scholarly journals HER2-specific chimeric antigen receptor-T cells for targeted therapy of metastatic colorectal cancer

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Jie Xu ◽  
Qingtao Meng ◽  
Hao Sun ◽  
Xinwei Zhang ◽  
Jun Yun ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Metastatic Colorectal Cancer ◽  
Chimeric Antigen Receptor ◽  
Malignant Tumors ◽  
Antigen Receptor ◽  
Tumor Xenograft ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

AbstractChimeric antigen receptor (CAR) - T cell therapy is a new class of cellular immunotherapies, which has made great achievements in the treatment of malignant tumors. Despite improvements in colorectal cancer (CRC) therapy, treatment of many patients fails because of metastasis and recurrence. The human epidermal growth factor receptor 2 (HER2) is a substantiated target for CAR-T therapy, and has been reported recently to be over-expressed in CRC, which may provide a potential therapeutic target for CRC treatment. Herein, HER2 was a promising target of metastatic colorectal cancer (mCRC) in CAR-T therapy as assessed by flow cytometry and tissue microarray (TMA) with 9-year survival follow-up data. Furthermore, HER2-specific CAR-T cells exhibited strong cytotoxicity and cytokine-secreting ability against CRC cells in vitro. Moreover, through the tumor-bearing model of the NOD-Prkdcem26cd52Il2rgem26Cd22/Nju (NCG) mice, HER2 CAR-T cells showed signs of effectively preventing CRC progression in three different xenograft models. Notably, HER2 CAR-T cells displayed greater aggressiveness in HER2+ CRC in the patient-derived tumor xenograft (PDX) models and had potent immunotherapeutic capacity for mCRC in the metastatic xenograft mouse models. In conclusion, our studies provide scientific evidence that HER2 CAR-T cells represent an emerging immunotherapy for the treatment of mCRC.

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.

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 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.

Chimeric antigen receptor (CAR) T cells genetically engineered to deliver IL-12 to the tumor microenvironment in ovarian cancer.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 141-141
Author(s):  
Oladapo O. Yeku ◽  
Terence Purdon ◽  
David R. Spriggs ◽  
Renier J. Brentjens
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Genetically Engineered ◽  
Ovarian Cancer Cells ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

141 Background: Chimeric antigen receptor (CAR) T cell therapy for solid tumor malignancies has not shown the same degree of clinical efficacy observed in hematologic malignancies such as B-ALL. The presence of an immunosuppressive cellular and cytokine microenvironment has been hypothesized as one reason for the failure of adoptive immunotherapy for solid tumors. In ovarian cancer, myeloid derived suppressor cells (MDSC) and immunosuppressive cytokines in the ascitic microenvironment have been reported. IL-12 is a proinflammatory cytokine produced by macrophages, dendritic cells (DC), and NK cells, and it has been shown to increase proliferation of T cells, induce differentiation of type 1 T helper cells, inhibit regulatory T cells, promote maturation of DCs, and enhance antigen presentation by macrophages. We hypothesize that CAR T cells genetically modified to constitutively secrete IL-12 will overcome a hostile tumor microenvironment in a peritoneal carcinomatosis model of ovarian cancer. Methods: CAR T cells were generated from retroviral transduction of second generation and IL-12 modified CAR’s directed to either an irrelevant CD-19 antigen or Muc16ecto. C57BL/6 mice were inoculated i.p with syngeneic ovarian cancer cells and treated with various CAR T cells. Results: Here we report increased production of IL-12, improved proliferation and cytotoxic activity of 4H1128ζ-IL12 CAR T cells. Further, we show increased levels of inflammatory cytokines at 24 and 48hrs after treatment of tumor-bearing mice, leading to increased survival at advanced stages of disease. Animals treated with 4H1128ζ-IL12 CAR T cells had decreased levels of F4/80+ CD11b+MDSCs. Genetic analysis of recovered MDSCs from the ascites of treated animals showed skewing towards an M1-phenotype via upregulation of cytokines, chemokines, MHC-II, and downregulation of Arg1. Furthermore, clodronate-mediated depletion of TAM’s further enhanced survival in mice treated with 4H1128ζ-IL12 CAR T cells. Conclusions: These results demonstrate the mechanisms of efficacy of localized delivery of IL-12 to the tumor microenvironment by 4H1128ζ-IL12 CAR T cells.

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.

Chimeric antigen receptor (CAR) T cells genetically engineered to deliver IL-12 to the tumor microenvironment in ovarian cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3050-3050 ◽  
Author(s):  
Oladapo O. Yeku ◽  
Terence Purdon ◽  
David R. Spriggs ◽  
Renier J. Brentjens
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Genetically Engineered ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T ◽  
Fas L

3050 Background: Chimeric antigen receptor (CAR) T cell therapy for solid tumor malignancies has not shown the same degree of clinical efficacy observed in hematologic malignancies. The presence of an immunosuppressive cytokine and cellular microenvironment has been hypothesized as one reason for the failure of adoptive immunotherapy for solid tumors. In ovarian cancer, the presence of tumor associated macrophages (TAMs) and immunosuppressive cytokines in the ascitic microenvironment have been reported. IL-12 is a proinflammatory cytokine produced by macrophages, dendritic cells (DC) and NK cells, and has been shown to increase proliferation of T cells and enhance antigen presentation by macrophages. We hypothesized that CAR T cells genetically modified to constitutively secrete IL-12 would overcome a hostile tumor microenvironment in a peritoneal carcinomatosis model of ovarian cancer. Methods: CAR T cells were generated from retroviral transduction of second generation and IL-12 modified CAR’s directed to either an irrelevant CD-19 antigen or Muc16ecto. Results: Here we report increased production of IL-12, improved proliferation and cytotoxic activity of 4H1128-IL12 CAR T cells. We show increased levels of inflammatory cytokines at 24 and 48hrs after treatment of tumor-bearing mice, leading to increased survival at advanced stages of disease. Mice treated with 4H1128-IL12 CAR T cells had decreased levels of F4/80+ CD11b+TAM’s. Genetic analysis of recovered TAM’s from the ascites of treated animals showed skewing towards an M1-phenotype via upregulation of cytokines, chemokines, MHC-II and downregulation of Arg1. Recovered 4H1128-IL12 CAR T cells showed upregulation of FAS-L and recovered TAMs showed increased expression of FAS suggesting FAS/FAS-L engagement was responsible for decreased TAMs. Blocking the FAS/FAS-L pathway led to recovery of TAM populations in 4H1128-IL12 treated mice. Finally, clodronate-mediated depletion of TAM’s further enhanced survival in mice treated with 4H1128-IL12 CAR T cells. Conclusions: These results demonstrate the mechanisms of efficacy of localized delivery of IL-12 to the tumor microenvironment by 4H1128-IL12 CAR T cells.

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.

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