A Clinical Research of CAR T Cells Targeting HER2 Positive Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Ovarian Cancer,Lung Cancer,Glioma,Colorectal Cancer,Gastric Cancer,Pancreatic Cancer,Breast Cancer
PROVIDER: 2210681 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:The main purpose of this research is to verify the safety of CEA targeted chimeric antigen receptor T cells and to determine the proper dosage of CAR T cells infused.
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Project description:Chimeric antigen receptor–T (CAR-T) cell therapies can eliminate relapsed and refractory tumors, but the durability of antitumor activity requires in vivo persistence. Differential signaling through the CAR costimulatory domain can alter the T cell metabolism, memory differentiation, and influence long-term persistence. CAR-T cells costimulated with 4-1BB or ICOS persist in xenograft models but those constructed with CD28 exhibit rapid clearance. Here, we show that a single amino acid residue in CD28 drove T cell exhaustion and hindered the persistence of CD28-based CAR-T cells and changing this asparagine to phenylalanine (CD28-YMFM) promoted durable antitumor control. In addition, CD28-YMFM CAR-T cells exhibited reduced T cell differentiation and exhaustion as well as increased skewing toward Th17 cells. Reciprocal modification of ICOS-containing CAR-T cells abolished in vivo persistence and antitumor activity. This finding suggests modifications to the costimulatory domains of CAR-T cells can enable longer persistence and thereby improve antitumor response.
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Project description:Chimeric antigen receptor (CAR) T cells are known to be potent in recognizing and eliminating tumor elimination, and effector functions. They induce marked responses in patients with refractory leukemia and lymphoma, but dysfunction of T cells is an inevitable obstacle for persistent curative effect. Extending the persistence of these cells without compromising their potency is supposed to improve treatment outcomes. We demonstrated that the SOCE (Store-Operated Calcium Entry) inhibitor BTP-2, rather than calcium chelator BAPTA-AM, diminished exhaustion and terminal differentiation of CAR-T cells both in tonic signaling and tumor antigen exposure models. And BTP-2 pretreated CAR-T cells showed improved antitumor potency and prolonged survival in NSG mice. To further investigate the biological impact of calcium signaling at the molecular level, we performed RNA-seq on CAR-T cells and CAR-T cells exposed to Nalm6 stimulation followed by treatment with DMSO, BAPTA and BTP-2.The high-throughput RNA sequencing (RNA-Seq) revealed that treatment with BTP-2 downregulates glycolysis pathway.
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Project description:In vivo persistence of chimeric antigen receptor (CAR) T cells correlates with therapeutic efficacy, yet CAR-specific factors that support persistence are not well resolved. Using a CAR containing a single chain variable fragment (scFv) specific for CD33 linked to a 4-1BB and CD3 zeta signaling domain that is currently in advanced clinical trials, we show that CAR-expression, in a ligand-independent manner, alters T cell differentiation during ex vivo expansion. CAR-transduced T cells displayed decreased naïve and stem memory populations and increased effector subsets relative to vector-transduced control cells, and this was associated with reduced in vivo persistence. Altered persistence was not due to antigen specificity or tumor presence, but was linked to tonic signaling through the CAR, most notably CD3 zeta ITAMs, prior to transfer. We identified the PI3K/AKT pathway in CD33 CAR T cells as responsible. Treatment with a PI3K inhibitor modulated the differentiation program of CAR T cells, preserved a less differentiated state without affecting T cell expansion, and improved in vivo persistence relative to control cells. These results help resolve mechanisms by which tonic signaling modulates CAR T cell fate, and identifies a novel pharmacologic approach to enhance the durability of CAR T cells for cell-based immunotherapy.
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Project description:Abstract. The use of large animal spontaneous models of solid cancers, such as dogs with osteosarcoma (OS), can help develop new cancer immunotherapy approaches, including chimeric antigen receptor (CAR) T cells. Therefore, the goal of the present study was to generate canine CAR T cells targeting the B7-H3 (CD276) co-stimulatory molecule overexpressed by several solid cancers, including OS and glioma in both humans and dogs, and to assess their ability to recognize B7-H3 expressed by canine OS cell lines or by canine tumors in xenograft models. A second objective was to determine whether a novel dual CAR that expressed a chemokine receptor together with the B7-H3 CAR improved the activity of the canine CAR T cells. Therefore, in the studies reported here we examined B7-H3 expression by canine OS tumors, evaluated target engagement by canine B7-H3 CAR T cells in vitro, and compared the relative effectiveness of B7-H3 CAR T cells versus B7-H3-CXCR2 dual CAR T cells in canine xenograft models. We found that most canine OS tumors expressed high levels of B7-H3, whereas levels were undetectable on normal dog tissues. In vitro, both B7-H3 CAR T cells demonstrated activation and OS-specific target killing in vitro, but there was significantly greater cytokine production by B7-H3-CXCR2 CAR T cells. In canine OS xenograft models, little antitumor activity was generated by B7-H3 CAR T cells, whereas B7-H3-CXCR2 CAR T cells significantly inhibited tumor growth, inducing complete tumor elimination in most treated mice. These findings indicated therefore that addition of a chemokine receptor could significantly improve the anti-tumor activity of canine B7-H3 CAR T cells, and that evaluation of this new dual CAR construct in dogs with primary or metastatic OS is warranted since such studies could provide a critical and realistic validation of the chemokine receptor concept.
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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.
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