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CAR-T Cell Therapy against Different Types of Cancer

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 June 2017) | Viewed by 57545

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Special Issue Editor

Dr. Vita Golubovskaya

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Guest Editor

1. Research and Business Development, Promab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA
2. Department of Medicine, University of Oklahoma, Oklahoma, OK 73126, USA
Interests: immunotherapy; CAR-T cells; tumor microenvironment; checkpoint protein; hypoxia; tumor survival signaling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

CAR-T (chimeric antigen receptor) cell therapy is a novel type of cellular immunotherapy that recently provided highly promising results in treating patients with hematological cancers and other types of cancer, such as glioblastoma. The chimeric antigen receptor construct involves a signaling peptide; antibody part (scFv, single chain variable fragment), which binds to tumor antigen; hinge; different co-activation domains and activation CD3 domains. Once CAR binds to the tumor antigen, a T cell expressing CAR initiates killing of tumor cells due to the turned-on signaling from co-and activation signals. There are many challenges for this novel therapy, such as increasing its safety, efficacy in solid cancers, and overcoming on-target-off-tumor activity. This Special Issue highlights novel approaches for CAR-T therapy, focuses on CAR-T therapy against different types of cancer, discusses challenges in manufacturing of CAR-T cells and presents clinical advances and summarized perspectives in this field.

Dr. Vita Golubovskaya
Guest Editor

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Published Papers (6 papers)

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Editorial

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152 KiB

Open AccessEditorial

CAR-T Cell Therapy: From the Bench to the Bedside

by Vita Golubovskaya

Cancers 2017, 9(11), 150; https://doi.org/10.3390/cancers9110150 - 31 Oct 2017

Cited by 26 | Viewed by 5837

Abstract

CAR (Chimeric Antigen receptor)-T cell therapy is a novel type of therapy that uses engineered T cells with an antibody single-chain variable fragment (ScFv) extracellular domain that binds tumor-associated antigens[...] Full article

(This article belongs to the Special Issue CAR-T Cell Therapy against Different Types of Cancer)

Research

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4376 KiB

Open AccessArticle

CD47-CAR-T Cells Effectively Kill Target Cancer Cells and Block Pancreatic Tumor Growth

by Vita Golubovskaya, Robert Berahovich, Hua Zhou, Shirley Xu, Hizkia Harto, Le Li, Cheng-Chi Chao, Mike Ming Mao and Lijun Wu

Cancers 2017, 9(10), 139; https://doi.org/10.3390/cancers9100139 - 21 Oct 2017

Cited by 66 | Viewed by 13739

Abstract

CD47 is a glycoprotein of the immunoglobulin superfamily that is often overexpressed in different types of hematological and solid cancer tumors and plays important role in blocking phagocytosis, increased tumor survival, metastasis and angiogenesis. In the present report, we designed CAR (chimeric antigen receptor)-T cells that bind CD47 antigen. We used ScFv (single chain variable fragment) from mouse CD47 antibody to generate CD47-CAR-T cells for targeting different cancer cell lines. CD47-CAR-T cells effectively killed ovarian, pancreatic and other cancer cells and produced high level of cytokines that correlated with expression of CD47 antigen. In addition, CD47-CAR-T cells significantly blocked BxPC3 pancreatic xenograft tumor growth after intratumoral injection into NSG mice. Moreover, we humanized mouse CD47 ScFv and showed that it effectively bound CD47 antigen. The humanized CD47-CAR-T cells also specifically killed ovarian, pancreatic, and cervical cancer cell lines and produced IL-2 that correlated with expression of CD47. Thus, CD47-CAR-T cells can be used as a novel cellular therapeutic agent for treating different types of cancer. Full article

(This article belongs to the Special Issue CAR-T Cell Therapy against Different Types of Cancer)

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Open AccessFeature PaperArticle

Most Do, but Some Do Not: CD4⁺CD25⁻ T Cells, but Not CD4⁺CD25⁺ Treg Cells, Are Cytolytic When Redirected by a Chimeric Antigen Receptor (CAR)

by Andreas A. Hombach and Hinrich Abken

Cancers 2017, 9(9), 112; https://doi.org/10.3390/cancers9090112 - 29 Aug 2017

Cited by 10 | Viewed by 5566

Abstract

Evidences are accumulating that CD4⁺ T cells can physiologically mediate antigen specific target cell lysis. By circumventing major histocompatibility complex (MHC)-restrictions through an engineered chimeric antigen receptor (CAR), CD4⁺ T cells lyse defined target cells as efficiently as do CD8⁺ T cells. However, the cytolytic capacity of redirected CD4⁺CD25⁻ T cells, in comparison with CD4⁺CD25⁺ regulatory T (Treg) cells was so far not thoroughly defined. Treg cells require a strong CD28 signal together with CD3ζ for activation. We consequently used a CAR with combined CD28CD3ζ signalling for redirecting CD4⁺CD25⁻ T cells and CD4⁺CD25⁺ Treg cells from the same donor. CAR redirected activation of these T cell subsets and induced a distinct cytokine pattern with high IL-10 and a lack of IL-2 release by Treg cells. Despite strong antigen-specific activation, CAR Treg cells produced only weak target cell lysis, whereas CD4⁺CD25⁻ CAR T cells were potent killers. Cytolysis did not correlate with the target cell sensitivity to Fas/FasL mediated killing; CD4⁺CD25⁻ T cells upregulated perforin and granzyme B upon CAR activation, whereas Treg cells did less. The different cytolytic capacities of CAR redirected conventional CD4⁺ cells and Treg cells imply their use for different purposes in cell therapy. Full article

(This article belongs to the Special Issue CAR-T Cell Therapy against Different Types of Cancer)

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Open AccessArticle

Quality-of-Life (QOL) during Screening for Phase 1 Trial Studies in Patients with Advanced Solid Tumors and Its Impact on Risk for Serious Adverse Events

by Sidra Anwar, Wei Tan, Chi-Chen Hong, Sonal Admane, Askia Dozier, Francine Siedlecki, Amy Whitworth, Ann Marie DiRaddo, Dawn DePaolo, Sandra M. Jacob, Wen Wee Ma, Austin Miller, Alex A. Adjei and Grace K. Dy

Cancers 2017, 9(7), 73; https://doi.org/10.3390/cancers9070073 - 26 Jun 2017

Cited by 7 | Viewed by 4680

Abstract

Background: Serious adverse events (SAEs) and subject replacements occur frequently in phase 1 oncology clinical trials. Whether baseline quality-of-life (QOL) or social support can predict risk for SAEs or subject replacement among these patients is not known. Methods: Between 2011–2013, 92 patients undergoing screening for enrollment into one of 22 phase 1 solid tumor clinical trials at Roswell Park Cancer Institute were included in this study. QOL Questionnaires (EORTC QLQ-C30 and FACT-G), Medical Outcomes Study Social Support Survey (MOSSSS), Charlson comorbidity scores (CCS) and Royal Marsden scores (RMS) were obtained at baseline. Frequency of dose limiting toxicities (DLTs), subject replacement and SAEs that occurred within the first 4 cycles of treatment were recorded. Fisher’s exact test and Mann-Whitney-Wilcoxon test were used to study the association between categorical and continuous variables, respectively. A linear transformation was used to standardize QOL scores. p-value ≤ 0.05 was considered statistically significant. Results: Baseline QOL, MOSSSS, CCS and RMS were not associated with subject replacement nor DLTs. Baseline EORTC QLQ-C30 scores were significantly lower among patients who encountered SAEs within the first 4 cycles (p = 0.04). Conclusions: Lower (worse) EORTC QLQ-C30 score at baseline is associated with SAE occurrence during phase 1 oncology trials. Full article

(This article belongs to the Special Issue CAR-T Cell Therapy against Different Types of Cancer)

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Review

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Open AccessFeature PaperReview

Chimeric Antigen Receptor (CAR) T Cell Therapy for Malignant Pleural Mesothelioma (MPM)

by Astero Klampatsa, Andrew R. Haas, Edmund K. Moon and Steven M. Albelda

Cancers 2017, 9(9), 115; https://doi.org/10.3390/cancers9090115 - 01 Sep 2017

Cited by 27 | Viewed by 17327

Abstract

Cancer immunotherapy has now become a recognized approach to treating cancers. In addition to checkpoint blockade, adoptive T cell transfer (ACT) using chimeric antigen receptors (CARs) has shown impressive clinical outcomes in leukemias and is now being explored in solid tumors. CARs are engineered receptors, stably or transiently transduced into T cells, that aim to enhance T cell effector function by recognizing and binding to a specific tumor-associated antigen. In this review, we provide a summary of CAR T cell preclinical studies and clinical trials for malignant pleural mesothelioma (MPM), a rare, locally invasive pleural cancer with poor prognosis. We list other attractive potential targets for CAR T cell therapy for MPM, and discuss augmentation strategies of CAR T cell therapy with other forms of immunotherapy in this disease. Full article

(This article belongs to the Special Issue CAR-T Cell Therapy against Different Types of Cancer)

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Open AccessReview

Regional Delivery of Chimeric Antigen Receptor (CAR) T-Cells for Cancer Therapy

by Praveen Sridhar and Fabio Petrocca

Cancers 2017, 9(7), 92; https://doi.org/10.3390/cancers9070092 - 18 Jul 2017

Cited by 68 | Viewed by 9570

Abstract

Chimeric Antigen Receptor (CAR) T-cells are T-cells with recombinant receptors targeted to tumor antigens. CAR-T cell therapy has emerged as a mode of immunotherapy and is now being extensively explored in hematologic cancer. In contrast, CAR-T cell use in solid tumors has been hampered by multiple obstacles. Several approaches have been taken to circumvent these obstacles, including the regional delivery of CAR-T cells. Regional CAR-T cell delivery can theoretically compensate for poor T-cell trafficking and tumor antigen specificity while avoiding systemic toxicity associated with intravenous delivery. We reviewed completed clinical trials for the treatment of glioblastoma and metastatic colorectal cancer and examined the data in these studies for safety, efficacy, and potential advantages that regional delivery may confer over systemic delivery. Our appraisal of the available literature revealed that regional delivery of CAR-T cells in both glioblastoma and hepatic colorectal metastases was generally well tolerated and efficacious in select instances. We propose that the regional delivery of CAR-T cells is an area of potential growth in the solid tumor immunotherapy, and look towards future clinical trials in head and neck cancer, mesothelioma, and peritoneal carcinomatosis as the use of this technique expands. Full article

(This article belongs to the Special Issue CAR-T Cell Therapy against Different Types of Cancer)

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