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Molecular Advances in Cancer Immunotherapy
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Molecular Advances in Cancer Immunotherapy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (20 January 2025) | Viewed by 14356

Special Issue Editor

Prof. Dr. Niels Schaft

E-Mail Website
Guest Editor
Department of Dermatology, Universitätsklinikum Erlangen, 91054 Erlangen, Germany
Interests: the clinical application of CAR-T cells and TCR-T cells against solid tumors, mainly melanoma; the optimization of CAR-T cells, CAR-NK cells, CAR-monocytes, and CAR-macrophages specific to several cancer antigens; the identification of new, more specific tumor antigens for CAR-T cell therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer immunotherapy is defined as stimulation of the immune system to treat cancer. Despite its relatively short definition, this encompasses a plethora of therapeutic possibilities ranging from cytokine treatments to antibody therapies, checkpoint inhibitors, cancer vaccines, adoptive (T-)cell therapies, and other therapies, or combinations thereof. Although cancer immunotherapy has been proven to be effective in patients with a broad variety of hematological and solid malignancies, there is increasing evidence that that its efficacy varies and that there is room for improvement. The therapies themselves should be improved, and investigations should be conducted on the negative influence of the tumor microenvironment (TME), toxicity management, adverse immune-related side effects, response prediction, and the use of immunotherapy in special patient populations. In this Special Issue, we would like to focus on molecular advances in cancer immunotherapy with a view to understanding how novel and/or improved immunotherapies can be developed for cancer treatment. Authors are invited to contribute original research papers or reviews to this Special Issue of IJMS, focusing on, but not limited to: cancer immunotherapy of solid tumors; new strategies for adoptive T-cell therapies; molecular manipulation of the tumor microenvironment; new targets for cancer immunotherapy; molecular mechanisms or therapy resistance; and improvements in checkpoint blockade therapy.

Prof. Dr. Niels Schaft
Guest Editor

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Keywords

  • checkpoint blockade
  • CAR-T cells
  • TIL
  • TCR transfer
  • therapy resistance
  • targets
  • tumor microenvironment
  • solid tumors

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Published Papers (6 papers)

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Research

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11 pages, 2180 KiB  
Article
Glycan Structures in Osteosarcoma as Targets for Lectin-Based Chimeric Antigen Receptor Immunotherapy
by Nele Prasse, Charlotte Wessolowski, Ingo Müller, Kerstin Cornils and Anna-Katharina Franke
Int. J. Mol. Sci. 2024, 25(10), 5344; https://doi.org/10.3390/ijms25105344 - 14 May 2024
Cited by 1 | Viewed by 1627
Abstract
Osteosarcoma is a type of bone cancer that primarily affects children and young adults. The overall 5-year survival rate for localized osteosarcoma is 70–75%, but it is only 20–30% for patients with relapsed or metastatic tumors. To investigate potential glycan-targeting structures for immunotherapy, [...] Read more.
Osteosarcoma is a type of bone cancer that primarily affects children and young adults. The overall 5-year survival rate for localized osteosarcoma is 70–75%, but it is only 20–30% for patients with relapsed or metastatic tumors. To investigate potential glycan-targeting structures for immunotherapy, we stained primary osteosarcomas with recombinant C-type lectin CD301 (MGL, CLEC10A) and observed moderate to strong staining on 26% of the tumors. NK92 cells expressing a CD301-CAR recognized and eliminated osteosarcoma cells in vitro. Cytotoxic activity assays correlated with degranulation and cytokine release assays. Combination with an inhibitory antibody against the immune checkpoint TIGIT (T-cell immunoreceptor with lg and ITIM domains) showed promising additional effects. Overall, this study showed, for the first time, the expression of CD301 ligands in osteosarcoma tissue and demonstrated their use as potential target structures for lectin-based immunotherapy. Full article
(This article belongs to the Special Issue Molecular Advances in Cancer Immunotherapy)
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11 pages, 1289 KiB  
Communication
Sequential Therapy with Ropeginterferon Alfa-2b and Anti-Programmed Cell Death 1 Antibody for Inhibiting the Recurrence of Hepatitis B-Related Hepatocellular Carcinoma: From Animal Modeling to Phase I Clinical Results
by Albert Qin, Chang-Ru Wu, Ming-Chih Ho, Chan-Yen Tsai and Pei-Jer Chen
Int. J. Mol. Sci. 2024, 25(1), 433; https://doi.org/10.3390/ijms25010433 - 28 Dec 2023
Cited by 5 | Viewed by 2162
Abstract
Hepatocellular carcinoma (HCC) usually recurs after curative surgical resection. Currently, no approved adjuvant therapy has been shown to reduce HCC recurrence rates. In this study, the in vivo effect of sequential combination treatment with recombinant mouse interferon-alpha (rmIFN-α) and an anti-mouse-PD1 antibody on [...] Read more.
Hepatocellular carcinoma (HCC) usually recurs after curative surgical resection. Currently, no approved adjuvant therapy has been shown to reduce HCC recurrence rates. In this study, the in vivo effect of sequential combination treatment with recombinant mouse interferon-alpha (rmIFN-α) and an anti-mouse-PD1 antibody on hepatitis B virus (HBV) clearance in mice was evaluated. A Phase I clinical trial was then conducted to assess the safety, tolerability, and inhibitory activity of sequential therapy with ropeginterferon alfa-2b and nivolumab in patients with HCC recurrence who underwent curative surgery for HBV-related HCC. The animal modeling study showed that HBV suppression was significantly greater with the rmIFN-α and anti-PD1 sequential combination treatment in comparison with sole treatment with rmIFN-α or anti-PD1. In the Phase I study, eleven patients completed the sequential therapy with ropeginterferon alfa-2b every two weeks for six doses at 450 µg, followed by three doses of nivolumab every two weeks up to 0.75 mg/kg. A notable decrease in or clearance of HBV surface antigen was observed in two patients. The dose-limiting toxicity of grade 3 alanine transaminase and aspartate aminotransferase increases was observed in one patient. The maximum tolerated dose was then determined. To date, no HCC recurrence has been observed. The treatment modality was well tolerated. These data support the further clinical development of sequential combination therapy as a post-surgery prophylactic measure against the recurrence of HBV-related HCC. Full article
(This article belongs to the Special Issue Molecular Advances in Cancer Immunotherapy)
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14 pages, 1274 KiB  
Article
Prognostic Impact of CD38- and IgκC-Positive Tumor-Infiltrating Plasma Cells in Triple-Negative Breast Cancer
by Anne-Sophie Heimes, Natali Riedel, Katrin Almstedt, Slavomir Krajnak, Roxana Schwab, Kathrin Stewen, Antje Lebrecht, Marco Johannes Battista, Walburgis Brenner, Annette Hasenburg and Marcus Schmidt
Int. J. Mol. Sci. 2023, 24(20), 15219; https://doi.org/10.3390/ijms242015219 - 16 Oct 2023
Cited by 5 | Viewed by 1664
Abstract
Due to a higher mutational load, triple-negative breast cancer (TNBC) is characterized by a higher immunogenicity compared to other subtypes. In this context, we analyzed the prognostic significance of tumor-infiltrating plasma cells in a cohort of 107 triple-negative breast cancer patients. Tumor-infiltrating plasma [...] Read more.
Due to a higher mutational load, triple-negative breast cancer (TNBC) is characterized by a higher immunogenicity compared to other subtypes. In this context, we analyzed the prognostic significance of tumor-infiltrating plasma cells in a cohort of 107 triple-negative breast cancer patients. Tumor-infiltrating plasma cells were analyzed via immunohistochemistry using the plasma cell markers CD38 and IgκC. The prognostic impact of the CD38 and IgκC expression was evaluated using the Kaplan–Meier plots and Cox regression analyses. A Spearman-Rho correlation coefficient was used to evaluate a possible association between plasma cell infiltration and the BRCA mutation status. The study cohort consisted of 107 patients with early-stage TNBC, who were treated between 2009 and 2016 at the Department of Gynecology and Obstetrics, University Medical Center Mainz, Germany. The median follow-up was five years. The Kaplan–Meier survival analysis showed that higher tumor infiltration with CD38-positive plasma cells was associated with significantly longer metastasis-free survival (MFS) (p = 0.039 Log Rank). In the multivariate Cox regression analysis for metastasis-free survival, in which additional clinicopathological factors (age, tumor size, nodal status, and grading) were considered, CD38 was identified as an independent prognostic factor within the analyzed cohort (HR 0.438, 95% CI 0.195–0.983; p = 0.045). In addition to the CD38 expression, the nodal status was also identified as an independent prognostic factor in multivariate Cox regression. Regarding the IgκC expression, a higher IgκC expression was shown to be associated with a better outcome, although this effect was not statistically significant. Furthermore, we were able to show a significant correlation between plasma cell infiltration and the BRCA mutation status. A favorable prognostic significance of tumor-infiltrating plasma cells could be demonstrated in triple-negative breast cancer immunohistochemically analyzed for the CD38 and IgκC expression. CD38 was identified as an independent prognostic factor via multivariate Cox regression. Full article
(This article belongs to the Special Issue Molecular Advances in Cancer Immunotherapy)
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Review

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25 pages, 1584 KiB  
Review
Non-Coding RNA in Tumor Cells and Tumor-Associated Myeloid Cells—Function and Therapeutic Potential
by Amanda Katharina Binder, Franziska Bremm, Jan Dörrie and Niels Schaft
Int. J. Mol. Sci. 2024, 25(13), 7275; https://doi.org/10.3390/ijms25137275 - 2 Jul 2024
Cited by 5 | Viewed by 2073
Abstract
The RNA world is wide, and besides mRNA, there is a variety of other RNA types, such as non-coding (nc)RNAs, which harbor various intracellular regulatory functions. This review focuses on small interfering (si)RNA and micro (mi)RNA, which form a complex network regulating mRNA [...] Read more.
The RNA world is wide, and besides mRNA, there is a variety of other RNA types, such as non-coding (nc)RNAs, which harbor various intracellular regulatory functions. This review focuses on small interfering (si)RNA and micro (mi)RNA, which form a complex network regulating mRNA translation and, consequently, gene expression. In fact, these RNAs are critically involved in the function and phenotype of all cells in the human body, including malignant cells. In cancer, the two main targets for therapy are dysregulated cancer cells and dysfunctional immune cells. To exploit the potential of mi- or siRNA therapeutics in cancer therapy, a profound understanding of the regulatory mechanisms of RNAs and following targeted intervention is needed to re-program cancer cells and immune cell functions in vivo. The first part focuses on the function of less well-known RNAs, including siRNA and miRNA, and presents RNA-based technologies. In the second part, the therapeutic potential of these technologies in treating cancer is discussed, with particular attention on manipulating tumor-associated immune cells, especially tumor-associated myeloid cells. Full article
(This article belongs to the Special Issue Molecular Advances in Cancer Immunotherapy)
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18 pages, 397 KiB  
Review
Biomarkers for Immune Checkpoint Inhibitor Response in NSCLC: Current Developments and Applicability
by Katiane Tostes, Aléxia Polo Siqueira, Rui Manuel Reis, Leticia Ferro Leal and Lidia Maria Rebolho Batista Arantes
Int. J. Mol. Sci. 2023, 24(15), 11887; https://doi.org/10.3390/ijms241511887 - 25 Jul 2023
Cited by 20 | Viewed by 3515
Abstract
Lung cancer has the highest mortality rate among all cancer types, resulting in over 1.8 million deaths annually. Immunotherapy utilizing immune checkpoint inhibitors (ICIs) has revolutionized the treatment of non-small cell lung cancer (NSCLC). ICIs, predominantly monoclonal antibodies, modulate co-stimulatory and co-inhibitory signals [...] Read more.
Lung cancer has the highest mortality rate among all cancer types, resulting in over 1.8 million deaths annually. Immunotherapy utilizing immune checkpoint inhibitors (ICIs) has revolutionized the treatment of non-small cell lung cancer (NSCLC). ICIs, predominantly monoclonal antibodies, modulate co-stimulatory and co-inhibitory signals crucial for maintaining immune tolerance. Despite significant therapeutic advancements in NSCLC, patients still face challenges such as disease progression, recurrence, and high mortality rates. Therefore, there is a need for predictive biomarkers that can guide lung cancer treatment strategies. Currently, programmed death-ligand 1 (PD-L1) expression is the only established biomarker for predicting ICI response. However, its accuracy and robustness are not consistently reliable. This review provides an overview of potential biomarkers currently under development or in the validation stage that hold promise in improving the classification of responders and non-responders to ICI therapy in the near future. Full article
(This article belongs to the Special Issue Molecular Advances in Cancer Immunotherapy)
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Graphical abstract

Other

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20 pages, 1263 KiB  
Perspective
Genetically Engineered T Cells and Recombinant Antibodies to Target Intracellular Neoantigens: Current Status and Future Directions
by Ana Maria Waaga-Gasser and Thomas Böldicke
Int. J. Mol. Sci. 2024, 25(24), 13504; https://doi.org/10.3390/ijms252413504 - 17 Dec 2024
Cited by 1 | Viewed by 2067
Abstract
Recombinant antibodies and, more recently, T cell receptor (TCR)-engineered T cell therapies represent two immunological strategies that have come to the forefront of clinical interest for targeting intracellular neoantigens in benign and malignant diseases. T cell-based therapies targeting neoantigens use T cells expressing [...] Read more.
Recombinant antibodies and, more recently, T cell receptor (TCR)-engineered T cell therapies represent two immunological strategies that have come to the forefront of clinical interest for targeting intracellular neoantigens in benign and malignant diseases. T cell-based therapies targeting neoantigens use T cells expressing a recombinant complete TCR (TCR-T cell), a chimeric antigen receptor (CAR) with the variable domains of a neoepitope-reactive TCR as a binding domain (TCR-CAR-T cell) or a TCR-like antibody as a binding domain (TCR-like CAR-T cell). Furthermore, the synthetic T cell receptor and antigen receptor (STAR) and heterodimeric TCR-like CAR (T-CAR) are designed as a double-chain TCRαβ-based receptor with variable regions of immunoglobulin heavy and light chains (VH and VL) fused to TCR-Cα and TCR-Cβ, respectively, resulting in TCR signaling. In contrast to the use of recombinant T cells, anti-neopeptide MHC (pMHC) antibodies and intrabodies neutralizing intracellular neoantigens can be more easily applied to cancer patients. However, different limitations should be considered, such as the loss of neoantigens, the modification of antigen peptide presentation, tumor heterogenicity, and the immunosuppressive activity of the tumor environment. The simultaneous application of immune checkpoint blocking antibodies and of CRISPR/Cas9-based genome editing tools to engineer different recombinant T cells with enhanced therapeutic functions could make T cell therapies more efficient and could pave the way for its routine clinical application. Full article
(This article belongs to the Special Issue Molecular Advances in Cancer Immunotherapy)
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