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14 pages, 3641 KiB

Open AccessArticle

Role of Epidermal Growth Factor Receptor-Specific CAR-T Cells in the Suppression of Esophageal Squamous Cell Carcinoma

by Chen Cheng, Heyang Cui, Huijuan Liu, Yueguang Wu, Ning Ding, Yongjia Weng, Weimin Zhang and Yongping Cui

Cancers 2022, 14(24), 6021; https://doi.org/10.3390/cancers14246021 - 7 Dec 2022

Viewed by 1494

Abstract

ESCC is a highly malignant tumor, and its morbidity and mortality in China account for more than 50% of the world’s total rates. As effective treatments are lacking, the 5-year survival rate of patients does not exceed 30%. CAR-T-cell-based immunotherapy has emerged as [...] Read more.

ESCC is a highly malignant tumor, and its morbidity and mortality in China account for more than 50% of the world’s total rates. As effective treatments are lacking, the 5-year survival rate of patients does not exceed 30%. CAR-T-cell-based immunotherapy has emerged as one of the most promising cancer treatments; however, there are relatively fewer reports regarding its application for ESCC. In this study, we conducted large-sample whole-genome sequencing (WGS) and RNA-seq analysis of patients with ESCC from China to examine the feasibility of EGFR-targeting CAR-T cells in the treatment of ESCC. We found much higher levels of EGFR gene amplification and overexpression in tumors than in the normal tissues, indicating that EGFR could be a promising target of CAR-T-cell-based immunotherapy in ESCC. Therefore, we tested EGFR-targeting CAR-T cells for lytic activity against ESCC cells as a model to establish cellular immunotherapy for ESCC. Five types of CAR-T cells targeting EGFR were constructed, two of which, CAR1-T and CAR2-T, showed a strong cytotoxicity against ESCC in in vitro and in vivo experiments. The results of this study suggest that CAR1-T and CAR2-T have the potential to be used for anti-ESCC immunotherapy in clinics. Full article

(This article belongs to the Special Issue Cancer: Advances in T Cell-Based Clinical Immunotherapies)

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17 pages, 2579 KiB

Open AccessArticle

Isolation of Neoantigen-Specific Human T Cell Receptors from Different Human and Murine Repertoires

by Corinna Grunert, Gerald Willimsky, Caroline Anna Peuker, Simone Rhein, Leo Hansmann, Thomas Blankenstein, Eric Blanc, Dieter Beule, Ulrich Keller, Antonio Pezzutto and Antonia Busse

Cancers 2022, 14(7), 1842; https://doi.org/10.3390/cancers14071842 - 6 Apr 2022

Cited by 2 | Viewed by 2869

Abstract

(1) Background: Mutation-specific T cell receptor (TCR)-based adoptive T cell therapy represents a truly tumor-specific immunotherapeutic strategy. However, isolating neoepitope-specific TCRs remains a challenge. (2) Methods: We investigated, side by side, different TCR repertoires—patients’ peripheral lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs), PBLs of [...] Read more.

(1) Background: Mutation-specific T cell receptor (TCR)-based adoptive T cell therapy represents a truly tumor-specific immunotherapeutic strategy. However, isolating neoepitope-specific TCRs remains a challenge. (2) Methods: We investigated, side by side, different TCR repertoires—patients’ peripheral lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs), PBLs of healthy donors, and a humanized mouse model—to isolate neoepitope-specific TCRs against eight neoepitope candidates from a colon cancer and an ovarian cancer patient. Neoepitope candidates were used to stimulate T cells from different repertoires in vitro to generate neoepitope-specific T cells and isolate the specific TCRs. (3) Results: We isolated six TCRs from healthy donors, directed against four neoepitope candidates and one TCR from the murine T cell repertoire. Endogenous processing of one neoepitope, for which we isolated one TCR from both human and mouse-derived repertoires, could be shown. No neoepitope-specific TCR could be generated from the patients’ own repertoire. (4) Conclusion: Our data indicate that successful isolation of neoepitope-specific TCRs depends on various factors such as the heathy donor’s TCR repertoire or the presence of a tumor microenvironment allowing neoepitope-specific immune responses of the host. We show the advantage and feasibility of using healthy donor repertoires and humanized mouse TCR repertoires to generate mutation-specific TCRs with different specificities, especially in a setting when the availability of patient material is limited. Full article

(This article belongs to the Special Issue Cancer: Advances in T Cell-Based Clinical Immunotherapies)

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16 pages, 1973 KiB

Open AccessEditor’s ChoiceArticle

Machine Learning Using Real-World and Translational Data to Improve Treatment Selection for NSCLC Patients Treated with Immunotherapy

by Arsela Prelaj, Mattia Boeri, Alessandro Robuschi, Roberto Ferrara, Claudia Proto, Giuseppe Lo Russo, Giulia Galli, Alessandro De Toma, Marta Brambilla, Mario Occhipinti, Sara Manglaviti, Teresa Beninato, Achille Bottiglieri, Giacomo Massa, Emma Zattarin, Rosaria Gallucci, Edoardo Gregorio Galli, Monica Ganzinelli, Gabriella Sozzi, Filippo G. M. de Braud, Marina Chiara Garassino, Marcello Restelli, Alessandra Laura Giulia Pedrocchi and Francesco Trovo' Show full author list Hide full author list

Cancers 2022, 14(2), 435; https://doi.org/10.3390/cancers14020435 - 16 Jan 2022

Cited by 15 | Viewed by 3447

Abstract

(1) Background: In advanced non-small cell lung cancer (aNSCLC), programmed death ligand 1 (PD-L1) remains the only biomarker for candidate patients to immunotherapy (IO). This study aimed at using artificial intelligence (AI) and machine learning (ML) tools to improve response and efficacy predictions [...] Read more.

(1) Background: In advanced non-small cell lung cancer (aNSCLC), programmed death ligand 1 (PD-L1) remains the only biomarker for candidate patients to immunotherapy (IO). This study aimed at using artificial intelligence (AI) and machine learning (ML) tools to improve response and efficacy predictions in aNSCLC patients treated with IO. (2) Methods: Real world data and the blood microRNA signature classifier (MSC) were used. Patients were divided into responders (R) and non-responders (NR) to determine if the overall survival of the patients was likely to be shorter or longer than 24 months from baseline IO. (3) Results: One-hundred sixty-four out of 200 patients (i.e., only those ones with PD-L1 data available) were considered in the model, 73 (44.5%) were R and 91 (55.5%) NR. Overall, the best model was the linear regression (RL) and included 5 features. The model predicting R/NR of patients achieved accuracy ACC = 0.756, F1 score F1 = 0.722, and area under the ROC curve AUC = 0.82. LR was also the best-performing model in predicting patients with long survival (24 months OS), achieving ACC = 0.839, F1 = 0.908, and AUC = 0.87. (4) Conclusions: The results suggest that the integration of multifactorial data provided by ML techniques is a useful tool to select NSCLC patients as candidates for IO. Full article

(This article belongs to the Special Issue Cancer: Advances in T Cell-Based Clinical Immunotherapies)

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Review

Jump to: Research

29 pages, 980 KiB

Open AccessReview

Controlling Cell Trafficking: Addressing Failures in CAR T and NK Cell Therapy of Solid Tumours

by Lydia G. White, Hannah E. Goy, Alinor J. Rose and Alexander D. McLellan

Cancers 2022, 14(4), 978; https://doi.org/10.3390/cancers14040978 - 15 Feb 2022

Cited by 13 | Viewed by 4721

Abstract

The precision guiding of endogenous or adoptively transferred lymphocytes to the solid tumour mass is obligatory for optimal anti-tumour effects and will improve patient safety. The recognition and elimination of the tumour is best achieved when anti-tumour lymphocytes are proximal to the malignant [...] Read more.

The precision guiding of endogenous or adoptively transferred lymphocytes to the solid tumour mass is obligatory for optimal anti-tumour effects and will improve patient safety. The recognition and elimination of the tumour is best achieved when anti-tumour lymphocytes are proximal to the malignant cells. For example, the regional secretion of soluble factors, cytotoxic granules, and cell-surface molecule interactions are required for the death of tumour cells and the suppression of neovasculature formation, tumour-associated suppressor, or stromal cells. The resistance of individual tumour cell clones to cellular therapy and the hostile environment of the solid tumours is a major challenge to adoptive cell therapy. We review the strategies that could be useful to overcoming insufficient immune cell migration to the tumour cell mass. We argue that existing ‘competitive’ approaches should now be revisited as complementary approaches to improve CAR T and NK cell therapy. Full article

(This article belongs to the Special Issue Cancer: Advances in T Cell-Based Clinical Immunotherapies)

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36 pages, 2541 KiB

Open AccessReview

T Cell Engaging Immunotherapies, Highlighting Chimeric Antigen Receptor (CAR) T Cell Therapy

by Elien De Bousser, Nico Callewaert and Nele Festjens

Cancers 2021, 13(23), 6067; https://doi.org/10.3390/cancers13236067 - 1 Dec 2021

Cited by 10 | Viewed by 5080

Abstract

In the past decade, chimeric antigen receptor (CAR) T cell technology has revolutionized cancer immunotherapy. This strategy uses synthetic CARs to redirect the patient’s own immune cells to recognize specific antigens expressed on the surface of tumor cells. The unprecedented success of anti-CD19 [...] Read more.

In the past decade, chimeric antigen receptor (CAR) T cell technology has revolutionized cancer immunotherapy. This strategy uses synthetic CARs to redirect the patient’s own immune cells to recognize specific antigens expressed on the surface of tumor cells. The unprecedented success of anti-CD19 CAR T cell therapy against B cell malignancies has resulted in its approval by the US Food and Drug Administration (FDA) in 2017. However, major scientific challenges still remain to be addressed for the broad use of CAR T cell therapy. These include severe toxicities, limited efficacy against solid tumors, and immune suppression in the hostile tumor microenvironment. Furthermore, CAR T cell therapy is a personalized medicine of which the production is time- and resource-intensive, which makes it very expensive. All these factors drive new innovations to engineer more powerful CAR T cells with improved antitumor activity, which are reviewed in this manuscript. Full article

(This article belongs to the Special Issue Cancer: Advances in T Cell-Based Clinical Immunotherapies)

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24 pages, 1796 KiB

Open AccessReview

Payload Delivery: Engineering Immune Cells to Disrupt the Tumour Microenvironment

by Daniel Fowler, Callum Nattress, Alba Southern Navarrete, Marta Barisa and Jonathan Fisher

Cancers 2021, 13(23), 6000; https://doi.org/10.3390/cancers13236000 - 29 Nov 2021

Cited by 3 | Viewed by 2745

Abstract

Although chimeric antigen receptor (CAR) T cells have shown impressive clinical success against haematological malignancies such as B cell lymphoma and acute lymphoblastic leukaemia, their efficacy against non-haematological solid malignancies has been largely disappointing. Solid tumours pose many additional challenges for CAR T [...] Read more.

Although chimeric antigen receptor (CAR) T cells have shown impressive clinical success against haematological malignancies such as B cell lymphoma and acute lymphoblastic leukaemia, their efficacy against non-haematological solid malignancies has been largely disappointing. Solid tumours pose many additional challenges for CAR T cells that have severely blunted their potency, including homing to the sites of disease, survival and persistence within the adverse conditions of the tumour microenvironment, and above all, the highly immunosuppressive nature of the tumour milieu. Gene engineering approaches for generating immune cells capable of overcoming these hurdles remain an unmet therapeutic need and ongoing area of research. Recent advances have involved gene constructs for membrane-bound and/or secretable proteins that provide added effector cell function over and above the benefits of classical CAR-mediated cytotoxicity, rendering immune cells not only as direct cytotoxic effectors against tumours, but also as vessels for payload delivery capable of both modulating the tumour microenvironment and orchestrating innate and adaptive anti-tumour immunity. We discuss here the novel concept of engineered immune cells as vessels for payload delivery into the tumour microenvironment, how these cells are better adapted to overcome the challenges faced in a solid tumour, and importantly, the novel gene engineering approaches required to deliver these more complex polycistronic gene constructs. Full article

(This article belongs to the Special Issue Cancer: Advances in T Cell-Based Clinical Immunotherapies)

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15 pages, 1739 KiB

Open AccessReview

Bispecific T Cell Engagers for the Treatment of Multiple Myeloma: Achievements and Challenges

by Kinan Alhallak, Jennifer Sun, Amanda Jeske, Chaelee Park, Jessica Yavner, Hannah Bash, Berit Lubben, Ola Adebayo, Ayah Khaskiah and Abdel Kareem Azab

Cancers 2021, 13(12), 2853; https://doi.org/10.3390/cancers13122853 - 8 Jun 2021

Cited by 7 | Viewed by 5161

Abstract

MM is the second most common hematological malignancy and represents approximately 20% of deaths from hematopoietic cancers. The advent of novel agents has changed the therapeutic landscape of MM treatment; however, MM remains incurable. T cell-based immunotherapy such as BTCEs is a promising [...] Read more.

MM is the second most common hematological malignancy and represents approximately 20% of deaths from hematopoietic cancers. The advent of novel agents has changed the therapeutic landscape of MM treatment; however, MM remains incurable. T cell-based immunotherapy such as BTCEs is a promising modality for the treatment of MM. This review article discusses the advancements and future directions of BTCE treatments for MM. Full article

(This article belongs to the Special Issue Cancer: Advances in T Cell-Based Clinical Immunotherapies)

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19 pages, 738 KiB

Open AccessReview

Effects of Chemotherapy Agents on Circulating Leukocyte Populations: Potential Implications for the Success of CAR-T Cell Therapies

by Nga T. H. Truong, Tessa Gargett, Michael P. Brown and Lisa M. Ebert

Cancers 2021, 13(9), 2225; https://doi.org/10.3390/cancers13092225 - 6 May 2021

Cited by 20 | Viewed by 3461

Abstract

Adoptive T-cell therapy using autologous T cells genetically modified to express cancer-specific chimeric antigen receptors (CAR) has emerged as a novel approach for cancer treatment. CAR-T cell therapy has been approved in several major jurisdictions for treating refractory or relapsed cases of B-cell [...] Read more.

Adoptive T-cell therapy using autologous T cells genetically modified to express cancer-specific chimeric antigen receptors (CAR) has emerged as a novel approach for cancer treatment. CAR-T cell therapy has been approved in several major jurisdictions for treating refractory or relapsed cases of B-cell precursor acute lymphoblastic leukaemia and diffuse large B-cell lymphoma. However, in solid cancer patients, several clinical studies of CAR-T cell therapy have demonstrated minimal therapeutic effects, thus encouraging interest in better integrating CAR-T cells with other treatments such as conventional cytotoxic chemotherapy. Increasing evidence shows that not only do chemotherapy drugs have tumoricidal effects, but also significantly modulate the immune system. Here, we discuss immunomodulatory effects of chemotherapy drugs on circulating leukocyte populations, including their ability to enhance cytotoxic effects and preserve the frequency of CD8⁺ T cells and to deplete immunosuppressive populations including regulatory T cells and myeloid-derived suppressor cells. By modulating the abundance and phenotype of leukocytes in the blood (the ‘raw material’ for CAR-T cell manufacturing), we propose that prior chemotherapy could facilitate production of the most effective CAR-T cell products. Further research is required to directly test this concept and identify strategies for the optimal integration of CAR-T cell therapies with cytotoxic chemotherapy for solid cancers. Full article

(This article belongs to the Special Issue Cancer: Advances in T Cell-Based Clinical Immunotherapies)

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