scholarly journals Improved survival of chimeric antigen receptor‐engineered T ( CAR ‐T) and tumor‐specific T cells caused by anti‐programmed cell death protein 1 single‐chain variable fragment‐producing CAR ‐T cells

2019 ◽  
Vol 110 (10) ◽  
pp. 3079-3088 ◽  
Author(s):  
Masao Nakajima ◽  
Yukimi Sakoda ◽  
Keishi Adachi ◽  
Hiroaki Nagano ◽  
Koji Tamada
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Single Chain Variable Fragment ◽  
Single Chain ◽  
Car T Cells ◽  
Car T ◽  
Cell Death Protein

112 Rational design of chimeric antigen receptor T cells against glypican 3 decouples toxicity from therapeutic efficacy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A124-A124
Author(s):  
Letizia Giardino ◽  
Ryan Gilbreth ◽  
Cui Chen ◽  
Erin Sult ◽  
Noel Monks ◽  
...  
Keyword(s):  
T Cells ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Single Chain ◽  
High Affinity ◽  
Car T Cells ◽  
Car T ◽  
Animal Care ◽  
Cytotoxic Function

BackgroundChimeric antigen receptor (CAR)-T therapy has yielded impressive clinical results in hematological malignancies and it is a promising approach for solid tumor treatment. However, toxicity, including on-target off-tumor antigen binding, is a concern hampering its broader use.MethodsIn selecting a lead CAR-T candidate against the oncofetal antigen glypican 3 (GPC3), we compared CAR bearing a low and high affinity single-chain variable fragment (scFv,) binding to the same epitope and cross-reactive with murine GPC3. We characterized low and high affinity CAR-T cells immunophenotype and effector function in vitro, followed by in vivo efficacy and safety studies in hepatocellular carcinoma (HCC) xenograft models.ResultsCompared to the high-affinity construct, the low-affinity CAR maintained cytotoxic function but did not show in vivo toxicity. High-affinity CAR-induced toxicity was caused by on-target off-tumor binding, based on the evidence that high-affinity but not low-affinity CAR, were toxic in non-tumor bearing mice and accumulated in organs with low expression of GPC3. To add another layer of safety, we developed a mean to target and eliminate CAR-T cells using anti-TNFα antibody therapy post-CAR-T infusion. This antibody functioned by eliminating early antigen-activated CAR-T cells, but not all CAR-T cells, allowing a margin where the toxic response could be effectively decoupled from anti-tumor efficacy.ConclusionsSelecting a domain with higher off-rate improved the quality of the CAR-T cells by maintaining cytotoxic function while reducing cytokine production and activation upon antigen engagement. By exploring additional traits of the CAR-T cells post-activation, we further identified a mechanism whereby we could use approved therapeutics and apply them as an exogenous kill switch that would eliminate early activated CAR-T following antigen engagement in vivo. By combining the reduced affinity CAR with this exogenous control mechanism, we provide evidence that we can modulate and control CAR-mediated toxicity.Ethics ApprovalAll animal experiments were conducted in a facility accredited by the Association for Assessment of Laboratory Animal Care (AALAC) under Institutional Animal Care and Use Committee (IACUC) guidelines and appropriate animal research approval.

Secretion of human soluble programmed cell death protein 1 by chimeric antigen receptor-modified T cells enhances anti-tumor efficacy

Cytotherapy ◽  
2020 ◽  
Vol 22 (12) ◽  
pp. 734-743 ◽  
Author(s):  
Ang Zhang ◽  
Yao Sun ◽  
Shenyu Wang ◽  
Jie Du ◽  
Xiangyun Gao ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Cell Death Protein

Programmed cell death protein 1 activation preferentially inhibits CD28.CAR–T cells

Cytotherapy ◽  
2018 ◽  
Vol 20 (10) ◽  
pp. 1259-1266 ◽  
Author(s):  
Sergey N. Zolov ◽  
Skyler P. Rietberg ◽  
Challice L. Bonifant
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Car T Cells ◽  
Car T ◽  
Cell Death Protein

scholarly journals Nucleofection with Plasmid DNA for CRISPR/Cas9-Mediated Inactivation of Programmed Cell Death Protein 1 in CD133-Specific CAR T Cells

2019 ◽  
Vol 30 (4) ◽  
pp. 446-458 ◽  
Author(s):  
Bian Hu ◽  
Yan Zou ◽  
Linlin Zhang ◽  
Jiaxing Tang ◽  
Gabriele Niedermann ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Plasmid Dna ◽  
Car T Cells ◽  
Car T ◽  
Cell Death Protein

scholarly journals Third-Generation Anti-CD47-Specific CAR-T Cells Effectively Kill Cancer Cells and Reduce the Genes Expression in Lung Cancer Cell Metastasis

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Huyen Thi La ◽  
Dao Bich Thi Tran ◽  
Hai Manh Tran ◽  
Linh Trong Nguyen
Keyword(s):  
T Cells ◽  
Cancer Cells ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Mrna Levels ◽  
Third Generation ◽  
Single Chain ◽  
Cell Surface Glycoprotein ◽  
Car T Cells ◽  
Car T

CD47 is a cell surface glycoprotein molecule, belonging to the immunoglobulin superfamily, binding to various proteins including integrins, thrombospondin-1, and signal regulatory protein α (SIRPα). CD47 is an important tumor antigen for the development and progression of various cancers. This study designed the chimeric antigen receptor T-cell (CAR-T) to bind to the CD47 to inhibit the expression of CD47. We used the complementarity-determining regions (CDRs) of the B6H12 mouse antibody grafted onto the IgG1 framework to create the humanized single-chain variable fragment (scFv) with linker (G4S)x3. scFv was used to design the chimeric antigen receptor with the structure CD8signal-CD47scFv-CD8a hinge-CD4TM-CD28-41BB-CD3ζ, which was then transformed into T lymphocytes by the lentivirus to create third generation of CAR-T. Results revealed that the new CAR-T cells efficiently killed A549 cancer cells. CAR-T inhibited the expression of genes involved in metastasis and invasion of cells A549 including beta actin, calreticulin, and cyclooxygenase 2 at mRNA levels.

scholarly journals Monoclonal antibodies and chimeric antigen receptor (CAR) T cells in the treatment of colorectal cancer

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ke-Tao Jin ◽  
Bo Chen ◽  
Yu-Yao Liu ◽  
H uan-Rong Lan ◽  
Jie-Ping Yan
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Monoclonal Antibodies ◽  
Immune Responses ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Therapeutic Approaches ◽  
Great Ability ◽  
Car T Cells ◽  
Car T

AbstractColorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer deaths worldwide. Besides common therapeutic approaches, such as surgery, chemotherapy, and radiotherapy, novel therapeutic approaches, including immunotherapy, have been an advent in CRC treatment. The immunotherapy approaches try to elicit patients` immune responses against tumor cells to eradicate the tumor. Monoclonal antibodies (mAbs) and chimeric antigen receptor (CAR) T cells are two branches of cancer immunotherapy. MAbs demonstrate the great ability to completely recognize cancer cell-surface receptors and blockade proliferative or inhibitory pathways. On the other hand, T cell activation by genetically engineered CAR receptor via the TCR/CD3 and costimulatory domains can induce potent immune responses against specific tumor-associated antigens (TAAs). Both of these approaches have beneficial anti-tumor effects on CRC. Herein, we review the different mAbs against various pathways and their applications in clinical trials, the different types of CAR-T cells, various specific CAR-T cells against TAAs, and their clinical use in CRC treatment.

PSMA targeted armored chimeric antigen receptor (CAR) T-cells in patients with advanced mCRPC: A phase I experience.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2534-2534
Author(s):  
Matthew H. Carabasi ◽  
Meredith McKean ◽  
Mark N. Stein ◽  
Michael Thomas Schweizer ◽  
Jason J. Luke ◽  
...  
Keyword(s):  
T Cells ◽  
Dose Level ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Dominant Negative ◽  
Car T Cells ◽  
Car T ◽  
Level 1 ◽  
Immune Toxicity

2534 Background: CART-PSMA-TGFβRDN cells are autologous T cells engineered via lentiviral transduction to express a dominant negative form of TGFβRII (TGFβRDN) and a chimeric antigen receptor (CAR) with specificity to prostate specific membrane antigen (PSMA). The TGFβRDN renders CAR T cells resistant to TGFβ-mediated immunosuppression. CART-PSMA-02 is a multi-center, open-label, Phase 1 study evaluating the safety and feasibility of dosing patients with metastatic castration resistant prostate cancer (mCRPC) with CART-PSMA-TGFβRDN (NCT04227275). Methods: This is a 3+3 dose escalation study to determine the recommended phase 2 dose and schedule of CART-PSMA-TGFβRDN cells following lymphodepleting chemotherapy with cyclophosphamide and fludarabine. Single and fractionated doses are being evaluated. A cohort expansion will enroll patients to further explore the safety of the selected dose and schedule. Results: As of January 2021, 6 patients (pts) have been treated. Two pts were treated in the first dose level (1-3 x107 transduced T cells (TDN)). Four pts were treated in the second dose level (1-3 x 108 TDN with fractionated dosing). AEs occurring in ≥50 % of pts included cytokine release syndrome (CRS), anemia, thrombocytopenia, increased creatinine, nausea, fatigue, pyrexia and dehydration. No DLTs occurred in the 1st dose level. Four pts in the 2nd dose level developed CRS (3 Gr 1 and 1 Gr 2). One pt developed rapid G2 CRS that progressed to Gr 5 encephalopathy and Gr 5 multi-organ failure. Ferritin levels peaked at 56,974 ng/ml (baseline 2,903 ng/mL) despite aggressive immunosuppressive therapy including tocilizumab, dexamtheasone and anakinra. The post infusion cytokine profile indicated elevations in IL-1RA, TNF-alpha, VEGF, IL-10, MIP-1b, IFN-gamma, GM-CSF and notably lower levels of IL6 compared to published reports of CD19 CART-mediated CRS. Autopsy findings were consistent with HLH/MAS, confirming overactivity of the monocyte/macrophage compartment. Based on these observations, a modified immune toxicity management strategy that includes prophylactic anakinra (an IL1R antagonist) was instituted. Preliminary evidence of clinical activity of CART-PSMA-TGFβRDN was noted in the 2nd dose level. Two of 3 pts with 1 month follow-up demonstrated PSA decreases from baseline (1 with >95% decrease, 1 with >50% decrease). Both pts had stable disease per RECIST v1.1. A third pt with only 1 week follow-up had a 40% PSA decrease. Additional data analyses from all infused patients are ongoing and data from pts managed with modified immune toxicity management will be presented. Conclusions: Initial data indicates a unique immune toxicity profile and the potential for anti-tumor activity in mCRPC pts treated with CART-PSMA-TGFβRDN. Modified immune toxicity management could lead to identification of a manageable safety profile and therapeutically active dose. Clinical trial information: NCT04227275.

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