Efficacy and safety of Her2-targeted chimeric antigen receptor (CAR) T cells using MyD88/CD40 costimulation and iCaspase-9 suicide switch.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 3050-3050 ◽  
Author(s):  
Aaron E Foster ◽  
Jeannette Crisostomo ◽  
Peter Chang ◽  
Pei-Yi Lin ◽  
Aruna Mahendravada ◽  
...  
Keyword(s):  
T Cells ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Efficacy And Safety ◽  
Car T Cells ◽  
Car T

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.

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.

A Novel High Throughput Process for Generation and Characterization of Chimeric Antigen Receptor (CAR) T Cells

2017 ◽  
Vol 17 ◽  
pp. S381-S382
Author(s):  
Sabarinath Venniyil Radhakrishnan ◽  
Adam Miles ◽  
Djordje Atanackovic ◽  
Tim Luetkens
Keyword(s):  
T Cells ◽  
High Throughput ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Car T Cells ◽  
Car T

scholarly journals Evaluation of chimeric antigen receptor T cell therapy in non-human primates infected with SHIV or SIV

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0248973
Author(s):  
Nami Iwamoto ◽  
Bhavik Patel ◽  
Kaimei Song ◽  
Rosemarie Mason ◽  
Sara Bolivar-Wagers ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Chimeric Antigen Receptor ◽  
Viral Suppression ◽  
Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

Achieving a functional cure is an important goal in the development of HIV therapy. Eliciting HIV-specific cellular immune responses has not been sufficient to achieve durable removal of HIV-infected cells due to the restriction on effective immune responses by mutation and establishment of latent reservoirs. Chimeric antigen receptor (CAR) T cells are an avenue to potentially develop more potent redirected cellular responses against infected T cells. We developed and tested a range of HIV- and SIV-specific chimeric antigen receptor (CAR) T cell reagents based on Env-binding proteins. In general, SHIV/SIV CAR T cells showed potent viral suppression in vitro, and adding additional CAR molecules in the same transduction resulted in more potent viral suppression than single CAR transduction. Importantly, the primary determinant of virus suppression potency by CAR was the accessibility to the Env epitope, and not the neutralization potency of the binding moiety. However, upon transduction of autologous T cells followed by infusion in vivo, none of these CAR T cells impacted either acquisition as a test of prevention, or viremia as a test of treatment. Our study illustrates limitations of the CAR T cells as possible antiviral therapeutics.

Clinical practice: chimeric antigen receptor (CAR) T cells: a major breakthrough in the battle against cancer

2020 ◽  
Vol 20 (4) ◽  
pp. 469-480 ◽  
Author(s):  
Stefan Lundh ◽  
In-Young Jung ◽  
Alexander Dimitri ◽  
Anish Vora ◽  
J. Joseph Melenhorst ◽  
...  
Keyword(s):  
T Cells ◽  
Clinical Practice ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Car T Cells ◽  
Car T

Chimeric Antigen Receptor T Cell Immunotherapy for Tumor: A Review of Patent Literatures

2019 ◽  
Vol 14 (1) ◽  
pp. 60-69
Author(s):  
Manxue Fu ◽  
Liling Tang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Limiting Factors ◽  
Car T Cells ◽  
Car T Cell ◽  
Cell Immunotherapy ◽  
Car T ◽  
T Cell Immunotherapy

Background: Chimeric Antigen Receptor (CAR) T cell immunotherapy, as an innovative method for tumor immunotherapy, acquires unprecedented clinical outcomes. Genetic modification not only provides T cells with the antigen-binding function but also endows T cells with better immunological functions both in solid and hematological cancer. However, the CAR T cell therapy is not perfect because of several reasons, such as tumor immune microenvironment, and autologous limiting factors of CAR T cells. Moreover, the safety of CAR T cells should be improved.Objective:Recently many patents and publications have reported the importance of CAR T cell immunotherapy. Based on the patents about CAR T cell immunotherapy, we conclude some methods for designing the CAR which can provide information to readers.Methods:In this review, we collect recent patents and publications, summarize some specific antigens for oncotherapy from patents and enumerate some approaches to conquering immunosuppression and reinforcing the immune response of CAR T cells. We also sum up some strategies for improving the safety of CAR T cell immunotherapy.Results:CAR T cell immunotherapy as a neotype cellular immunotherapy has been proved effective in oncotherapy and authorized by FDA. Improvements in CAR designing enhance functions of CAR T cells.Conclusion:This review, summarizing antigens and approaches to overcome defects of CAR T cell immunotherapy from patents and publications, might contribute to a broad readership.

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