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.

scholarly journals HIV-1-Specific Chimeric Antigen Receptor T Cells Fail To Recognize and Eliminate the Follicular Dendritic Cell HIV Reservoir In Vitro

2020 ◽  
Vol 94 (10) ◽  
Author(s):  
Matthew T. Ollerton ◽  
Edward A. Berger ◽  
Elizabeth Connick ◽  
Gregory F. Burton
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Follicular Dendritic

ABSTRACT The major obstacle to a cure for HIV infection is the persistence of replication-competent viral reservoirs during antiretroviral therapy. HIV-specific chimeric antigen receptor (CAR) T cells have been developed to target latently infected CD4+ T cells that express virus either spontaneously or after intentional latency reversal. Whether HIV-specific CAR-T cells can recognize and eliminate the follicular dendritic cell (FDC) reservoir of HIV-bound immune complexes (ICs) is unknown. We created HIV-specific CAR-T cells using human peripheral blood mononuclear cells (PBMCs) and a CAR construct that enables the expression of CD4 (domains 1 and 2) and the carbohydrate recognition domain of mannose binding lectin (MBL) to target native HIV Env (CD4-MBL CAR). We assessed CAR-T cell cytotoxicity using a carboxyfluorescein succinimidyl ester (CFSE) release assay and evaluated CAR-T cell activation through interferon gamma (IFN-γ) production and CD107a membrane accumulation by flow cytometry. CD4-MBL CAR-T cells displayed potent lytic and functional responses to Env-expressing cell lines and HIV-infected CD4+ T cells but were ineffective at targeting FDC bearing HIV-ICs. CD4-MBL CAR-T cells were unresponsive to cell-free HIV or concentrated, immobilized HIV-ICs in cell-free experiments. Blocking intercellular adhesion molecule-1 (ICAM-1) inhibited the cytolytic response of CD4-MBL CAR-T cells to Env-expressing cell lines and HIV-infected CD4+ T cells, suggesting that factors such as adhesion molecules are necessary for the stabilization of the CAR-Env interaction to elicit a cytotoxic response. Thus, CD4-MBL CAR-T cells are unable to eliminate the FDC-associated HIV reservoir, and alternative strategies to eradicate this reservoir must be sought. IMPORTANCE Efforts to cure HIV infection have focused primarily on the elimination of latently infected CD4+ T cells. Few studies have addressed the unique reservoir of infectious HIV that exists on follicular dendritic cells (FDCs), persists in vivo during antiretroviral therapy, and likely contributes to viral rebound upon cessation of antiretroviral therapy. We assessed the efficacy of a novel HIV-specific chimeric antigen receptor (CAR) T cell to target both HIV-infected CD4+ T cells and the FDC reservoir in vitro. Although CAR-T cells eliminated CD4+ T cells that express HIV, they did not respond to or eliminate FDC bound to HIV. These findings reveal a fundamental limitation to CAR-T cell therapy to eradicate HIV.

scholarly journals Profile of Capillary-Leak Syndrome in Patients Received Chimeric Antigen Receptor T Cell Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5204-5204 ◽  
Author(s):  
Yongxian Hu ◽  
Jingjing Feng ◽  
Mi Shao ◽  
He Huang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Capillary Leak Syndrome ◽  
Capillary Leak ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

Abstract Background: Autologous T cells modified to express a chimeric antigen receptor (CAR-T) has demonstrated exciting efficacy in treating leukemia and there has been some reports about the toxicities recently. However, the spectrum of capillary-leak syndrome (CLS) associated with CAR-T cell therapy has not been systematically evaluated, which can be a life threatening complication as results of the cytokine release syndrome (CRS). Therefore, as the use of CAR-T therapy continues to expand to broader applications, it is prudent to characterize the profile of CLS to help providers guide safe management. Method: We reviewed all acute lymphoblastic leukemia (ALL) patients who had participated in the clinical trial from our center to receive CAR-T therapy between 2016-2018. Patients analyzed in the study received either CD19 CAR-T cells or CD19 plus CD22 CAR-T cells. The diagnosis of CLS includes edema, acute hypotension and hemoconcentration with hypoproteinemia or hypoalbuminemia. CRS grading was evaluated with Lee's criteria for CRS. Result: 42 ALL patients were included in this study with the mean age of 27(8-52) years old. 11(11/42, 26.2%) patients were diagnosed as CLS and 31 were not. It was observed that CLS was more common in patients who developed severe CRS. Patients with CLS was found to have high rate of hypotension and use of gamma globulin.(Table 1) Top level concentration of serum IL-6 in CLS patients was much higher than that in non-CLS patients (16438.7 vs 3292.7 pg/mL, p=0.0016), which is consistent with the well recognized concept of IL-6 as an indicator of CRS.(Figure 1) It is important to notice that CLS patients had lower levels of serum total protein (TP, 43.7 vs 52.8 g/L, p=0.0005) and serum albumin (ALB, 27.4 vs 33.8 g/L, p=0.0011), while the hemoglobin (HGB) concentration showed no difference, suggesting that TP and ALB might be better indicators for CLS than HGB, although hemoconcentration, hypoproteinemia and hypoalbuminemia are both important in diagnosis.(Figure 2) Moreover, there was no significant difference in age, gender, Ph type of ALL, type of CAR-T cells infused and death ratio.(Table 1) Although CRS has been reported to be related with disease burden before the therapy, our data showed no difference of it between the patients with and without CLS. Conclusion: In conclusion, we have evaluated a basic profile of CLS among CAR-T patients in our center and the study indicates that CLS warrants extra attention for patients who receive CAR-T therapy. Further investigations are required to elucidate best practices for prevention and management of CLS in CAR-T therapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Clinical Development and Manufacture of Chimeric Antigen Receptor T cells and the Role of Leukapheresis

2017 ◽  
Vol 13 (01) ◽  
pp. 28 ◽  
Author(s):  
Andrew Fesnak ◽  
Una O’Doherty ◽  
◽  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Large Scale ◽  
Mononuclear Cells ◽  
Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Adoptive transfer of chimeric antigen receptor (CAR) T cells is a powerful targeted immunotherapeutic technique. CAR T cells are manufactured by harvesting mononuclear cells, typically via leukapheresis from a patient’s blood, then activating, modifying the T cells to express a transgene encoding a tumour-specific CAR, and infusing the CAR T cells into the patient. Gene transfer is achieved through the use of retroviral or lentiviral vectors, although non-viral delivery systems are being investigated. This article discusses the challenges associated with each stage of this process. Despite the need for a consistent end product, there is inherent variability in cellular material obtained from critically ill patients who have been exposed to cytotoxic therapy. It is important to carefully select target antigens to maximise effect and minimise toxicity. Various types of CAR T cell toxicity have been documented: this includes “on target, on tumour”, “on target, off tumour” and “off target” toxicity. A growing body of clinical evidence supports the efficacy and safety of CAR T cell therapy; CAR T cells targeting CD19 in B cell leukemias are the best-studied therapy to date. However, providing personalised therapy on a large scale remains challenging; a future aim is to produce a universal “off the shelf” CAR T cell.

scholarly journals The roles of T cell competition and stochastic extinction events in chimeric antigen receptor T cell therapy

2021 ◽  
Vol 288 (1947) ◽  
Author(s):  
Gregory J. Kimmel ◽  
Frederick L. Locke ◽  
Philipp M. Altrock
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Chimeric antigen receptor (CAR) T cell therapy is a remarkably effective immunotherapy that relies on in vivo expansion of engineered CAR T cells, after lymphodepletion (LD) by chemotherapy. The quantitative laws underlying this expansion and subsequent tumour eradication remain unknown. We develop a mathematical model of T cell–tumour cell interactions and demonstrate that expansion can be explained by immune reconstitution dynamics after LD and competition among T cells. CAR T cells rapidly grow and engage tumour cells but experience an emerging growth rate disadvantage compared to normal T cells. Since tumour eradication is deterministically unstable in our model, we define cure as a stochastic event, which, even when likely, can occur at variable times. However, we show that variability in timing is largely determined by patient variability. While cure events impacted by these fluctuations occur early and are narrowly distributed, progression events occur late and are more widely distributed in time. We parameterized our model using population-level CAR T cell and tumour data over time and compare our predictions with progression-free survival rates. We find that therapy could be improved by optimizing the tumour-killing rate and the CAR T cells' ability to adapt, as quantified by their carrying capacity. Our tumour extinction model can be leveraged to examine why therapy works in some patients but not others, and to better understand the interplay of deterministic and stochastic effects on outcomes. For example, our model implies that LD before a second CAR T injection is necessary.

scholarly journals Chimeric Antigen Receptor T Cell Therapy for Solid Tumors: Current Status, Obstacles and Future Strategies

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 191 ◽  
Author(s):  
Benjamin Heyman ◽  
Yiping Yang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Solid Tumors ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Current Status ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

Chimeric antigen receptor T cells (CAR T Cells) have led to dramatic improvements in the survival of cancer patients, most notably those with hematologic malignancies. Early phase clinical trials in patients with solid tumors have demonstrated them to be feasible, but unfortunately has yielded limited efficacy for various cancer types. In this article we will review the background on CAR T cells for the treatment of solid tumors, focusing on the unique obstacles that solid tumors present for the development of adoptive T cell therapy, and the novel approaches currently under development to overcome these hurdles.

scholarly journals Clinical Study on the CD19-Targeted Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Acute Lymphoblast Leukemia: A Single Center of Real World Data

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4834-4834
Author(s):  
Jing Huang ◽  
Zhi Liu ◽  
Ruiming Ou ◽  
Liling Zheng ◽  
Yangmin Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell Therapy ◽  
Car T ◽  
Acute Lymphoblast Leukemia

Abstract Objective To evaluate the efficacy and safety of the CD19-targeted chimeric antigen receptor T-cell(CD19-CAR-T) therapy for relapsed/refractory B-cell acute lymphoblast leukemia(B-ALL). Methods The efficacy and safety of CD19-CAR-T cells(4-1BB costimulatory domain) in treatment of 34 patients with relapsed/refractory B-ALL from March 2015 to December 2019 in the Department of Hematology of Guangdong Second Province Hospital were collected analyzed retrospectively. There were 18 cases (52.9%) with high-risk cytogenetic or molecular markers, 14 cases (41.2%) with tumor load was ≥50% before transfusion, 24 cases (70.6%) with ECOG score ≥2. The number of chemotherapy courses received before transfusion was 2-15, the median number of chemotherapy courses was 5. There were 32 autogenous CAR-T cells and 2 donor-derived CAR-T cells, 11 of them received allogeneic hematopoietic stem cell transplantation (allo-HSCT) before transfusion. All were mouse CAR-T cells. Fludarabine + Cyclophosphamide (FC) regimen was used for pretreatment before transfusion, and the number of CAR-T cells was 1 ~ 13.4×10 6/kg. Results All 34 patients received CD19-targeted CAR-T cell therapy. 22 patients obtained MRD- after 1 month, CR rate was 64.7%. 20 patients maintained MRD- after 2 months, and the CR rate was 58.8%. 13 patients still maintained MRD- after 3 months, with a CR rate of 38.2%. 4 patients with recurrence presented CD19 negative recurrence. 10 patients underwent Allo-HSCT after CR acquisition, 6 of them maintained a continuous CR state, and 4 patients died after recurrence. Cytokines release syndrome (CRS) was observed in 31 patients (91.2%). Among them, there were 20 patients (64.5%) with grade 1 ~ 2, 8 patients (25.8%) with grade 3 ~ 4, and 3 patients (9.7%) with grade 5. The cytokines levels of IL-6 and IFN-γ were mainly increased in 20 (64.5%) and 18 (58.1%) patients, respectively. Common clinical adverse reactions are: fever with 32 cases (94.1%), pancytopenia with 28 cases (82.4%), chills with 17 cases (50.0%), fatigue with 26 cases (76.5%), hypotension with 27 cases (79.4%), tachycardia with 24 cases (70.6%), hypofibrinogenemia with 20 cases (58.8%), hypoproglobinemia with 27 cases (79.4%), neurotoxicity with 15 cases (44.1%), nausea with 16 cases (47.1%), vomiting with 14 cases (41.2%), hypoalbuminemia with 25 cases (73.5%), transaminase eleations with 16 cases (47.1%), electrolyte metabolic disorders with 27 cases (79.4%) , hypoxemiawith 15 cases (44.1%). Conclusion CAR-T cells therapy is a novel method for the treatment of refractory/recurrent B-ALL with CD19 antigen positive, which can make patients achieved complete remission in a short time, even achieved MRD negative, and most of the CRS appeared in the process of treatment can be controlled by treatment, but the recurrence rate is higher after 3 months later, and can appear CD19 negative relapse. Allo-HSCT as soon as possible after obtaining CR can enable some patients to obtain sustained CR.Therefore, more clinical studies are needed to explore the clinical application of CAR-T cell therapy. Currently, it is believed that bridging with allo-HSCT may be a solution to achieve sustained CR. 【Key words】Chimeric antigen receptor T-cell; Relapsed/refractory acute lymphoblast leukemia; Efficacy; Safety; Cytokine release syndrome Disclosures No relevant conflicts of interest to declare.

scholarly journals Killing Mechanisms of Chimeric Antigen Receptor (CAR) T Cells

2019 ◽  
Vol 20 (6) ◽  
pp. 1283 ◽  
Author(s):  
Mohamed-Reda Benmebarek ◽  
Clara Karches ◽  
Bruno Cadilha ◽  
Stefanie Lesch ◽  
Stefan Endres ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Effective adoptive T cell therapy (ACT) comprises the killing of cancer cells through the therapeutic use of transferred T cells. One of the main ACT approaches is chimeric antigen receptor (CAR) T cell therapy. CAR T cells mediate MHC-unrestricted tumor cell killing by enabling T cells to bind target cell surface antigens through a single-chain variable fragment (scFv) recognition domain. Upon engagement, CAR T cells form a non-classical immune synapse (IS), required for their effector function. These cells then mediate their anti-tumoral effects through the perforin and granzyme axis, the Fas and Fas ligand axis, as well as the release of cytokines to sensitize the tumor stroma. Their persistence in the host and functional outputs are tightly dependent on the receptor’s individual components—scFv, spacer domain, and costimulatory domains—and how said component functions converge to augment CAR T cell performance. In this review, we bring forth the successes and limitations of CAR T cell therapy. We delve further into the current understanding of how CAR T cells are designed to function, survive, and ultimately mediate their anti-tumoral effects.

Interventions and Outcomes of Adult Patients with B-ALL Progressing After CD19 Chimeric Antigen Receptor T Cell Therapy

Blood ◽  
2021 ◽  
Author(s):  
Kitsada Wudhikarn ◽  
Jessica R Flynn ◽  
Isabelle Rivière ◽  
Mithat Gonen ◽  
Xiuyan Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Adult Patients ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

CD19-targeted chimeric antigen receptor (CAR) T cell therapy has become a breakthrough treatment for patients with relapsed/refractory B acute lymphoblastic leukemia (B-ALL). However, despite the high initial response rate, the majority of adult patients with B-ALL progress after CD19 CAR T therapy. Data on the natural history, management, and outcome of adult B-ALL progressing after CD19 CAR T cells have not been described in detail. Herein, we report comprehensive data of 38 adult B-ALL patients who progressed after CD19 CAR T therapy at our institution. The median time to progression after CAR T therapy was 5.5 months. Median survival after post-CAR T progression was 7.4 months. A high disease burden at the time of CAR T cell infusion was significantly associated with risk of post-CAR T progression. Thirty patients (79%) received salvage treatment for post-CAR T disease progression and 13 patients (43%) achieved complete remission (CR), but remission duration was short. Notably, 7 of 12 patients (58.3%) achieved CR after blinatumomab and/or inotuzumab administered after post-CAR T failure. Multivariate analysis demonstrated longer remission duration from CAR T cells was associated with superior survival after progression following CAR T therapy. In conclusion, overall prognosis of adult B-ALL patients progressing after CD19 CAR T cells was poor though a subset of patients achieved sustained remissions to salvage treatments including blinatumomab, inotuzumab and re-infusion of CAR T cells. Novel therapeutic strategies are needed to reduce risk of progression after CAR T therapy and improve outcomes of these patients.

scholarly journals Distribution Measurements of Chimeric Antigen Receptor-Modified T Cells Against CD19

2020 ◽  
Author(s):  
Zhitao Ying ◽  
Ting He ◽  
Xiaopei Wang ◽  
Wen Zheng ◽  
Ningjing Lin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Target Cells ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Abstract Backgroud: The unprecedented efficacy of chimeric antigen receptor (CAR) T-cell immunotherapy of CD19+ B-cell malignancies has opened a new and useful way for the treatment of malignant tumor. Nonetheless, there are still formidable challenges in the field of CAR-T cell therapy, such as the biodistribution of CAR-T cells in vivo.Methods: We demonstrated the distribution of CAR-T cells in the absence of target cells or with target cells in the mice and the dynamic changes in the patient blood over time after infusion were deteced by qPCR and FACS. Results: CAR-T cells still proliferated in the mice without target cells and peaked at 2 weeks. However, CAR-T cells did not increase significantly in the presence of target cells within 2 weeks after infusion, but expanded at 6 weeks. In the clinical trial, we found that CAR-T cells peaked at 7-21days after infusion and can last for as long as 510 days in the peripheral blood of patients. Simultaneously, mild side-effects were noted which can be effectively controlled within two months in these patients.Conclusions: CAR-T cells can expand themselves with or without target cells in mice. CAR-T cells can persistence for a long time in patients.

scholarly journals Infection Temperature Affects the Phenotype and Function of Chimeric Antigen Receptor T Cells Produced via Lentiviral Technology

2021 ◽  
Vol 12 ◽  
Author(s):  
Xin Jin ◽  
Wenyi Lu ◽  
Meng Zhang ◽  
Xia Xiong ◽  
Rui Sun ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Immune Checkpoints ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
And Function

Chimeric antigen receptor (CAR)-T cell therapy has become an important method for the treatment of hematological tumors. Lentiviruses are commonly used gene transfer vectors for preparing CAR-T cells, and the conditions for preparing CAR-T cells vary greatly. This study reported for the first time the influence of differences in infection temperature on the phenotype and function of produced CAR-T cells. Our results show that infection at 4 degrees produces the highest CAR-positive rate of T cells, infection at 37 degrees produces the fastest proliferation in CAR-T cells, and infection at 32 degrees produces CAR-T cells with the greatest proportion of naive cells and the lowest expression of immune checkpoints. Therefore, infection at 32 degrees is recommended to prepare CAR-T cells. CAR-T cells derived from infection at 32 degrees seem to have a balance between function and phenotype. Importantly, they have increased oncolytic ability. This research will help optimize the generation of CAR-T cells and improve the quality of CAR-T cell products.

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