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Antigens and Cancer Therapy

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

Deadline for manuscript submissions: closed (31 May 2020) | Viewed by 58836

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Dr. Michael Morgan

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Guest Editor

Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany
Interests: chimeric antigen receptors (CARs); cell therapy; natural killer cells; oncogenes; signal transduction; immunotherapy; hematology; leukemia
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Axel Schambach

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Guest Editor

1. Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany
2. Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Interests: gene therapy; vector design; CARs; TRUCKs; hematology; stem cells; leukemia; iPSC; ovarian carcinoma
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Dr. Rüdiger Klapdor

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Guest Editor

Department of Gynecology and Obstetrics and Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany
Interests: gynecologic oncology; surgical oncology; ovarian cancer; cervical cancer; endometrial cancer; vulvar cancer; immunology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The promise of precision medicine strategies to improve current cancer patient treatment protocols has captivated the hopes of scientists, clinicians, and patients alike. Combined advances in biomedical and genetic engineering technologies are bringing us closer to realizing this lofty goal. The clinical translation of immunotherapeutic approaches to treat cancer is rapidly expanding and includes the application of (1) antigen-specific vaccines, (2) monoclonal antibodies, and (3) genetically engineered immune cells (e.g., T cells, natural killer (NK) cells, macrophages) that express chimeric antigen receptors (CARs) designed to specifically recognize neoantigens or tumor-associated antigens (TAAs).

These novel anti-cancer strategies share the common aim to (re)activate immune responses for the targeted elimination of tumor cells and, in the best case, to prevent cancer recurrence. Additionally, monoclonal antibodies can be conjugated with chemotherapeutics or radioisotopes for the precise delivery of anti-cancer agents. Although great strides in these directions have been achieved, important challenges such as side effects and lack or loss of long-term disease control, for example due to tumor (antigen) heterogeneity and immune evasion mechanisms, remain to be addressed. We anticipate that novel approaches in precision diagnostics will further support the development and success of the clinical translation of tailored anti-cancer therapies, such as vaccines, antibodies, and CAR-T/NK cells.

This Special Issue will highlight current and emerging concepts for neoantigen/TAA discovery and targeting, including recent progress in preclinical and clinical studies that are leading to improved therapeutic options for cancer patients.

Dr. Michael Morgan
Prof. Axel Schambach
Dr. Rüdiger Klapdor
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

neoantigens
tumor-associated antigens
tumor targeting
antibodies
CARs
TRUCKs
immunotherapies
T cells
NK cells
signal transduction

Published Papers (10 papers)

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Research

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22 pages, 3360 KiB

Open AccessArticle

Multi-Omics and Informatics Analysis of FFPE Tissues Derived from Melanoma Patients with Long/Short Responses to Anti-PD1 Therapy Reveals Pathways of Response

by Saurabh K. Garg, Eric A. Welsh, Bin Fang, Yuliana I. Hernandez, Trevor Rose, Jhanelle Gray, John M. Koomen, Anders Berglund, James J. Mulé and Joseph Markowitz

Cancers 2020, 12(12), 3515; https://doi.org/10.3390/cancers12123515 - 26 Nov 2020

Cited by 5 | Viewed by 3650

Abstract

Anti-PD-1 based immune therapies are thought to be dependent on antigen processing and presentation mechanisms. To characterize the immune-dependent mechanisms that predispose stage III/IV melanoma patients to respond to anti-PD-1 therapies, we performed a multi-omics study consisting of expression proteomics and targeted immune-oncology-based mRNA sequencing. Formalin-fixed paraffin-embedded tissue samples were obtained from stage III/IV patients with melanoma prior to anti-PD-1 therapy. The patients were first stratified into poor and good responders based on whether their tumors had or had not progressed while on anti-PD-1 therapy for 1 year. We identified 263 protein/gene candidates that displayed differential expression, of which 223 were identified via proteomics and 40 via targeted-mRNA analyses. The downstream analyses of expression profiles using MetaCore software demonstrated an enrichment of immune system pathways involved in antigen processing/presentation and cytokine production/signaling. Pathway analyses showed interferon (IFN)-γ-mediated signaling via NF-κB and JAK/STAT pathways to affect immune processes in a cell-specific manner and to interact with the inducible nitric oxide synthase. We review these findings within the context of available literature on the efficacy of anti-PD-1 therapy. The comparison of good and poor responders, using efficacy of PD-1-based therapy at 1 year, elucidated the role of antigen presentation in mediating response or resistance to anti-PD-1 blockade. Full article

(This article belongs to the Special Issue Antigens and Cancer Therapy)

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22 pages, 2849 KiB

Open AccessArticle

Design and Characterization of an “All-in-One” Lentiviral Vector System Combining Constitutive Anti-G_D2 CAR Expression and Inducible Cytokines

by Katharina Zimmermann, Johannes Kuehle, Anna Christina Dragon, Melanie Galla, Christina Kloth, Loreen Sophie Rudek, I. Erol Sandalcioglu, Belal Neyazi, Thomas Moritz, Johann Meyer, Claudia Rossig, Bianca Altvater, Britta Eiz-Vesper, Michael Alexander Morgan, Hinrich Abken and Axel Schambach

Cancers 2020, 12(2), 375; https://doi.org/10.3390/cancers12020375 - 06 Feb 2020

Cited by 66 | Viewed by 7035

Abstract

Genetically modified T cells expressing chimeric antigen receptors (CARs) so far have mostly failed in the treatment of solid tumors owing to a number of limitations, including an immunosuppressive tumor microenvironment and insufficient CAR T cell activation and persistence. Next-generation approaches using CAR T cells that secrete transgenic immunomodulatory cytokines upon CAR signaling, known as TRUCKs (“T cells redirected for universal cytokine-mediated killing”), are currently being explored. As TRUCKs were engineered by the transduction of T cells with two separate vectors, we developed a lentiviral modular “all-in-one” vector system that combines constitutive CAR expression and inducible nuclear factor of activated T cells (NFAT)-driven transgene expression for more efficient production of TRUCKs. Activation of the G_D2-specific CAR via GD2⁺ target cells induced NFAT promoter-driven cytokine release in primary human T cells, and indicated a tight linkage of CAR-specific activation and transgene expression that was further improved by a modified NFATsyn promoter. As proof-of-concept, we showed that T cells containing the “all-in-one” vector system secrete the immunomodulatory cytokines interleukin (IL)12 or IL18 upon co-cultivation with primary human GD2⁺ tumor cells, resulting in enhanced effector cell properties and increased monocyte recruitment. This highlights the potential of our system to simplify application of TRUCK-modified T cells in solid tumor therapy. Full article

(This article belongs to the Special Issue Antigens and Cancer Therapy)

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15 pages, 1797 KiB

Open AccessFeature PaperArticle

Rapid Assessment of Functional Avidity of Tumor-Specific T Cell Receptors Using an Antigen-Presenting Tumor Cell Line Electroporated with Full-Length Tumor Antigen mRNA

by Diana Campillo-Davo, Maarten Versteven, Gils Roex, Hans De Reu, Sanne van der Heijden, Sébastien Anguille, Zwi N. Berneman, Viggo F. I. Van Tendeloo and Eva Lion

Cancers 2020, 12(2), 256; https://doi.org/10.3390/cancers12020256 - 21 Jan 2020

Cited by 12 | Viewed by 4918

Abstract

The functional avidity of T-cell receptor (TCR)-engineered T cells towards their cognate epitope plays a crucial role in successfully targeting and killing tumor cells expressing the tumor-associated antigen (TAA). When evaluating in vitro functional T-cell avidity, an important aspect that is often neglected is the antigen-presenting cell (APC) used in the assay. Cell-based models for antigen-presentation, such as tumor cell lines, represent a valid alternative to autologous APCs due to their availability, off-the-shelf capabilities, and the broad range of possibilities for modification via DNA or messenger RNA (mRNA) transfection. To find a valuable model APC for in vitro validation of TAA Wilms’ tumor 1 (WT1)-specific TCRs, we tested four different WT1 peptide-pulsed HLA-A2+ tumor cell lines commonly used in T-cell stimulation assays. We found the multiple myeloma cell line U266 to be a suitable model APC to evaluate differences in mean functional avidity (EC50) values of transgenic TCRs following transfection in 2D3 Jurkat T cells. Next, to assess the dose-dependent antigen-specific responsiveness of WT1 TCR-engineered 2D3 T cells to endogenously processed epitopes, we electroporated U266 cells with different amounts of full-length antigen WT1 mRNA. Finally, we analyzed the functional avidity of WT1 TCR-transfected primary CD8 T cells towards WT1 mRNA-electroporated U266 cells. In this study, we demonstrate that both the APC and the antigen loading method (peptide pulsing versus full-length mRNA transfection) to analyze T-cell functional avidity have a significant impact on the EC50 values of a given TCR. For rapid assessment of the functional avidity of a cloned TCR towards its endogenously processed MHC I-restricted epitope, we showcase that the TAA mRNA-transfected U266 cell line is a suitable and versatile model APC. Full article

(This article belongs to the Special Issue Antigens and Cancer Therapy)

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Review

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30 pages, 1406 KiB

Open AccessReview

Towards Clinical Implementation of Adeno-Associated Virus (AAV) Vectors for Cancer Gene Therapy: Current Status and Future Perspectives

by Ulrich T. Hacker, Martin Bentler, Dorota Kaniowska, Michael Morgan and Hildegard Büning

Cancers 2020, 12(7), 1889; https://doi.org/10.3390/cancers12071889 - 14 Jul 2020

Cited by 34 | Viewed by 7436

Abstract

Adeno-associated virus (AAV) vectors have gained tremendous attention as in vivo delivery systems in gene therapy for inherited monogenetic diseases. First market approvals, excellent safety data, availability of large-scale production protocols, and the possibility to tailor the vector towards optimized and cell-type specific gene transfer offers to move from (ultra) rare to common diseases. Cancer, a major health burden for which novel therapeutic options are urgently needed, represents such a target. We here provide an up-to-date overview of the strategies which are currently developed for the use of AAV vectors in cancer gene therapy and discuss the perspectives for the future translation of these pre-clinical approaches into the clinic. Full article

(This article belongs to the Special Issue Antigens and Cancer Therapy)

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37 pages, 1611 KiB

Open AccessReview

Harnessing NK Cell Checkpoint-Modulating Immunotherapies

by Sachin Kumar Singh Chauhan, Ulrike Koehl and Stephan Kloess

Cancers 2020, 12(7), 1807; https://doi.org/10.3390/cancers12071807 - 06 Jul 2020

Cited by 10 | Viewed by 7297

Abstract

During the host immune response, the precise balance of the immune system, regulated by immune checkpoint, is required to avoid infection and cancer. These immune checkpoints are the mainstream regulator of the immune response and are crucial for self-tolerance. During the last decade, various new immune checkpoint molecules have been studied, providing an attractive path to evaluate their potential role as targets for effective therapeutic interventions. Checkpoint inhibitors have mainly been explored in T cells until now, but natural killer (NK) cells are a newly emerging target for the determination of checkpoint molecules. Simultaneously, an increasing number of therapeutic dimensions have been explored, including modulatory and inhibitory checkpoint molecules, either causing dysfunction or promoting effector functions. Furthermore, the combination of the immune checkpoint with other NK cell-based therapeutic strategies could also strengthen its efficacy as an antitumor therapy. In this review, we have undertaken a comprehensive review of the literature to date regarding underlying mechanisms of modulatory and inhibitory checkpoint molecules. Full article

(This article belongs to the Special Issue Antigens and Cancer Therapy)

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28 pages, 1194 KiB

Open AccessReview

Uncovering the Tumor Antigen Landscape: What to Know about the Discovery Process

by Sara Feola, Jacopo Chiaro, Beatriz Martins and Vincenzo Cerullo

Cancers 2020, 12(6), 1660; https://doi.org/10.3390/cancers12061660 - 23 Jun 2020

Cited by 21 | Viewed by 6303

Abstract

According to the latest available data, cancer is the second leading cause of death, highlighting the need for novel cancer therapeutic approaches. In this context, immunotherapy is emerging as a reliable first-line treatment for many cancers, particularly metastatic melanoma. Indeed, cancer immunotherapy has attracted great interest following the recent clinical approval of antibodies targeting immune checkpoint molecules, such as PD-1, PD-L1, and CTLA-4, that release the brakes of the immune system, thus reviving a field otherwise poorly explored. Cancer immunotherapy mainly relies on the generation and stimulation of cytotoxic CD8 T lymphocytes (CTLs) within the tumor microenvironment (TME), priming T cells and establishing efficient and durable anti-tumor immunity. Therefore, there is a clear need to define and identify immunogenic T cell epitopes to use in therapeutic cancer vaccines. Naturally presented antigens in the human leucocyte antigen-1 (HLA-I) complex on the tumor surface are the main protagonists in evocating a specific anti-tumor CD8+ T cell response. However, the methodologies for their identification have been a major bottleneck for their reliable characterization. Consequently, the field of antigen discovery has yet to improve. The current review is intended to define what are today known as tumor antigens, with a main focus on CTL antigenic peptides. We also review the techniques developed and employed to date for antigen discovery, exploring both the direct elution of HLA-I peptides and the in silico prediction of epitopes. Finally, the last part of the review analyses the future challenges and direction of the antigen discovery field. Full article

(This article belongs to the Special Issue Antigens and Cancer Therapy)

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19 pages, 1119 KiB

Open AccessReview

A Multidisciplinary Review of the Roles of Cripto in the Scientific Literature Through a Bibliometric Analysis of its Biological Roles

by Elisa Rodrigues Sousa, Eugenio Zoni, Sofia Karkampouna, Federico La Manna, Peter C. Gray, Marta De Menna and Marianna Kruithof-de Julio

Cancers 2020, 12(6), 1480; https://doi.org/10.3390/cancers12061480 - 05 Jun 2020

Cited by 12 | Viewed by 3859

Abstract

Cripto is a small glycosylphosphatidylinisitol (GPI)-anchored and secreted oncofetal protein that plays important roles in regulating normal physiological processes, including stem cell differentiation, embryonal development, and tissue growth and remodeling, as well as pathological processes such as tumor initiation and progression. Cripto functions as a co-receptor for TGF-β ligands such as Nodal, GDF1, and GDF3. Soluble and secreted forms of Cripto also exhibit growth factor-like activity and activate SRC/MAPK/PI3K/AKT pathways. Glucose-Regulated Protein 78 kDa (GRP78) binds Cripto at the cell surface and has been shown to be required for Cripto signaling via both TGF-β and SRC/MAPK/PI3K/AKT pathways. To provide a comprehensive overview of the scientific literature related to Cripto, we performed, for the first time, a bibliometric analysis of the biological roles of Cripto as reported in the scientific literature covering the last 10 years. We present different fields of knowledge in comprehensive areas of research on Cripto, ranging from basic to translational research, using a keyword-driven approach. Our ultimate aim is to aid the scientific community in conducting targeted research by identifying areas where research has been conducted so far and, perhaps more importantly, where critical knowledge is still missing. Full article

(This article belongs to the Special Issue Antigens and Cancer Therapy)

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29 pages, 1234 KiB

Open AccessEditor’s ChoiceReview

BCMA-Targeting Therapy: Driving a New Era of Immunotherapy in Multiple Myeloma

by Shih-Feng Cho, Liang Lin, Lijie Xing, Yuyin Li, Tengteng Yu, Kenneth C Anderson and Yu-Tzu Tai

Cancers 2020, 12(6), 1473; https://doi.org/10.3390/cancers12061473 - 05 Jun 2020

Cited by 38 | Viewed by 7860

Abstract

The treatment of multiple myeloma (MM) has entered into a new era of immunotherapy. Novel immunotherapies will significantly improve patient outcome via simultaneously targeting malignant plasma cell (PC) and reversing immunocompromised bone marrow (BM) microenvironment. B-cell maturation antigen (BCMA), selectively expressed in PCs and a key receptor for A proliferation-inducing ligand (APRIL), is highly expressed in MM cells from patients at all stages. The APRIL/BCMA signal cascades promote the survival and drug resistance of MM cells and further modulate immunosuppressive BM milieu. Impressively, anti-BCMA immunotherapeutic reagents, including chimeric antigen receptor (CAR), antibody-drug conjugate (ADC) and bispecific T cell engager (BiTE) have all shown high response rates in their first clinical trials in relapse and refractory patients with very limited treatment options. These results rapidly inspired numerous development of next-generation anti-BCMA biotherapeutics, i.e., bispecific molecule, bispecific or trispecific antibodies, a novel form of CAR T/NK cells and T Cell Antigen Coupler (TAC) receptors, antibody-coupled T cell receptor (ACTR) as well as a cancer vaccine. We here highlight seminal preclinical and clinical studies on novel BCMA-based immunotherapies as effective monotherapy and discuss their potential in combination with current anti-MM and novel checkpoint drugs in earlier disease stages to further achieve durable responses in patients. Full article

(This article belongs to the Special Issue Antigens and Cancer Therapy)

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19 pages, 851 KiB

Open AccessReview

Overcoming Heterogeneity of Antigen Expression for Effective CAR T Cell Targeting of Cancers

by Sareetha Kailayangiri, Bianca Altvater, Malena Wiebel, Silke Jamitzky and Claudia Rossig

Cancers 2020, 12(5), 1075; https://doi.org/10.3390/cancers12051075 - 26 Apr 2020

Cited by 55 | Viewed by 5052

Abstract

Chimeric antigen receptor (CAR) gene-modified T cells (CAR T cells) can eradicate B cell malignancies via recognition of surface-expressed B lineage antigens. Antigen escape remains a major mechanism of relapse and is a key barrier for expanding the use of CAR T cells towards solid cancers with their more diverse surface antigen repertoires. In this review we discuss strategies by which cancers become amenable to effective CAR T cell therapy despite heterogeneous phenotypes. Pharmaceutical approaches have been reported that selectively upregulate individual target antigens on the cancer cell surface to sensitize antigen-negative subclones for recognition by CARs. In addition, advanced T cell engineering strategies now enable CAR T cells to interact with more than a single antigen simultaneously. Still, the choice of adequate targets reliably and selectively expressed on the cell surface of tumor cells but not normal cells, ideally by driving tumor growth, is limited, and even dual or triple antigen targeting is unlikely to cure most solid tumors. Innovative receptor designs and combination strategies now aim to recruit bystander cells and alternative cytolytic mechanisms that broaden the activity of CAR-engineered T cells beyond CAR antigen-dependent tumor cell recognition. Full article

(This article belongs to the Special Issue Antigens and Cancer Therapy)

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22 pages, 292 KiB

Open AccessReview

Current Status and Future Perspectives of Immunotherapy for Locally Advanced or Metastatic Urothelial Carcinoma: A Comprehensive Review

by Tae Jin Kim, Kang Su Cho and Kyo Chul Koo

Cancers 2020, 12(1), 192; https://doi.org/10.3390/cancers12010192 - 13 Jan 2020

Cited by 31 | Viewed by 4728

Abstract

Advancements in the understanding of tumor immunology in urothelial carcinoma (UC) have led to U.S Food and Drug Administration (FDA) approval of five novel anti-programmed cell death protein-1/ligand 1 (PD-1/L1) checkpoint inhibitors. In 2017, the anti-PD-L1 antibody atezolizumab and the anti-PD-1 antibody pembrolizumab gained approval for use in cisplatin-ineligible patients with locally advanced and metastatic UC. These approvals were based on single-arm trials, IMvigor210 (atezolizumab) and KEYNOTE-052 (pembrolizumab). Since then, additional checkpoint inhibitors, including avelumab, durvalumab, and nivolumab, have gained approval. Preliminary results suggest additional benefits with combinations of these agents in both first- and subsequent-line therapies, inferring a paradigm shift in the future treatment approach in advanced UC. Ongoing clinical trials will investigate how to utilize predictive biomarkers for optimal patient selection and to incorporate immunotherapy into earlier lines of multimodal treatment. In this comprehensive review, we summarize the evidence supporting the use of checkpoint inhibitors for patients with UC, and highlight ongoing clinical trials that are investigating novel combinations of immunotherapy in various disease settings. Full article

(This article belongs to the Special Issue Antigens and Cancer Therapy)

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