. Phosphorylation events triggered by CAR-mediated recognition of target cells were quantified by mass spectrometry.
2019-11-07 | PXD007086 | Pride
Project description:Adoptive transfer of anti-CD19 chimeric antigen receptor (CAR)-engineered T cells has shown impressive clinical responses in patients with refractory B-cell malignancies. However, therapeutic effects of CAR-T cells targeting other hematologic malignancies and solid tumors are not yet satisfactory. Although inefficient tumor trafficking and multiple immunosuppressive molecules impede CAR-T cell effector responses, signals delivered by the current CAR constructs may still be insufficient to fully activate antitumor T cell functions. Optimal T cell activation and proliferation requires multiple signals including T cell receptor (TCR) engagement (signal 1), costimulation (signal 2), and cytokine engagement (signal 3). CAR genes developed to date contain a CD3z domain and costimulatory domain(s), but not a domain to transmit signal 3. In this study, we have developed a novel CAR construct capable of inducing cytokine signaling in an antigen-dependent manner. The new generation CD19 CAR encodes a cytoplasmic domain of IL-2RB and STAT3-binding YXXQ motif together with CD3z and CD28 domains (28-IL2RB-z (YXXQ)). The 28-IL2RB-z (YXXQ) CAR-T cells showed antigen-dependent JAK-STAT, especially the STAT3-mediated pathway activation, which promoted their proliferation and prevented terminal differentiation. The 28-IL2RB-z (YXXQ) CAR-T cells demonstrated superior in vivo persistence and antileukemia effects compared with the currently used CARs in multiple tumor models.
2020-02-15 | GSE95037 | GEO
Project description:Adoptive transfer of anti-CD19 chimeric antigen receptor (CAR)-engineered T cells has shown impressive clinical responses in patients with refractory B-cell malignancies. However, therapeutic effects of CAR-T cells targeting other hematologic malignancies and solid tumors are not yet satisfactory. Although inefficient tumor trafficking and multiple immunosuppressive molecules impede CAR-T cell effector responses, signals delivered by the current CAR constructs may still be insufficient to fully activate antitumor T cell functions. Optimal T cell activation and proliferation requires multiple signals including T cell receptor (TCR) engagement (signal 1), costimulation (signal 2), and cytokine engagement (signal 3). CAR genes developed to date contain a CD3z domain and costimulatory domain(s), but not a domain to transmit signal 3. In this study, we have developed a novel CAR construct capable of inducing cytokine signaling in an antigen-dependent manner. The new generation CD19 CAR encodes a cytoplasmic domain of IL-2RB and STAT3-binding YXXQ motif together with CD3z and CD28 domains (28-DIL2RB-z (YXXQ)). The 28-DIL2RB-z (YXXQ) CAR-T cells showed antigen-dependent JAK-STAT, especially the STAT3-mediated pathway activation, which promoted their proliferation and prevented terminal differentiation. The 28-DIL2RB-z (YXXQ) CAR-T cells demonstrated superior in vivo persistence and antileukemia effects compared with the currently used CARs in multiple tumor models.
2018-01-21 | GSE103906 | GEO
Project description:Adoptive transfer of chimeric antigen receptor (CAR)-T cells is expected to become the first line of treatment for multiple malignancies, following the enormous success of anti-CD19 therapies. However, their mechanism of action is not fully understood, and clear guidelines for the design of safe and efficient receptors are missing. We hereby describe a systematic analysis of the CAR “interactome” in human primary T cells, which allowed us to identify molecular traits that influence CAR-T cell efficacy. Interactome analysis was based on immunoprecipitation of CARs followed by protein identification by mass spectrometry.
2019-11-07 | PXD007085 | Pride
Project description:γδ-T lymphocytes are cells of the innate immune system exerting potent natural cytotoxicity against bacteria, viruses and tumours. This ability, coupled with their negligible alloreactivity, makes them attractive for adoptive immunotherapy approaches. To achieve a cell product suitable for clinical use, a protocol offering the possibility to generate and expand high numbers of polyclonal γδ-T cells is required. In this study, we designed a robust protocol to either manually or automatically expand high numbers of functional polyclonal memory γδ-T cells under good manufacturing practice conditions, with the additional possibility of gene-modification to improve anti-tumour activity, proving the feasibility of establishing an allogeneic “third-party T-cell bank” for off-the-shelf use. Engineered artificial antigen-presenting cells (aAPCs) expressing CD86/41BBL/CD40L and the cytomegalovirus (CMV)-antigen-pp65 were used for γδ-T cell production. The presence of CMV-pp65 and CD40L proved to be crucial for expansion of the memory Vδ1 subpopulation. To allow clinical translation and guarantee patient safety, aAPCs were stably transduced with an inducible suicide gene. The proposed cell product represents an attractive therapeutic option endowed with broad clinical applications, including treatment of viral infections in highly immunocompromised patients, treatment of aggressive malignancies refractory to conventional approaches and, ultimately, innovative platform for development of off-the-shelf CAR-T-cell products.
2019-11-18 | PXD015506 | Pride
Project description:This model of the use of chimeric antigen receptor (CAR)-T cell therapy in the treatment of solid tumours is described in the article:
"Dual-Target CAR-Ts with On- and Off-Tumour Activity May Override Immune Suppression in Solid Cancers: A Mathematical Proof of Concept"
Odelaisy León-Triana, Antonio Pérez-Martínez, Manuel Ramírez-Orellana and Víctor M. Pérez-García
Cancers 2021, 13, 703.; doi: 10.3390/cancers13040703
Comment:
This is the first mathematical model, derived from equations 1 and 2, used in the paper.
Reproduction of Fig. 5a was achieved by setting alpha_1 = 0.04, different to the value quoted in the article caption for Fig. 5.
Abstract:
Chimeric antigen receptor (CAR)-T cell-based therapies have achieved substantial success against B-cell malignancies, which has led to a growing scientific and clinical interest in extending their use to solid cancers. However, results for solid tumours have been limited up to now, in part due to the immunosuppressive tumour microenvironment, which is able to inactivate CAR-T cell clones. In this paper we put forward a mathematical model describing the competition of CAR-T and tumour cells, taking into account their immunosuppressive capacity. Using the mathematical model, we show that the use of large numbers of CAR-T cells targetting the solid tumour antigens could overcome the immunosuppressive potential of cancer. To achieve such high levels of CAR-T cells we propose, and study computationally, the manufacture and injection of CAR-T cells targetting two antigens: CD19 and a tumour-associated antigen. We study in silico the resulting dynamics of the disease after the injection of this product and find that the expansion of the CAR-T cell population in the blood and lymphopoietic organs could lead to the massive production of an army of CAR-T cells targetting the solid tumour, and potentially overcoming its immune suppression capabilities. This strategy could benefit from the combination with PD-1 inhibitors and low tumour loads. Our computational results provide theoretical support for the treatment of different types of solid tumours using T cells engineered with combination treatments of dual CARs with on- and off-tumour activity and anti-PD-1 drugs after completion of classical cytoreductive treatments.
2021-07-23 | BIOMD0000001013 | BioModels
Project description:This model of the use of chimeric antigen receptor (CAR)-T cell therapy in the treatment of solid tumours is described in the article:
"Dual-Target CAR-Ts with On- and Off-Tumour Activity May Override Immune Suppression in Solid Cancers: A Mathematical Proof of Concept"
Odelaisy León-Triana, Antonio Pérez-Martínez, Manuel Ramírez-Orellana and Víctor M. Pérez-García
Cancers 2021, 13, 703.; doi: 10.3390/cancers13040703
Comment:
This is the second mathematical model, derived from equations 3 to 6, used in the paper.
Reproduction of Figure 5b was achieved by setting alpha_1 = 0.183, in substitution for alpha_1 = 0.2 as quoted in the article.
Abstract:
Chimeric antigen receptor (CAR)-T cell-based therapies have achieved substantial success against B-cell malignancies, which has led to a growing scientific and clinical interest in extending their use to solid cancers. However, results for solid tumours have been limited up to now, in part due to the immunosuppressive tumour microenvironment, which is able to inactivate CAR-T cell clones. In this paper we put forward a mathematical model describing the competition of CAR-T and tumour cells, taking into account their immunosuppressive capacity. Using the mathematical model, we show that the use of large numbers of CAR-T cells targetting the solid tumour antigens could overcome the immunosuppressive potential of cancer. To achieve such high levels of CAR-T cells we propose, and study computationally, the manufacture and injection of CAR-T cells targetting two antigens: CD19 and a tumour-associated antigen. We study in silico the resulting dynamics of the disease after the injection of this product and find that the expansion of the CAR-T cell population in the blood and lymphopoietic organs could lead to the massive production of an army of CAR-T cells targetting the solid tumour, and potentially overcoming its immune suppression capabilities. This strategy could benefit from the combination with PD-1 inhibitors and low tumour loads. Our computational results provide theoretical support for the treatment of different types of solid tumours using T cells engineered with combination treatments of dual CARs with on- and off-tumour activity and anti-PD-1 drugs after completion of classical cytoreductive treatments.
2021-07-14 | BIOMD0000001014 | BioModels
Project description:Chimeric antigen receptors (CARs) are synthetic proteins that redirect T cell specificity by linking an extracellular ligand binding domain to intracellular T cell signaling domains. CAR-expressing T (CAR-T) cells have demonstrated significant efficacy for the treatment of refractory B cell malignancies and are being evaluated as immunotherapeutic reagents for many other cancers. CAR designs are based on the fundamental principles of TCR recognition and most CARs employ the T cell-activating CD3z endodomain alongside a costimulatory domain from CD28 or 4-1BB. However, emerging data suggest that CD28/CD3z and 4-1BB/CD3z signaling modules promote divergent metabolic pathways, gene expression programs, and cell fates. To determine how CAR phosphoprotein signaling drives these disparate cell fates, we analyzed CAR ligation-induced signaling networks in primary human T cells using shotgun mass spectrometry. We isolated CD8+CD62L+ T cells from healthy donors and introduced a CD28/CD3z or 4-1BB/CD3z CAR by lentiviral transduction. Transduced T cells were purified by FACS and expanded once in vitro. When the cells returned to a resting state, CD28/CD3z or 4-1BB/CD3z CAR-T cells were stimulated for 10 or 45 minutes with magnetic microbeads coated with a monoclonal antibody specific for a 9 amino acid tag in the CAR extracellular sequence. CAR-T cells were also left unstimulated for 10 or 45 minutes to serve as controls. Altogether, 8 unique conditions were tested in an experiment and three independent experiments were performed.
2018-08-13 | PXD007921 | Pride