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Cancers
Special Issues
Novel Combinatorial Approaches for Immunotherapy and Targeted Therapies in Cancer
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Novel Combinatorial Approaches for Immunotherapy and Targeted Therapies in Cancer

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

Deadline for manuscript submissions: closed (31 March 2025) | Viewed by 17936

Special Issue Editors

Dr. Claudia De Lorenzo

E-Mail Website
Guest Editor
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80134 Napoli, Italy
Interests: biochemistry; antibodies; fusion proteins; immunoconjugates; bi-specific antibodies; phage display; immunobiotechnology; breast cancer; cancer immunotherapy; cardioncology; signal transduction
Special Issues, Collections and Topics in MDPI journals
Dr. Laura Cerchia

E-Mail Website
Guest Editor
Institute of Experimental Endocrinology and Oncology “G. Salvatore” National Research Council (IEOS-CNR), 80131 Naples, Italy
Interests: nucleic acid aptamer; SELEX technology; tumor markers; targeted therapy; targeted drug delivery; cancer theranostics; cancer cell biology and signaling; chemotherapy resistance; tumor microenvironment; TNBC
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Immunotherapy, based on the use of novel human monoclonal antibodies (mAbs) with antitumor or immunomodulatory activity, is an increasingly important strategy for cancer management. Targeted drugs can be directed against tumor-associated antigens (TAA) that are overexpressed on the cell surface of tumor cells to either inhibit their oncogenic function or to specifically deliver toxic compounds. Alternatively, they can be used in cancer therapy to regulate specific T-cell responses, targeting immune checkpoints (ICs), such as Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) or Programmed Death-1 (PD-1), thus enhancing the protective role of the immune system against cancer.

The main limit of this strategy is that an immune checkpoint blockade may induce resistance to the treatment with IC inhibitors (ICIs), owing to several molecular escape mechanisms. Thus, many ongoing clinical trials are currently testing these novel agents in combinatorial treatments, in order to obtain stronger therapeutic responses against the tumors with respect to single agent treatments.

A successful combinatorial treatment was indeed represented by ipilimumab (anti-CTLA-4 mAb) and nivolumab (anti-PD-1 mAb), which is currently in clinical use for patients affected by metastatic melanoma and has achieved higher therapeutic efficacy in terms of overall survival with respect to monotherapies. A recent study of a clinical trial in phase 1b includes patients treated with the combination of atezolizumab (anti-PD-L1 mAb) plus ipilimumab for locally advanced or metastatic non-small cell lung cancer (NSCLC).

Other findings highlight the synergistic activity of the PD-1/PD-L1 pathway with Lymphocyte Activation Gene-3 (Lag-3) or T-cell immunoglobulin and mucin-3 (Tim3), which together induce a more efficient tumor escape. In particular, their blockade through combinatorial treatments led to stronger immune responses against tumors in several mouse models, and recently, the combination of Nivolumab and anti-LAG-3 monoclonal antibody Relatlimab has been approved by FDA for metastatic melanoma. These data suggest that combinatorial treatments might be a valid approach to achieve a more efficient antitumor activity.   

Furthermore, atezolizumab has entered the clinic, in combination with nab-paclitaxel, for locally advanced or metastatic triple-negative breast cancer, and several ongoing clinical studies are exploring the treatment effectiveness of immunotherapy combined with chemotherapeutic drugs and/or various other targeting agents.

This Special Issue invites original research articles and timely reviews on all aspects regarding combinatorial approaches for the immunotherapy of cancer, highlighting problems, solutions, and future directions in the development of new therapeutic combinatorial approaches.

Dr. Claudia De Lorenzo
Dr. Laura Cerchia
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 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

  • antibody-based therapeutics
  • antitumor immunity
  • active cancer targeting
  • aptamer-based targeted therapies
  • aptamer-based immunotherapeutics

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Published Papers (5 papers)

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Research

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18 pages, 3895 KiB  
Article
A Comparison of the Antitumor Efficacy of Novel Multi-Specific Tribodies with Combinations of Approved Immunomodulatory Antibodies
by Lorenzo Manna, Rosa Rapuano Lembo, Asami Yoshioka, Koji Nakamura, Margherita Passariello and Claudia De Lorenzo
Cancers 2023, 15(22), 5345; https://doi.org/10.3390/cancers15225345 - 9 Nov 2023
Cited by 3 | Viewed by 1723
Abstract
Many advances in antitumor therapies have been achieved with antagonistic antibodies targeting the programmed cell death protein 1 (PD-1) or its ligand (PD-L1); however, many cancer patients still develop resistance to anti–PD-1/PD-L1 treatments often associated with the upregulation of other immune checkpoints such [...] Read more.
Many advances in antitumor therapies have been achieved with antagonistic antibodies targeting the programmed cell death protein 1 (PD-1) or its ligand (PD-L1); however, many cancer patients still develop resistance to anti–PD-1/PD-L1 treatments often associated with the upregulation of other immune checkpoints such as Lymphocyte Activation Gene-3 (LAG-3). In order to verify whether it is possible to overcome these limits, we analyzed and compared the effects of combinations of the clinically validated anti-LAG-3 mAb (Relatlimab) with anti-PD-1 (Pembrolizumab) or anti-PD-L1 (Atezolizumab) monoclonal antibodies (mAbs) with those of novel bispecific tribodies (TRs), called TR0304 and TR0506, previously generated in our lab by combining the binding moieties of novel human antibodies targeting the same ICs of the mentioned mAbs. In particular, TR0304, made up of a Fab derived from an anti-PD-L1 mAb and two single-chain variable fragments (scFvs) derived from an anti-LAG-3 mAb, was tested in comparison with Relatlimab plus Atezolizumab, and TR0506, made up of an antigen-binding fragment (Fab) derived from the same anti-LAG-3 mAb and two scFvs derived from an anti-PD-1 mAb, was tested in comparison with Relatlimab and Pembrolizumab. We found that the two novel TRs showed similar binding affinity to the targets with respect to validated mAbs, even though they recognized distinct or only partially overlapping epitopes. When tested for their functional properties, they showed an increased ability to induce lymphocyte activation and stronger in vitro cytotoxicity against tumor cells compared to combinatorial treatments of clinically validated mAbs. Considering that tribodies also have other advantages with respect to combinatorial treatments, such as reduced production costs and lower dose requirements, we think that these novel immunomodulatory TRs could be used for therapeutic applications, particularly in monotherapy-resistant cancer patients. Full article
(This article belongs to the Special Issue Novel Combinatorial Approaches for Immunotherapy and Targeted Therapies in Cancer)
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18 pages, 2998 KiB  
Article
Sialic Acids on Tumor Cells Modulate IgA Therapy by Neutrophils via Inhibitory Receptors Siglec-7 and Siglec-9
by Chilam Chan, Marta Lustig, J. H. Marco Jansen, Laura Garcia Villagrasa, Leon Raymakers, Lois A. Daamen, Thomas Valerius, Geert van Tetering and Jeanette H. W. Leusen
Cancers 2023, 15(13), 3405; https://doi.org/10.3390/cancers15133405 - 29 Jun 2023
Cited by 6 | Viewed by 3704
Abstract
Immunotherapy with targeted therapeutic antibodies is often ineffective in long-term responses in cancer patients due to resistance mechanisms such as overexpression of checkpoint molecules. Similar to T lymphocytes, myeloid immune cells express inhibitory checkpoint receptors that interact with ligands overexpressed on cancer cells, [...] Read more.
Immunotherapy with targeted therapeutic antibodies is often ineffective in long-term responses in cancer patients due to resistance mechanisms such as overexpression of checkpoint molecules. Similar to T lymphocytes, myeloid immune cells express inhibitory checkpoint receptors that interact with ligands overexpressed on cancer cells, contributing to treatment resistance. While CD47/SIRPα-axis inhibitors in combination with IgA therapy have shown promise, complete tumor eradication remains a challenge, indicating the presence of other checkpoints. We investigated hypersialylation on the tumor cell surface as a potential myeloid checkpoint and found that hypersialylated cancer cells inhibit neutrophil-mediated tumor killing through interactions with sialic acid-binding immunoglobulin-like lectins (Siglecs). To enhance antibody-dependent cellular cytotoxicity (ADCC) using IgA as therapeutic, we explored strategies to disrupt the interaction between tumor cell sialoglycans and Siglecs expressed on neutrophils. We identified Siglec-9 as the primary inhibitory receptor, with Siglec-7 also playing a role to a lesser extent. Blocking Siglec-9 enhanced IgA-mediated ADCC by neutrophils. Concurrent expression of multiple checkpoint ligands necessitated a multi-checkpoint-blocking approach. In certain cancer cell lines, combining CD47 blockade with desialylation improved IgA-mediated ADCC, effectively overcoming resistance that remained when blocking only one checkpoint interaction. Our findings suggest that a combination of CD47 blockade and desialylation may be necessary to optimize cancer immunotherapy, considering the upregulation of checkpoint molecules by tumor cells to evade immune surveillance. Full article
(This article belongs to the Special Issue Novel Combinatorial Approaches for Immunotherapy and Targeted Therapies in Cancer)
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16 pages, 2619 KiB  
Article
CD28 and 41BB Costimulatory Domains Alone or in Combination Differentially Influence Cell Surface Dynamics and Organization of Chimeric Antigen Receptors and Early Activation of CAR T Cells
by Marianna Mezősi-Csaplár, Árpád Szöőr and György Vereb
Cancers 2023, 15(12), 3081; https://doi.org/10.3390/cancers15123081 - 7 Jun 2023
Cited by 12 | Viewed by 3855
Abstract
Chimeric antigen receptor (CAR)-modified T cells brought a paradigm shift in the treatment of chemotherapy-resistant lymphomas. Conversely, clinical experience with CAR T cells targeting solid tumors has been disheartening, indicating the necessity of their molecular-level optimization. While incorporating CD28 or 41BB costimulatory domains [...] Read more.
Chimeric antigen receptor (CAR)-modified T cells brought a paradigm shift in the treatment of chemotherapy-resistant lymphomas. Conversely, clinical experience with CAR T cells targeting solid tumors has been disheartening, indicating the necessity of their molecular-level optimization. While incorporating CD28 or 41BB costimulatory domains into CARs in addition to the CD3z signaling domain improved the long-term efficacy of T cell products, their influence on early tumor engagement has yet to be elucidated. We studied the antigen-independent self-association and membrane diffusion kinetics of first- (.z), second- (CD28.z, 41BB.z), and third- (CD28.41BB.z) generation HER2-specific CARs in the resting T cell membrane using super-resolution AiryScan microscopy and fluorescence correlation spectroscopy, in correlation with RoseTTAFold-based structure prediction and assessment of oligomerization in native Western blot. While .z and CD28.z CARs formed large, high-density submicron clusters of dimers, 41BB-containing CARs formed higher oligomers that assembled into smaller but more numerous membrane clusters. The first-, second-, and third-generation CARs showed progressively increasing lateral diffusion as the distance of their CD3z domain from the membrane plane increased. Confocal microscopy analysis of immunological synapses showed that both small clusters of highly mobile CD28.41BB.z and large clusters of less mobile .z CAR induced more efficient CD3ζ and pLck phosphorylation than CD28.z or 41BB.z CARs of intermediate mobility. However, electric cell-substrate impedance sensing revealed that the CD28.41BB.z CAR performs worst in sequential short-term elimination of adherent tumor cells, while the .z CAR is superior to all others. We conclude that the molecular structure, membrane organization, and mobility of CARs are critical design parameters that can predict the development of an effective immune synapse. Therefore, they need to be taken into account alongside the long-term biological effects of costimulatory domains to achieve an optimal therapeutic effect. Full article
(This article belongs to the Special Issue Novel Combinatorial Approaches for Immunotherapy and Targeted Therapies in Cancer)
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23 pages, 5609 KiB  
Article
Combination of Expanded Allogeneic NK Cells and T Cell-Based Immunotherapy Exert Enhanced Antitumor Effects
by Xiao Wang, Xuejiao Yang, Yueping Wang, Yunshuo Chen, Ying Yang, Siqi Shang, Wenbo Wang and Yueying Wang
Cancers 2023, 15(1), 251; https://doi.org/10.3390/cancers15010251 - 30 Dec 2022
Cited by 4 | Viewed by 4103
Abstract
Immunotherapies based on immune checkpoint blockade, neoantigen-reactive tumor-infiltrating lymphocytes and T cell receptor-engineered T cells (TCR-T) have achieved favorable clinical outcomes in tumor treatment. However, sustained immune response and tumor regression have been observed only in a few patients due to immune escape. [...] Read more.
Immunotherapies based on immune checkpoint blockade, neoantigen-reactive tumor-infiltrating lymphocytes and T cell receptor-engineered T cells (TCR-T) have achieved favorable clinical outcomes in tumor treatment. However, sustained immune response and tumor regression have been observed only in a few patients due to immune escape. Natural killer (NK) cells can mediate direct tumor lysis and target cancer cells with low or no expression of human leukocyte antigen class I (HLA-I) that are no longer recognized by T cells during immune escape. Therefore, the combination of T cell-based immunotherapy and NK cell therapy is a promising strategy for improving antitumor response and response rate. However, allogeneic NK cells for adoptive cell therapy have been limited by both the required cell number and quality. Here, we developed an efficient manufacturing system that relies on genetically modified K562 cells for the expansion of high-quality NK cells derived from peripheral blood mononuclear cells. NK cells with the optimal expansion and activity were identified by comparing the different culture systems. Furthermore, we demonstrated that the cooperation of NK cells with tumor-reactive T cells or with NY-ESO-1-specific TCR-T cells further enhanced tumors lysis, especially against tumors with downregulated HLA-I expression. The advantages of HLA-mismatch and non-rejection by other allogeneic immune cells demonstrated the potential of “off-the-shelf” NK cells with the capacity to target tumors for immunotherapy. Our results indicate that the combination strategy based on T cell and allogeneic NK cell immunotherapy might have potential for overcoming the barrier of immune incompetence caused by HLA-I downregulation. Full article
(This article belongs to the Special Issue Novel Combinatorial Approaches for Immunotherapy and Targeted Therapies in Cancer)
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Review

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16 pages, 2260 KiB  
Review
Single-Cell Transcriptomics for Unlocking Personalized Cancer Immunotherapy: Toward Targeting the Origin of Tumor Development Immunogenicity
by Saeed Khodayari, Hamid Khodayari, Elnaz Saeedi, Habibollah Mahmoodzadeh, Alireza Sadrkhah and Karim Nayernia
Cancers 2023, 15(14), 3615; https://doi.org/10.3390/cancers15143615 - 14 Jul 2023
Cited by 8 | Viewed by 3095
Abstract
Cancer immunotherapy is a promising approach for treating malignancies through the activation of anti-tumor immunity. However, the effectiveness and safety of immunotherapy can be limited by tumor complexity and heterogeneity, caused by the diverse molecular and cellular features of tumors and their microenvironments. [...] Read more.
Cancer immunotherapy is a promising approach for treating malignancies through the activation of anti-tumor immunity. However, the effectiveness and safety of immunotherapy can be limited by tumor complexity and heterogeneity, caused by the diverse molecular and cellular features of tumors and their microenvironments. Undifferentiated tumor cell niches, which we refer to as the “Origin of Tumor Development” (OTD) cellular population, are believed to be the source of these variations and cellular heterogeneity. From our perspective, the existence of distinct features within the OTD is expected to play a significant role in shaping the unique tumor characteristics observed in each patient. Single-cell transcriptomics is a high-resolution and high-throughput technique that provides insights into the genetic signatures of individual tumor cells, revealing mechanisms of tumor development, progression, and immune evasion. In this review, we explain how single-cell transcriptomics can be used to develop personalized cancer immunotherapy by identifying potential biomarkers and targets specific to each patient, such as immune checkpoint and tumor-infiltrating lymphocyte function, for targeting the OTD. Furthermore, in addition to offering a possible workflow, we discuss the future directions of, and perspectives on, single-cell transcriptomics, such as the development of powerful analytical tools and databases, that will aid in unlocking personalized cancer immunotherapy through the targeting of the patient’s cellular OTD. Full article
(This article belongs to the Special Issue Novel Combinatorial Approaches for Immunotherapy and Targeted Therapies in Cancer)
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