Chimeric antigen receptor T-cell therapy for breast cancer

2021 ◽  
Author(s):  
Mighmig Simonian Gharghani ◽  
Miganoosh Simonian ◽  
Faezeh Bakhtiari ◽  
Mozhan Haji Ghaffari ◽  
Ghazaleh Fazli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Malignant Tumors ◽  
The Novel ◽  
Antigen Receptors ◽  
Chimeric Antigen Receptors ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Relative Safety ◽  
Car T

One of the main reasons that researchers pay enormous attention to immunotherapy is that, despite significant advances in conventional therapy approaches, breast cancer remains the leading cause of death from malignant tumors among women. Genetically modifying T cells with chimeric antigen receptors (CAR) is one of the novel methods that has exhibited encouraging activity with relative safety, further urging investigators to develop several CAR T cells to target overexpressed antigens in breast tumors. This article is aimed not only to present such CAR T cells and discuss their remarkable results but also indicates their shortcomings with the hope of achieving possible strategies for improving therapeutic response.

scholarly journals Engineering Next-Generation CAR-T Cells for Better Toxicity Management

2020 ◽  
Vol 21 (22) ◽  
pp. 8620
Author(s):  
Alain E. Andrea ◽  
Andrada Chiron ◽  
Stéphanie Bessoles ◽  
Salima Hacein-Bey-Abina
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Receptors ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Safety Strategies ◽  
Life Threatening ◽  
Preclinical And Clinical Studies

Immunoadoptive therapy with genetically modified T lymphocytes expressing chimeric antigen receptors (CARs) has revolutionized the treatment of patients with hematologic cancers. Although clinical outcomes in B-cell malignancies are impressive, researchers are seeking to enhance the activity, persistence, and also safety of CAR-T cell therapy—notably with a view to mitigating potentially serious or even life-threatening adverse events like on-target/off-tumor toxicity and (in particular) cytokine release syndrome. A variety of safety strategies have been developed by replacing or adding various components (such as OFF- and ON-switch CARs) or by combining multi-antigen-targeting OR-, AND- and NOT-gate CAR-T cells. This research has laid the foundations for a whole new generation of therapeutic CAR-T cells. Here, we review the most promising CAR-T cell safety strategies and the corresponding preclinical and clinical studies.

scholarly journals CAR T-cell therapy for glioblastoma: recent clinical advances and future challenges

2018 ◽  
Vol 20 (11) ◽  
pp. 1429-1438 ◽  
Author(s):  
Stephen J Bagley ◽  
Arati S Desai ◽  
Gerald P Linette ◽  
Carl H June ◽  
Donald M O’Rourke
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Hematologic Malignancies ◽  
Antigen Receptors ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract In patients with certain hematologic malignancies, the use of autologous T cells genetically modified to express chimeric antigen receptors (CARs) has led to unprecedented clinical responses. Although progress in solid tumors has been elusive, recent clinical studies have demonstrated the feasibility and safety of CAR T-cell therapy for glioblastoma. In addition, despite formidable barriers to T-cell localization and effector function in glioblastoma, signs of efficacy have been observed in select patients. In this review, we begin with a discussion of established obstacles to systemic therapy in glioblastoma and how these may be overcome by CAR T cells. We continue with a summary of previously published CAR T-cell trials in GBM, and end by outlining the key therapeutic challenges associated with the use of CAR T cells in this disease.

Phase I study of adoptive immunotherapy for advanced MUC1* positive breast cancer with autologous T cells engineered to express a chimeric antigen receptor, huMNC2-CAR44 specific for a cleaved form of MUC1 (MUC1*).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2663-TPS2663
Author(s):  
Jennifer M. Specht ◽  
David G. Maloney ◽  
Cecilia Yeung ◽  
Vicky Wu ◽  
Cynthia Bamdad
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Dose Escalation ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

TPS2663 Background: Chimeric antigen receptor (CAR) T cell therapy targeting CD19 results in marked tumor regression for patients with CD19+ malignancies. It would be ideal to extend the success of CAR-T cell therapy to epithelial cancers. MUC1* is a post-translationally modified/cleaved form of mucin 1 (MUC1) that is frequently expressed on breast tumors, functions as a growth factor receptor, and a promising antigen for CAR-T cell therapy. Minerva Biotechnologies developed a CAR (huMNC2-CAR44) which recognizes MUC1* and does not bind to full-length or MUC1* negative cells. huMNC2-CAR44 product consists of autologous T cells transduced with a lentiviral vector encoding humanized MNC2-scFv (MUC1* targeting head), sequences from CD8 𝛼 leader, hinge and transmembrane domains, 4-1BB and CD3ζ domains. Methods: NCT04020575 is a phase I study evaluating the safety of adoptively transferred autologous T cells genetically modified to express huMNC2-CAR44 in patients with metastatic MUC1* positive breast cancer. After screening, leukapheresis is performed, CD8+ and CD4+ T cells are selected, transduced with huMNC2-CAR44, expanded, and antigen stimulated in vitro. Lymphodepletion with cyclophosphamide and fludarabine is followed by infusion of huMNC2-CAR44 CAR-T cells in escalating doses (3.3 x 105 CAR+ T cells/kg – 1 x 107 CAR+ T cells/kg). Key inclusion criteria include metastatic breast cancer of known ER, PR and HER2 status, MUC1* membrane expression > or = 30% with 2+ staining by IHC, measurable or evaluable disease, receipt of standard systemic therapies known to confer benefit, age > 18, informed consent, adequate organ function, and KPS > or = 60%. Patients with active autoimmune disease, uncontrolled infection, anticipated survival < 3 months, and/or untreated CNS metastases are not eligible. The primary objective is to identify the maximum tolerated (MTD) dose of huMNC2-CAR44 T cells by CTCAE v5 and Lee criteria. Secondary objectives include persistence and phenotype of adoptively transferred huMNC2-CAR44 T cells and preliminary antitumor activity. Exploratory objectives include trafficking of huMNC2-CAR44 T cells to tumor sites, effector function of huMNC2-CAR44 T cells in vivo, association between tumor MUC1* expression and huMNC2-CAR44 T cell persistence and response, change in tumor immune microenvironment by multiplex IHC in pre- and post-treatment tumor biopsies. Dose escalation is completed using a "3+3" design. Once the MTD has been determined, up to 15 more patients will be enrolled in each of 3 expansion cohorts (Luminal, HER2 positive, and TNBC) to inform future huMNC2-CAR44 T cell trials. Study is open to screening and enrollment in dose escalation. Up to 69 patients may be enrolled in dose escalation and expansion phases. Clinical trial information: NCT04020575.

scholarly journals Therapeutic Applications of Engineered Chimeric Antigen Receptors-T cell for Cancer Therapy

2021 ◽  
Author(s):  
Amina Hussain
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Therapy ◽  
Malignant Tumors ◽  
Adoptive Cell Therapy ◽  
Clinical Results ◽  
Antigen Receptors ◽  
Chimeric Antigen Receptors ◽  
T Cell Therapy

Findings of new targeted treatments with adequate safety evaluations is essential for better cancer cures and mortality rates. Immunotherapy holds promise for patients with relapsed disease, with the ability to elicit long-term remissions. Emerging promising clinical results in B-cell malignancy using gene-altered T-lymphocytes uttering chimeric antigen receptors have sparked a lot of interest. This treatment could open the path for a major difference in the way we treat tumors that are resistant or recurring. Genetically altered T cells used to produce tumor-specific chimeric antigen receptors are resurrected field of adoptive cell therapy by demonstrating remarkable success in the treatment of malignant tumors. Because of the molecular complexity of chimeric antigen receptors -T cells, a variety of engineering approaches to improve safety and effectiveness are necessary to realize larger therapeutic uses. In this study, we investigate at new strategies for enhancing chimeric antigen receptors-T cell therapy by altering chimeric antigen receptors proteins, T lymphocytes, and their relations with other solid tumor microenvironment (TME) aspects.

Novel Antigen-Specific Expansion of T Cells Transduced with a CD19 Chimeric Antigen Receptor

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3262-3262
Author(s):  
Daniel W. Lee ◽  
James N Kochenderfer ◽  
Christoph Rader ◽  
Rimas J Orentas ◽  
Crystal L Mackall
Keyword(s):  
T Cells ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
K562 Cells ◽  
Antigen Receptors ◽  
Chimeric Antigen Receptors ◽  
Car T Cells ◽  
Car T ◽  
Expansion Protocol ◽  
Specific Expansion

Abstract Abstract 3262 Relapsed acute lymphoblastic leukemia (ALL) remains a difficult challenge for both pediatric and adult patients. Chimeric antigen receptors (CARs) are genetically engineered molecules expressed in transduced T lymphocytes. CARs express both a target binding motif and TCRzeta signals needed for T cell activation, with or without other costimulatory domains. CARs that target CD19 (expressed on most ALL blasts) are being studied in several clinical trials in adults and are planned for pediatric relapsed/refractory ALL. To date, CARs have been expanded ex vivo using antigen-independent techniques. This project sought to develop antigen specific expansion of cells transduced with a CD19-specific CAR by employing artificial APCs (aAPCs) and to explore whether the method of expansion impacted functionality of CD19-CAR T cells. aAPCs used in these studies express the high affinity Fc receptor (CD64) and the costimulatory molecule CD137L (aAPC-41BBL). We created an Fc-CD19 fusion protein that when loaded onto the aAPCs, engages the chimeric antigen receptor and induces antigen specific activation. Antigen-specific vs. non-specific approaches to activation and expansion of CAR expressing T cells were compared using three different expansion protocols (EPs). CD19-CAR transduced T cells were expanded with A) irradiated aAPC-41BBL loaded with anti-OKT3, B) irradiated aAPC-41BBL loaded with rFc-CD19 or C) irradiated allogeneic PBMC feeder cells with anti-OKT3. Briefly, OKT3 and IL-2 activated T cells were transduced with CD19CAR, control CAR (Her2-specific), or non-transduced (Mock). All cultures were maintained in IL-2. Functionality was assessed in a 4-hour 51Cr release assay against 4 distinct CD19+ ALL cell lines, K562 cells, and K562 stably transfected with CD19 (K562-CD19) or NGFR (K562-NGFR). Results demonstrate similar significant levels of CD19-specific cytotoxicity in the 4h assay at E:T ratios as low as 2.5:1, regardless of the expansion protocol used (20-40% lysis of all CD19+ targets when expanded by OKT3/aAPC, 40–60% lysis with rFc-CD19/aAPC, and 35–45% lysis with allogeneic feeders and OKT3). To evaluate cytotoxicity in long term culture, CD19-CAR T cells expanded using the three protocols were co-cultured with ALL cell targets for 4 days, then flow cytometry was performed to enumerate surviving ALL cells as determined by CD22+ staining. NALM6 and K562-CD19 cells were entirely eliminated even at an E:T ratio of 2.5:1 by CD19-CAR T cells, regardless of expansion protocol, and not by any of the 3 Mock EPs. Therefore, these results demonstrate that the cytolytic potential of CAR transduced T cells is similar, regardless of whether expansion occurs via CD3 signaling or via the chimeric receptor itself. Interestingly, we did observe substantial NK mediated killing in these assays, which correlated with CD56+ cell content and was eliminated by cold target inhibition using K562 cells. Studies are underway to determine whether differences in NK killing varies with expansion protocol. In summary, Fc-bearing artificial antigen presenting cells combined with CAR specific Fc fusion proteins provide a potential off-the-shelf reagent for antigen specific expansion of T cells with chimeric antigen receptors. This could overcome variable transduction efficiencies and allow administration of a more homogenous population of CAR specific T cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals STING agonist promotes CAR T cell trafficking and persistence in breast cancer

2020 ◽  
Vol 218 (2) ◽  
Author(s):  
Nuo Xu ◽  
Douglas C. Palmer ◽  
Alexander C. Robeson ◽  
Peishun Shou ◽  
Hemamalini Bommiasamy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cell Trafficking ◽  
T Cell Therapy ◽  
T Cell Trafficking ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

CAR T therapy targeting solid tumors is restrained by limited infiltration and persistence of those cells in the tumor microenvironment (TME). Here, we developed approaches to enhance the activity of CAR T cells using an orthotopic model of locally advanced breast cancer. CAR T cells generated from Th/Tc17 cells given with the STING agonists DMXAA or cGAMP greatly enhanced tumor control, which was associated with enhanced CAR T cell persistence in the TME. Using single-cell RNA sequencing, we demonstrate that DMXAA promoted CAR T cell trafficking and persistence, supported by the generation of a chemokine milieu that promoted CAR T cell recruitment and modulation of the immunosuppressive TME through alterations in the balance of immune-stimulatory and suppressive myeloid cells. However, sustained tumor regression was accomplished only with the addition of anti–PD-1 and anti–GR-1 mAb to Th/Tc17 CAR T cell therapy given with STING agonists. This study provides new approaches to enhance adoptive T cell therapy in solid tumors.

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 Engineering Chimeric Antigen Receptors

Acta Naturae ◽  
2017 ◽  
Vol 9 (1) ◽  
pp. 6-14 ◽  
Author(s):  
S. V. Kulemzin ◽  
V. V. Kuznetsova ◽  
M. Mamonkin ◽  
A. V. Taranin ◽  
А. A. Gorchakov
Keyword(s):  
T Cells ◽  
Target Cells ◽  
Cytotoxic Lymphocytes ◽  
Antigen Receptors ◽  
Chimeric Antigen Receptors ◽  
Car T Cells ◽  
Car T ◽  
Protein Molecules ◽  
Alternative Approaches ◽  
Anti Tumor Activity

Chimeric antigen receptors (CARs) are recombinant protein molecules that redirect cytotoxic lymphocytes toward malignant and other target cells. The high feasibility of manufacturing CAR-modified lymphocytes for the therapy of cancer has spurred the development and optimization of new CAR T cells directed against a broad range of target antigens. In this review, we describe the main structural and functional elements constituting a CAR, discuss the roles of these elements in modulating the anti-tumor activity of CAR T cells, and highlight alternative approaches to CAR engineering.

scholarly journals Anti-Mesothelin CAR T cell therapy for malignant mesothelioma

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Laura Castelletti ◽  
Dannel Yeo ◽  
Nico van Zandwijk ◽  
John E. J. Rasko
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Malignant Mesothelioma ◽  
Oncolytic Viruses ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

AbstractMalignant mesothelioma (MM) is a treatment-resistant tumor originating in the mesothelial lining of the pleura or the abdominal cavity with very limited treatment options. More effective therapeutic approaches are urgently needed to improve the poor prognosis of MM patients. Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a novel potential treatment for this incurable solid tumor. The tumor-associated antigen mesothelin (MSLN) is an attractive target for cell therapy in MM, as this antigen is expressed at high levels in the diseased pleura or peritoneum in the majority of MM patients and not (or very modestly) present in healthy tissues. Clinical trials using anti-MSLN CAR T cells in MM have shown that this potential therapeutic is relatively safe. However, efficacy remains modest, likely due to the MM tumor microenvironment (TME), which creates strong immunosuppressive conditions and thus reduces anti-MSLN CAR T cell tumor infiltration, efficacy and persistence. Various approaches to overcome these challenges are reviewed here. They include local (intratumoral) delivery of anti-MSLN CAR T cells, improved CAR design and co-stimulation, and measures to avoid T cell exhaustion. Combination therapies with checkpoint inhibitors as well as oncolytic viruses are also discussed. Preclinical studies have confirmed that increased efficacy of anti-MSLN CAR T cells is within reach and offer hope that this form of cellular immunotherapy may soon improve the prognosis of MM patients.

scholarly journals CAR-T in Cancer Treatment: Develop in Self-Optimization, Win-Win in Cooperation

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1955
Author(s):  
Feifei Guo ◽  
Jiuwei Cui
Keyword(s):  
T Cells ◽  
Cancer Treatment ◽  
Unmet Needs ◽  
Hematologic Malignancies ◽  
Limiting Factors ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell Therapy ◽  
Car T ◽  
Application Prospects

Despite remarkable achievements in the treatment of hematologic malignancies, chimeric antigen receptor (CAR)-T cell therapy still faces many obstacles. The limited antitumor activity and persistence of infused CAR-T cells, especially in solid tumors, are the main limiting factors for CAR-T therapy. Moreover, clinical security and accessibility are important unmet needs for the application of CAR-T therapy. In view of these challenges, many potentially effective solutions have been proposed and confirmed. Both the independent and combined strategies of CAR-T therapy have exhibited good application prospects. Thus, in this review, we have discussed the cutting-edge breakthroughs in CAR-T therapy for cancer treatment, with the aim of providing a reference for addressing the current challenges.

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