Research

14 pages, 8411 KiB

Open AccessArticle

CAR T-Cell Persistence Correlates with Improved Outcome in Patients with B-Cell Lymphoma

by Valerie Wittibschlager, Ulrike Bacher, Katja Seipel, Naomi Porret, Gertrud Wiedemann, Claudia Haslebacher, Michèle Hoffmann, Michael Daskalakis, Dilara Akhoundova and Thomas Pabst

Int. J. Mol. Sci. 2023, 24(6), 5688; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065688 - 16 Mar 2023

Cited by 12 | Viewed by 3531

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has led to profound and durable tumor responses in a relevant subset of patients with relapsed/refractory (r/r) B-cell lymphomas. Still, some patients show insufficient benefit or relapse after CAR T-cell therapy. We performed a retrospective study to [...] Read more.

Chimeric antigen receptor (CAR) T-cell therapy has led to profound and durable tumor responses in a relevant subset of patients with relapsed/refractory (r/r) B-cell lymphomas. Still, some patients show insufficient benefit or relapse after CAR T-cell therapy. We performed a retrospective study to investigate the correlation between CAR T-cell persistence in the peripheral blood (PB) at 6 months, assessed by droplet digital PCR (ddPCR), with CAR T-cell treatment outcome. 92 patients with r/r B-cell lymphomas were treated with CD19-targeting CAR T-cell therapies at our institution between 01/2019–08/2022. Six months post-treatment, 15 (16%) patients had no detectable circulating CAR-T constructs by ddPCR. Patients with CAR T-cell persistence had a significantly higher CAR T-cell peak (5432 vs. 620 copies/ug cfDNA, p = 0.0096), as well as higher incidence of immune effector cell-associated neurotoxicity syndrome (37% vs. 7%, p = 0.0182). After a median follow-up of 8.5 months, 31 (34%) patients relapsed. Lymphoma relapses were less frequent among patients with CAR T-cell persistence (29% vs. 60%, p = 0.0336), and CAR T-cell persistence in the PB at 6 months was associated with longer progression-free survival (PFS) (HR 2.79, 95% CI: 1.09–7.11, p = 0.0319). Moreover, we observed a trend towards improved overall survival (OS) (HR 1.99, 95% CI: 0.68–5.82, p = 0.2092) for these patients. In our cohort of 92 B-cell lymphomas, CAR T-cell persistence at 6 months was associated with lower relapse rates and longer PFS. Moreover, our data confirm that 4-1BB-CAR T-cells have a longer persistence as compared to CD-28-based CAR T-cells. Full article

(This article belongs to the Special Issue CAR-T Cell Therapy 2.0)

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20 pages, 7336 KiB

Open AccessArticle

Structure of the Signal Transduction Domain in Second-Generation CAR Regulates the Input Efficiency of CAR Signals

by Kento Fujiwara, Masaki Kitaura, Ayaka Tsunei, Hotaka Kusabuka, Erika Ogaki and Naoki Okada

Int. J. Mol. Sci. 2021, 22(5), 2476; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052476 - 01 Mar 2021

Cited by 9 | Viewed by 2536

Abstract

T cells that are genetically engineered to express chimeric antigen receptor (CAR) have a strong potential to eliminate tumor cells, yet the CAR-T cells may also induce severe side effects due to an excessive immune response. Although optimization of the CAR structure is [...] Read more.

T cells that are genetically engineered to express chimeric antigen receptor (CAR) have a strong potential to eliminate tumor cells, yet the CAR-T cells may also induce severe side effects due to an excessive immune response. Although optimization of the CAR structure is expected to improve the efficacy and toxicity of CAR-T cells, the relationship between CAR structure and CAR-T cell functions remains unclear. Here, we constructed second-generation CARs incorporating a signal transduction domain (STD) derived from CD3ζ and a 2nd STD derived from CD28, CD278, CD27, CD134, or CD137, and investigated the impact of the STD structure and signaling on CAR-T cell functions. Cytokine secretion of CAR-T cells was enhanced by 2nd STD signaling. T cells expressing CAR with CD278-STD or CD137-STD proliferated in an antigen-independent manner by their STD tonic signaling. CAR-T cells incorporating CD28-STD or CD278-STD between TMD and CD3ζ-STD showed higher cytotoxicity than first-generation CAR or second-generation CARs with other 2nd STDs. The potent cytotoxicity of these CAR-T cells was not affected by inhibiting the 2nd STD signals, but was eliminated by placing the STDs after the CD3ζ-STD. Our data highlighted that CAR activity was affected by STD structure as well as by 2nd STD signaling. Full article

(This article belongs to the Special Issue CAR-T Cell Therapy 2.0)

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Review

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10 pages, 603 KiB

Open AccessReview

Chimeric Antigen Receptor T-Cell Therapy: What We Expect Soon

by Massimo Martino, Virginia Naso, Barbara Loteta, Filippo Antonio Canale, Marta Pugliese, Caterina Alati, Gerardo Musuraca, Davide Nappi, Anna Gaimari, Fabio Nicolini, Massimiliano Mazza, Sara Bravaccini, Daniele Derudas, Giovanni Martinelli and Claudio Cerchione

Int. J. Mol. Sci. 2022, 23(21), 13332; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113332 - 01 Nov 2022

Cited by 10 | Viewed by 2161

Abstract

The treatment landscape for hematologic malignancies has changed since the recent approval of highly effective chimeric antigen receptor T-cell therapies (CAR-T). Moreover, more than 600 active trials are currently ongoing. However, early enthusiasm should be tempered since several issues are still unsolved and [...] Read more.

The treatment landscape for hematologic malignancies has changed since the recent approval of highly effective chimeric antigen receptor T-cell therapies (CAR-T). Moreover, more than 600 active trials are currently ongoing. However, early enthusiasm should be tempered since several issues are still unsolved and represent the challenges for the coming years. The lack of initial responses and early relapse are some hurdles to be tackled. Moreover, new strategies are needed to increase the safety profile or shorten the manufacturing process during CAR-T cells therapy production. Nowadays, most clinically evaluated CAR-T cells products are derived from autologous immune cells. The use of allogeneic CAR-T cells products generated using cells from healthy donors has the potential to change the scenario and overcome many of these limitations. In addition, CAR-T cells carry a high price tag, and there is an urgent need to understand how to pay for these therapies as many of today’s current payment systems do not feature the functionality to address the reimbursement gap. Finally, the clinical experience with CAR-T cells for solid tumors has been less encouraging, and development in this setting is desirable. Full article

(This article belongs to the Special Issue CAR-T Cell Therapy 2.0)

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21 pages, 1488 KiB

Open AccessReview

Emerging Approaches for Solid Tumor Treatment Using CAR-T Cell Therapy

by Hyunmin Chung, Haiyoung Jung and Ji-Yoon Noh

Int. J. Mol. Sci. 2021, 22(22), 12126; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212126 - 09 Nov 2021

Cited by 9 | Viewed by 4228

Abstract

Cancer immunotherapy is becoming more important in the clinical setting, especially for cancers resistant to conventional chemotherapy, including targeted therapy. Chimeric antigen receptor (CAR)-T cell therapy, which uses patient’s autologous T cells, combined with engineered T cell receptors, has shown remarkable results, with [...] Read more.

Cancer immunotherapy is becoming more important in the clinical setting, especially for cancers resistant to conventional chemotherapy, including targeted therapy. Chimeric antigen receptor (CAR)-T cell therapy, which uses patient’s autologous T cells, combined with engineered T cell receptors, has shown remarkable results, with five US Food and Drug Administration (FDA) approvals to date. CAR-T cells have been very effective in hematologic malignancies, such as diffuse large B cell lymphoma (DLBCL), B cell acute lymphoblastic leukemia (B-ALL), and multiple myeloma (MM); however, its effectiveness in treating solid tumors has not been evaluated clearly. Therefore, many studies and clinical investigations are emerging to improve the CAR-T cell efficacy in solid tumors. The novel therapeutic approaches include modifying CARs in multiple ways or developing a combination therapy with immune checkpoint inhibitors and chemotherapies. In this review, we focus on the challenges and recent advancements in CAR-T cell therapy for solid tumors. Full article

(This article belongs to the Special Issue CAR-T Cell Therapy 2.0)

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13 pages, 509 KiB

Open AccessReview

CAR T-Cell Therapy in Hematological Malignancies

by Theresa Haslauer, Richard Greil, Nadja Zaborsky and Roland Geisberger

Int. J. Mol. Sci. 2021, 22(16), 8996; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168996 - 20 Aug 2021

Cited by 70 | Viewed by 9680

Abstract

Chimeric antigen receptor (CAR) T-cells (CAR T-cells) are a promising therapeutic approach in treating hematological malignancies. CAR T-cells represent engineered autologous T-cells, expressing a synthetic CAR, targeting tumor-associated antigens (TAAs) independent of major histocompatibility complex (MHC) presentation. The most common target is CD19 [...] Read more.

Chimeric antigen receptor (CAR) T-cells (CAR T-cells) are a promising therapeutic approach in treating hematological malignancies. CAR T-cells represent engineered autologous T-cells, expressing a synthetic CAR, targeting tumor-associated antigens (TAAs) independent of major histocompatibility complex (MHC) presentation. The most common target is CD19 on B-cells, predominantly used for the treatment of lymphoma and acute lymphocytic leukemia (ALL), leading to approval of five different CAR T-cell therapies for clinical application. Despite encouraging clinical results, treatment of other hematological malignancies such as acute myeloid leukemia (AML) remains difficult. In this review, we focus especially on CAR T-cell application in different hematological malignancies as well as strategies for overcoming CAR T-cell dysfunction and increasing their efficacy. Full article

(This article belongs to the Special Issue CAR-T Cell Therapy 2.0)

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14 pages, 1114 KiB

Open AccessReview

New Era of Immunotherapy in Pediatric Brain Tumors: Chimeric Antigen Receptor T-Cell Therapy

by Wan-Tai Wu, Wen-Ying Lin, Yi-Wei Chen, Chun-Fu Lin, Hsin-Hui Wang, Szu-Hsien Wu and Yi-Yen Lee

Int. J. Mol. Sci. 2021, 22(5), 2404; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052404 - 27 Feb 2021

Cited by 5 | Viewed by 3599

Abstract

Immunotherapy, including chimeric antigen receptor (CAR) T-cell therapy, immune checkpoint inhibitors, cancer vaccines, and dendritic cell therapy, has been incorporated as a fifth modality of modern cancer care, along with surgery, radiation, chemotherapy, and target therapy. Among them, CAR T-cell therapy emerges as [...] Read more.

Immunotherapy, including chimeric antigen receptor (CAR) T-cell therapy, immune checkpoint inhibitors, cancer vaccines, and dendritic cell therapy, has been incorporated as a fifth modality of modern cancer care, along with surgery, radiation, chemotherapy, and target therapy. Among them, CAR T-cell therapy emerges as one of the most promising treatments. In 2017, the first two CAR T-cell drugs, tisagenlecleucel and axicabtagene ciloleucel for B-cell acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL), respectively, were approved by the Food and Drug Administration (FDA). In addition to the successful applications to hematological malignancies, CAR T-cell therapy has been investigated to potentially treat solid tumors, including pediatric brain tumor, which serves as the leading cause of cancer-associated death for children and adolescents. However, the employment of CAR T-cell therapy in pediatric brain tumors still faces multiple challenges, such as CAR T-cell transportation and expansion through the blood–brain barrier, and identification of the specific target antigen on the tumor surface and immunosuppressive tumor microenvironment. Nevertheless, encouraging outcomes in both clinical and preclinical trials are coming to light. In this article, we outline the current propitious progress and discuss the obstacles needed to be overcome in order to unveil a new era of treatment in pediatric brain tumors. Full article

(This article belongs to the Special Issue CAR-T Cell Therapy 2.0)

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14 pages, 819 KiB

Open AccessReview

Chimeric Antigen Receptor-Engineered T Cell Therapy for the Management of Patients with Metastatic Prostate Cancer: A Comprehensive Review

by Young Dong Yu and Tae Jin Kim

Int. J. Mol. Sci. 2021, 22(2), 640; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020640 - 11 Jan 2021

Cited by 10 | Viewed by 3922

Abstract

Prostate cancer (PCa) has a vast clinical spectrum from the hormone-sensitive setting to castration-resistant metastatic disease. Thus, chemotherapy regimens and the administration of androgen receptor axis-targeted (ARAT) agents for advanced PCa have shown limited therapeutic efficacy. Scientific advances in the field of molecular [...] Read more.

Prostate cancer (PCa) has a vast clinical spectrum from the hormone-sensitive setting to castration-resistant metastatic disease. Thus, chemotherapy regimens and the administration of androgen receptor axis-targeted (ARAT) agents for advanced PCa have shown limited therapeutic efficacy. Scientific advances in the field of molecular medicine and technological developments over the last decade have paved the path for immunotherapy to become an essential clinical modality for the treatment of patients with metastatic PCa. However, several immunotherapeutic agents have shown poor outcomes in patients with advanced disease, possibly due to the low PCa mutational burden. Adoptive cellular approaches utilizing chimeric antigen receptor T cells (CAR-T) targeting cancer-specific antigens would be a solution for circumventing the immune tolerance mechanisms. The immunotherapeutic regimen of CAR-T cell therapy has shown potential in the eradication of hematologic malignancies, and current clinical objectives maintain the equivalent efficacy in the treatment of solid tumors, including PCa. This review will explore the current modalities of CAR-T therapy in the disease spectrum of PCa while describing key limitations of this immunotherapeutic approach and discuss future directions in the application of immunotherapy for the treatment of metastatic PCa and patients with advanced disease. Full article

(This article belongs to the Special Issue CAR-T Cell Therapy 2.0)

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Other

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7 pages, 1404 KiB

Open AccessCase Report

Two Cases of Pancytopenia with Coombs-Negative Hemolytic Anemia after Chimeric Antigen Receptor T-Cell Therapy

by Dominik Kiem, Michael Leisch, Daniel Neureiter, Theresa Haslauer, Alexander Egle, Thomas Melchardt, Max S. Topp and Richard Greil

Int. J. Mol. Sci. 2021, 22(11), 5449; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115449 - 21 May 2021

Cited by 3 | Viewed by 2465

Abstract

Background: Chimeric antigen receptor (CAR) T-cells are changing the therapeutic landscape of hematologic malignancies. Severe side effects include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), but prolonged cytopenia has also been reported. The underlying mechanism for prolonged cytopenia is [...] Read more.

Background: Chimeric antigen receptor (CAR) T-cells are changing the therapeutic landscape of hematologic malignancies. Severe side effects include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), but prolonged cytopenia has also been reported. The underlying mechanism for prolonged cytopenia is poorly understood so far. Cases: Severe pancytopenia with grade 2-3 anemia was marked 2–3 months after treatment. Laboratory evaluation revealed undetectable levels of haptoglobin with increased reticulocyte counts. Coomb’s tests were negative, no schistocytes were detected on blood smear, and infectious causes were ruled out. Increased erythropoiesis without lymphoma infiltration was noted on bone marrow biopsy. A spontaneous increase in haptoglobin and hemoglobin levels was observed after several weeks. For one patient, peripheral CAR-T levels were monitored over time. We observed a decline at the same time as hemoglobin levels began to rise, implying a potential causality. Conclusion: To our knowledge, we describe the first two cases of Coombs-negative hemolytic anemia after CAR-T treatment for B-cell lymphoma. We encourage routine monitoring for hemolytic anemia after CAR-T treatment and also encourage further investigations on the underlying mechanism. Full article

(This article belongs to the Special Issue CAR-T Cell Therapy 2.0)

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