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Identification and Clinical Application of Immunological Receptors Targeting Mutated Antigens...
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Identification and Clinical Application of Immunological Receptors Targeting Mutated Antigens Expressed by Solid Tumors

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 24575

Special Issue Editor

Dr. Anna Pasetto

E-Mail Website
Guest Editor
Department of Laboratory Medicine, Karolinska Institutet, Division of Clinical Microbiology, ANA Futura, Alfred Nobels Allé 8, Campus Flemingsberg, 14152 Huddinge, Sweden
Interests: solid tumor immunotherapy; TCR; CAR; neoantigens; gene and cell therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Immunotherapy for solid tumors represents the current challenge in cancer treatment. The astonishing results achieved in the treatment of leukemia and lymphomas seem hard to obtain for solid cancers, and the reasons for this are not clear. The key factors in developing successful immunotherapy are the choice of the antigen to target the tumor cells and the immune receptors used to perform the attack. Many strategies using TCRs specific for shared or mutated cancer antigens and different generations of CARs have been developed but only a few showed promising results in patients. There is a need for a deeper understanding of the discriminating factors between successful and unsuccessful therapies.

This Special Issue of Cancers, therefore, encompasses new research articles and timely reviews on the identification and clinical application of immunological receptors targeting mutated antigens expressed by solid tumors.

Prof. Dr. Anna Pasetto
Guest Editor

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

  • TCR
  • CAR
  • solid tumors
  • mutated antigens
  • clinical trials

Published Papers (7 papers)

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Editorial

Jump to: Research, Review

4 pages, 169 KiB  
Editorial
Identification and Clinical Application of Immunological Receptors Targeting Mutated Antigens Expressed by Solid Tumors
by Anna Pasetto
Cancers 2020, 12(10), 2818; https://doi.org/10.3390/cancers12102818 - 30 Sep 2020
Viewed by 1374
Abstract
In the recent years, immunotherapy has achieved impressive results utilizing different approaches, from (chimeric antigen receptor) CAR-T cells directed against CD19 for the treatment of leukemia and lymphomas to the Nobel prize-winning strategy of check-point inhibition for the treatment of several solid tumors [...] Read more.
In the recent years, immunotherapy has achieved impressive results utilizing different approaches, from (chimeric antigen receptor) CAR-T cells directed against CD19 for the treatment of leukemia and lymphomas to the Nobel prize-winning strategy of check-point inhibition for the treatment of several solid tumors [...] Full article
(This article belongs to the Special Issue Identification and Clinical Application of Immunological Receptors Targeting Mutated Antigens Expressed by Solid Tumors)

Research

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18 pages, 2980 KiB  
Article
Inhibiting Lysine Demethylase 1A Improves L1CAM-Specific CAR T Cell Therapy by Unleashing Antigen-Independent Killing via the FAS-FASL Axis
by Ornela Sulejmani, Laura Grunewald, Lena Andersch, Silke Schwiebert, Anika Klaus, Annika Winkler, Kathy Astrahantseff, Angelika Eggert, Anton G. Henssen, Johannes H. Schulte, Kathleen Anders and Annette Künkele
Cancers 2021, 13(21), 5489; https://doi.org/10.3390/cancers13215489 - 31 Oct 2021
Cited by 3 | Viewed by 2681
Abstract
Chimeric antigen receptor (CAR) T cell therapy has emerged as a promising treatment strategy, however, therapeutic success against solid tumors such as neuroblastoma remains modest. Recurrence of antigen-poor tumor variants often ultimately results in treatment failure. Using antigen-independent killing mechanisms such as the [...] Read more.
Chimeric antigen receptor (CAR) T cell therapy has emerged as a promising treatment strategy, however, therapeutic success against solid tumors such as neuroblastoma remains modest. Recurrence of antigen-poor tumor variants often ultimately results in treatment failure. Using antigen-independent killing mechanisms such as the FAS receptor (FAS)-FAS ligand (FASL) axis through epigenetic manipulation may be a way to counteract the escape achieved by antigen downregulation. Analysis of public RNA-sequencing data from primary neuroblastomas revealed that a particular epigenetic modifier, the histone lysine demethylase 1A (KDM1A), correlated negatively with FAS expression. KDM1A is known to interact with TP53 to repress TP53-mediated transcriptional activation of genes, including FAS. We showed that pharmacologically blocking KDM1A activity in neuroblastoma cells with the small molecule inhibitor, SP-2509, increased FAS cell-surface expression in a strictly TP53-dependent manner. FAS upregulation sensitized neuroblastoma cells to FAS-FASL-dependent killing and augmented L1CAM-directed CAR T cell therapy against antigen-poor or even antigen-negative tumor cells in vitro. The improved therapeutic response was abrogated when the FAS-FASL interaction was abolished with an antagonistic FAS antibody. Our results show that KDM1A inhibition unleashes an antigen-independent killing mechanism via the FAS-FASL axis to make tumor cell variants that partially or totally suppress antigen expression susceptible to CAR T cell therapy. Full article
(This article belongs to the Special Issue Identification and Clinical Application of Immunological Receptors Targeting Mutated Antigens Expressed by Solid Tumors)
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22 pages, 5250 KiB  
Article
Enhancement of NK Cell Antitumor Effector Functions Using a Bispecific Single Domain Antibody Targeting CD16 and the Epidermal Growth Factor Receptor
by Elisa C. Toffoli, Abdolkarim Sheikhi, Roeland Lameris, Lisa A. King, Amanda van Vliet, Bruce Walcheck, Henk M. W. Verheul, Jan Spanholtz, Jurriaan Tuynman, Tanja D. de Gruijl and Hans J. van der Vliet
Cancers 2021, 13(21), 5446; https://doi.org/10.3390/cancers13215446 - 29 Oct 2021
Cited by 11 | Viewed by 2807
Abstract
The ability to kill tumor cells while maintaining an acceptable safety profile makes Natural Killer (NK) cells promising assets for cancer therapy. Strategies to enhance the preferential accumulation and activation of NK cells in the tumor microenvironment can be expected to increase the [...] Read more.
The ability to kill tumor cells while maintaining an acceptable safety profile makes Natural Killer (NK) cells promising assets for cancer therapy. Strategies to enhance the preferential accumulation and activation of NK cells in the tumor microenvironment can be expected to increase the efficacy of NK cell-based therapies. In this study, we show binding of a novel bispecific single domain antibody (VHH) to both CD16 (FcRγIII) on NK cells and the epidermal growth factor receptor (EGFR) on tumor cells of epithelial origin. The bispecific VHH triggered CD16- and EGFR-dependent activation of NK cells and subsequent lysis of tumor cells, regardless of the KRAS mutational status of the tumor. Enhancement of NK cell activation by the bispecific VHH was also observed when NK cells of colorectal cancer (CRC) patients were co-cultured with EGFR expressing tumor cells. Finally, higher levels of cytotoxicity were found against patient-derived metastatic CRC cells in the presence of the bispecific VHH and autologous peripheral blood mononuclear cells or allogeneic CD16 expressing NK cells. The anticancer activity of CD16-EGFR bispecific VHHs reported here merits further exploration to assess its potential therapeutic activity either alone or in combination with adoptive NK cell-based therapeutic approaches. Full article
(This article belongs to the Special Issue Identification and Clinical Application of Immunological Receptors Targeting Mutated Antigens Expressed by Solid Tumors)
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17 pages, 2450 KiB  
Article
CD28 Co-Stimulus Achieves Superior CAR T Cell Effector Function against Solid Tumors Than 4-1BB Co-Stimulus
by Ana Textor, Laura Grunewald, Kathleen Anders, Anika Klaus, Silke Schwiebert, Annika Winkler, Maria Stecklum, Jana Rolff, Anton G. Henssen, Uta E. Höpken, Angelika Eggert, Johannes H. Schulte, Michael C. Jensen, Thomas Blankenstein and Annette Künkele
Cancers 2021, 13(5), 1050; https://doi.org/10.3390/cancers13051050 - 2 Mar 2021
Cited by 18 | Viewed by 4538
Abstract
Spacer or co-stimulatory components in chimeric antigen receptor (CAR) design influence CAR T cell effector function. Few preclinical mouse models optimally support CAR candidate pre-selection for clinical development. Here we use a model in which murine CAR T cells can be exploited with [...] Read more.
Spacer or co-stimulatory components in chimeric antigen receptor (CAR) design influence CAR T cell effector function. Few preclinical mouse models optimally support CAR candidate pre-selection for clinical development. Here we use a model in which murine CAR T cells can be exploited with human tumor xenografts. This mouse-in-mouse approach avoids limitations caused by species-specific factors crucial for CAR T cell survival, trafficking and function. We compared trafficking, expansion and tumor control for T cells expressing different CAR construct designs targeting two antigens (L1CAM or HER2), structurally identical except for spacer (long or short) or co-stimulatory (4-1BB or CD28) domains to be evaluated. Using monoclonal, murine-derived L1CAM-specific CAR T cells in Rag-/- mice harboring established xenografted tumors from a human neuroblastoma cell line revealed a clear superiority in CAR T cell trafficking using CD28 co-stimulation. L1CAM-targeting short spacer-CD28/ζ CAR T cells expanded the most at the tumor site and induced initial tumor regression. Treating patient-derived neuroblastoma xenografts with human L1CAM-targeting CAR T cells confirmed the superiority of CD28 co-stimulus. CD28 superiority was also demonstrated with HER2-specific CAR T cells (targeting ovarian carcinoma xenografts). Our findings encourage incorporating CD28 signaling into CAR design for adoptive T cell treatment of solid tumors. Full article
(This article belongs to the Special Issue Identification and Clinical Application of Immunological Receptors Targeting Mutated Antigens Expressed by Solid Tumors)
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Review

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20 pages, 1093 KiB  
Review
The Identification and Clinical Applications of Mutated Antigens in the Era of Immunotherapy
by Yae Kye, Lokesh Nagineni, Shrikanth Gadad, Fabiola Ramirez, Hannah Riva, Lorena Fernandez, Michelle Samaniego, Nathan Holland, Rose Yeh, Kei Takigawa, Subramanian Dhandayuthapani and Jessica Chacon
Cancers 2022, 14(17), 4255; https://doi.org/10.3390/cancers14174255 - 31 Aug 2022
Cited by 3 | Viewed by 1837
Abstract
The era of personalized cancer therapy is here. Advances in the field of immunotherapy have paved the way for the development of individualized neoantigen-based therapies that can translate into favorable treatment outcomes and fewer side effects for patients. Addressing challenges related to the [...] Read more.
The era of personalized cancer therapy is here. Advances in the field of immunotherapy have paved the way for the development of individualized neoantigen-based therapies that can translate into favorable treatment outcomes and fewer side effects for patients. Addressing challenges related to the identification, access, and clinical application of neoantigens is critical to accelerating the development of individualized immunotherapy for cancer patients. Full article
(This article belongs to the Special Issue Identification and Clinical Application of Immunological Receptors Targeting Mutated Antigens Expressed by Solid Tumors)
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26 pages, 992 KiB  
Review
Neoantigen-Reactive T Cells: The Driving Force behind Successful Melanoma Immunotherapy
by Lindy Davis, Ashley Tarduno and Yong-Chen Lu
Cancers 2021, 13(23), 6061; https://doi.org/10.3390/cancers13236061 - 1 Dec 2021
Cited by 4 | Viewed by 4260
Abstract
Patients with metastatic cutaneous melanoma have experienced significant clinical responses after checkpoint blockade immunotherapy or adoptive cell therapy. Neoantigens are mutated proteins that arise from tumor-specific mutations. It is hypothesized that the neoantigen recognition by T cells is the critical step for T-cell-mediated [...] Read more.
Patients with metastatic cutaneous melanoma have experienced significant clinical responses after checkpoint blockade immunotherapy or adoptive cell therapy. Neoantigens are mutated proteins that arise from tumor-specific mutations. It is hypothesized that the neoantigen recognition by T cells is the critical step for T-cell-mediated anti-tumor responses and subsequent tumor regressions. In addition to describing neoantigens, we review the sentinel and ongoing clinical trials that are helping to shape the current treatments for patients with cutaneous melanoma. We also present the existing evidence that establishes the correlations between neoantigen-reactive T cells and clinical responses in melanoma immunotherapy. Full article
(This article belongs to the Special Issue Identification and Clinical Application of Immunological Receptors Targeting Mutated Antigens Expressed by Solid Tumors)
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21 pages, 1797 KiB  
Review
Identification and Targeting of Mutant Peptide Neoantigens in Cancer Immunotherapy
by Daniel J. Verdon and Misty R. Jenkins
Cancers 2021, 13(16), 4245; https://doi.org/10.3390/cancers13164245 - 23 Aug 2021
Cited by 15 | Viewed by 6366
Abstract
In recent decades, adoptive cell transfer and checkpoint blockade therapies have revolutionized immunotherapeutic approaches to cancer treatment. Advances in whole exome/genome sequencing and bioinformatic detection of tumour-specific genetic variations and the amino acid sequence alterations they induce have revealed that T cell mediated [...] Read more.
In recent decades, adoptive cell transfer and checkpoint blockade therapies have revolutionized immunotherapeutic approaches to cancer treatment. Advances in whole exome/genome sequencing and bioinformatic detection of tumour-specific genetic variations and the amino acid sequence alterations they induce have revealed that T cell mediated anti-tumour immunity is substantially directed at mutated peptide sequences, and the identification and therapeutic targeting of patient-specific mutated peptide antigens now represents an exciting and rapidly progressing frontier of personalized medicine in the treatment of cancer. This review outlines the historical identification and validation of mutated peptide neoantigens as a target of the immune system, and the technical development of bioinformatic and experimental strategies for detecting, confirming and prioritizing both patient-specific or “private” and frequently occurring, shared “public” neoantigenic targets. Further, we examine the range of therapeutic modalities that have demonstrated preclinical and clinical anti-tumour efficacy through specifically targeting neoantigens, including adoptive T cell transfer, checkpoint blockade and neoantigen vaccination. Full article
(This article belongs to the Special Issue Identification and Clinical Application of Immunological Receptors Targeting Mutated Antigens Expressed by Solid Tumors)
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