Cancers

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23 pages, 8280 KiB

Open AccessArticle

Taxifolin Inhibits the Growth of Non-Small-Cell Lung Cancer via Downregulating Genes Displaying Novel and Robust Associations with Immune Evasion Factors

by Xiaozeng Lin, Ying Dong, Yan Gu, Fengxiang Wei, Jingyi Peng, Yingying Su, Yanjun Wang, Chengzhi Yang, Sandra Vega Neira, Anil Kapoor and Damu Tang

Cancers 2023, 15(19), 4818; https://doi.org/10.3390/cancers15194818 - 30 Sep 2023

Cited by 3 | Viewed by 1654

Abstract

Using an LL2 cell-based syngeneic mouse LC model, taxifolin suppressed allografts along with the appearance of 578 differentially expressed genes (DEGs). These DEGs were associated with enhancement of processes related to the extracellular matrix and lymphocyte chemotaxis as well as the reduction in [...] Read more.

Using an LL2 cell-based syngeneic mouse LC model, taxifolin suppressed allografts along with the appearance of 578 differentially expressed genes (DEGs). These DEGs were associated with enhancement of processes related to the extracellular matrix and lymphocyte chemotaxis as well as the reduction in pathways relevant to cell proliferation. From these DEGs, we formulated 12-gene (TxflSig) and 7-gene (TxflSig1) panels; both predicted response to ICB (immune checkpoint blockade) therapy more effectively in non-small-cell lung cancer (NSCLC) than numerous well-established ICB biomarkers, including PD-L1. In both panels, the mouse counterparts of ITGAL, ITGAX, and TMEM119 genes were downregulated by taxifolin. They were strongly associated with immune suppression in LC, evidenced by their robust correlations with the major immunosuppressive cell types (MDSC, Treg, and macrophage) and multiple immune checkpoints in NSCLC and across multiple human cancer types. ITGAL, ITGAX, and IIT (ITGAL-ITGAX-TMEM119) effectively predicted NSCLC’s response to ICB therapy; IIT stratified the mortality risk of NSCLC. The stromal expressions of ITGAL and ITGAX, together with tumor expression of TMEM119 in NSCLC, were demonstrated. Collectively, we report multiple novel ICB biomarkers—TxflSig, TxflSig1, IIT, ITGAL, and ITGAX—and taxifolin-derived attenuation of immunosuppressive activities in NSCLC, suggesting the inclusion of taxifolin in ICB therapies for NSCLC. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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17 pages, 3612 KiB

Open AccessArticle

The 2EF Antibody Targets a Unique N-Terminal Epitope of Trop-2 and Enhances the In Vivo Activity of the Cancer-Selective 2G10 Antibody

by Emanuela Guerra, Marco Trerotola, Valeria Relli, Rossano Lattanzio, Martina Ceci, Khouloud Boujnah, Ludovica Pantalone, Roberta Di Pietro, Manuela Iezzi, Nicola Tinari and Saverio Alberti

Cancers 2023, 15(14), 3721; https://doi.org/10.3390/cancers15143721 - 22 Jul 2023

Cited by 5 | Viewed by 2216

Abstract

Trop-2 proteolytic processing in cancer cells exposes epitopes that were specifically targeted by the 2G10 antibody. We sought additional recognition of Trop-2 within difficult-to-reach, densely packed tumor sites. Trop-2 deletion mutants were employed in immunization and screening procedures, and these led to the [...] Read more.

Trop-2 proteolytic processing in cancer cells exposes epitopes that were specifically targeted by the 2G10 antibody. We sought additional recognition of Trop-2 within difficult-to-reach, densely packed tumor sites. Trop-2 deletion mutants were employed in immunization and screening procedures, and these led to the recognition of a novel epitope in the N-terminal region of Trop-2, by the 2EF antibody. The 2EF mAb was shown to bind Trop-2 at cell–cell junctions in MCF-7 breast cancer cells, and in deeply seated sites in prostate cancer, that were inaccessible to benchmark anti-Trop-2 antibodies. The 2EF antibody was shown to inhibit the growth of HT29 colon tumor cells in vitro, with the highest activity at high cell density. In vivo, 2EF showed anticancer activity against SKOv3 ovarian, Colo205, HT29, HCT116 colon and DU-145 prostate tumors, with the highest impact on densely packed tumor sites, whereby 2EF outcompeted benchmark anti-Trop-2 antibodies. Given the different recognition modes of Trop-2 by 2EF and 2G10, we hypothesized the effective interaction of the two mAb in vivo. The 2EF mAb was indeed demonstrated to enhance the activity of 2G10 against tumor xenotransplants, opening novel avenues for Trop-2-targeted therapy. We humanized 2EF by state-of-the-art CDR grafting/re-modeling, yielding the Hu2EF for therapy of Trop-2-expressing tumors in patients. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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19 pages, 2211 KiB

Open AccessArticle

Combined Blockade of TIGIT and PD-L1 Enhances Anti-Neuroblastoma Efficacy of GD2-Directed Immunotherapy with Dinutuximab Beta

by Nikolai Siebert, Maxi Zumpe, Christian Heinrich Schwencke, Simon Biskupski, Sascha Troschke-Meurer, Justus Leopold, Alexander Zikoridse and Holger N. Lode

Cancers 2023, 15(13), 3317; https://doi.org/10.3390/cancers15133317 - 23 Jun 2023

Cited by 7 | Viewed by 2027

Abstract

Immunotherapies against high-risk neuroblastoma (NB), using the anti-GD2 antibody (Ab) dinutuximab beta (DB), significantly improved patient survival. Ab-dependent cellular cytotoxicity (ADCC) is one of the main mechanisms of action and it is primarily mediated by NK cells. To further improve antitumor efficacy, we [...] Read more.

Immunotherapies against high-risk neuroblastoma (NB), using the anti-GD2 antibody (Ab) dinutuximab beta (DB), significantly improved patient survival. Ab-dependent cellular cytotoxicity (ADCC) is one of the main mechanisms of action and it is primarily mediated by NK cells. To further improve antitumor efficacy, we investigated here a combinatorial immunotherapy with DB and the double immune checkpoint blockade of T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and programmed cell death ligand-1 (PD-L1). The effects of ADCC, mediated by DB against NB cells on NK-cell activity, and the expression of TIGIT and CD226 and their ligands CD112 and CD155, as well as of PD-1 and PD-L1 on NB and effector cells, were investigated using flow cytometry. ADCC was assessed with a calcein-AM-based cytotoxicity assay. The efficacy of a combinatorial immunotherapy with DB, given as a long-term treatment, and the double immune checkpoint blockade of TIGIT and PD-L1 was shown using a resistant murine model of NB, followed by an analysis of the tumor tissue. We detected both TIGIT ligands, CD112 and CD155, on all NB cell lines analyzed. Although ADCC by DB resulted in a strong activation of NK cells leading to an effective tumor cell lysis, a remarkable induction of PD-L1 expression on NB cells, and of TIGIT and PD-1 on effector cells, especially on NK cells, was observed. Additional anti-TIGIT or anti-PD-L1 treatments effectively inhibited tumor growth and improved survival of the mice treated with DB. The superior antitumor effects were observed in the “DB + double immune checkpoint blockade” group, showing an almost complete eradication of the tumors and the highest OS, even under resistant conditions. An analysis of tumor tissue revealed both TIGIT and TIGIT ligand expression on myeloid-derived suppressor cells (MDSCs), suggesting additional mechanisms of protumoral effects in NB. Our data show that the targeting of TIGIT and PD-L1 significantly improves the antitumor efficacy of anti-GD2 immunotherapy, with DB presenting a new effective combinatorial treatment strategy against high-risk tumors. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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23 pages, 6951 KiB

Open AccessArticle

B7H3 Role in Reshaping Immunosuppressive Landscape in MSI and MSS Colorectal Cancer Tumours

by Sylwia Mielcarska, Miriam Dawidowicz, Agnieszka Kula, Paweł Kiczmer, Hanna Skiba, Małgorzata Krygier, Magdalena Chrabańska, Jerzy Piecuch, Monika Szrot, Błażej Ochman, Julia Robotycka, Bogumiła Strzałkowska, Zenon Czuba, Dariusz Waniczek and Elżbieta Świętochowska

Cancers 2023, 15(12), 3136; https://doi.org/10.3390/cancers15123136 - 10 Jun 2023

Cited by 6 | Viewed by 2339

Abstract

The study aimed to assess the expression of B7H3 concerning clinicopathological and histological parameters, including MSI/MSS status, CD-8 cells, tumour-infiltrating lymphocytes (TILs), budding, TNM scale and grading. Moreover, we analyzed the B7H3-related pathways using available online datasets and the immunological context of B7H3 [...] Read more.

The study aimed to assess the expression of B7H3 concerning clinicopathological and histological parameters, including MSI/MSS status, CD-8 cells, tumour-infiltrating lymphocytes (TILs), budding, TNM scale and grading. Moreover, we analyzed the B7H3-related pathways using available online datasets and the immunological context of B7H3 expression, through the 48-cytokine screening panel of cancer tissues homogenates, immunogenic features and immune composition. The study included 158 patients diagnosed with CRC. To assess B7H3 levels, we performed an immunohistochemistry method (IHC) and enzyme-linked immunosorbent assay (ELISA). To elucidate the immune composition of colorectal cancer, we performed the Bio-Plex Pro Human 48-cytokine panel. To study biological characteristics of B7H3, we used online databases. Expression of B7H3 was upregulated in CRC tumour tissues in comparison to adjacent noncancerous margin tissues. The concentrations of B7H3 in tumours were positively associated with T parameter of patients and negatively with tumour-infiltrating lymphocytes score. Additionally, Principal Component Analysis showed that B7H3 expression in tumours correlated positively with cytokines associated with M2-macrophages and protumour growth factors. The expression of B7H3 in tumours was independent of MSI/MSS status. These findings will improve our understanding of B7H3 role in colorectal cancer immunity. Our study suggests that B7-H3 is a promising potential target for cancer therapy. Further studies must clarify the mechanisms of B7H3 overexpression and its therapeutic importance in colorectal cancer. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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19 pages, 1461 KiB

Open AccessArticle

Multicenter International Study of the Consensus Immunoscore for the Prediction of Relapse and Survival in Early-Stage Colon Cancer

by Bernhard Mlecnik, Alessandro Lugli, Gabriela Bindea, Florence Marliot, Carlo Bifulco, Jiun-Kae Jack Lee, Inti Zlobec, Tilman T. Rau, Martin D. Berger, Iris D. Nagtegaal, Elisa Vink-Börger, Arndt Hartmann, Carol I. Geppert, Julie Kolwelter, Susanne Merkel, Robert Grützmann, Marc Van den Eynde, Anne Jouret-Mourin, Alex Kartheuser, Daniel Léonard, Christophe Remue, Julia Wang, Prashant Bavi, Michael H. A. Roehrl, Pamela S. Ohashi, Linh T. Nguyen, SeongJun Han, Heather L. MacGregor, Sara Hafezi-Bakhtiari, Bradly G. Wouters, Giuseppe V. Masucci, Emilia K. Andersson, Eva Zavadova, Michal Vocka, Jan Spacek, Lubos Petruzelka, Bohuslav Konopasek, Pavel Dundr, Helena Skalova, Kristyna Nemejcova, Gerardo Botti, Fabiana Tatangelo, Paolo Delrio, Gennaro Ciliberto, Michele Maio, Luigi Laghi, Fabio Grizzi, Tessa Fredriksen, Bénédicte Buttard, Lucie Lafontaine, Pauline Maby, Amine Majdi, Assia Hijazi, Carine El Sissy, Amos Kirilovsky, Anne Berger, Christine Lagorce, Christopher Paustian, Carmen Ballesteros-Merino, Jeroen Dijkstra, Carlijn van de Water, Shannon van Lent-van Vliet, Nikki Knijn, Ana-Maria Mușină, Dragos-Viorel Scripcariu, Boryana Popivanova, Mingli Xu, Tomonobu Fujita, Shoichi Hazama, Nobuaki Suzuki, Hiroaki Nagano, Kiyotaka Okuno, Toshihiko Torigoe, Noriyuki Sato, Tomohisa Furuhata, Ichiro Takemasa, Prabhu Patel, Hemangini H. Vora, Birva Shah, Jayendrakumar B. Patel, Kruti N. Rajvik, Shashank J. Pandya, Shilin N. Shukla, Yili Wang, Guanjun Zhang, Yutaka Kawakami, Francesco M. Marincola, Paolo A. Ascierto, Bernard A. Fox, Franck Pagès and Jérôme Galon Show full author list Hide full author list

Cancers 2023, 15(2), 418; https://doi.org/10.3390/cancers15020418 - 8 Jan 2023

Cited by 13 | Viewed by 4598

Abstract

Background: The prognostic value of Immunoscore was evaluated in Stage II/III colon cancer (CC) patients, but it remains unclear in Stage I/II, and in early-stage subgroups at risk. An international Society for Immunotherapy of Cancer (SITC) study evaluated the pre-defined consensus Immunoscore in [...] Read more.

Background: The prognostic value of Immunoscore was evaluated in Stage II/III colon cancer (CC) patients, but it remains unclear in Stage I/II, and in early-stage subgroups at risk. An international Society for Immunotherapy of Cancer (SITC) study evaluated the pre-defined consensus Immunoscore in tumors from 1885 AJCC/UICC-TNM Stage I/II CC patients from Canada/USA (Cohort 1) and Europe/Asia (Cohort 2). METHODS: Digital-pathology is used to quantify the densities of CD3+ and CD8+ T-lymphocyte in the center of tumor (CT) and the invasive margin (IM). The time to recurrence (TTR) was the primary endpoint. Secondary endpoints were disease-free survival (DFS), overall survival (OS), prognosis in Stage I, Stage II, Stage II-high-risk, and microsatellite-stable (MSS) patients. RESULTS: High-Immunoscore presented with the lowest risk of recurrence in both cohorts. In Stage I/II, recurrence-free rates at 5 years were 78.4% (95%-CI, 74.4–82.6), 88.1% (95%-CI, 85.7–90.4), 93.4% (95%-CI, 91.1–95.8) in low, intermediate and high Immunoscore, respectively (HR (Hi vs. Lo) = 0.27 (95%-CI, 0.18–0.41); p < 0.0001). In Cox multivariable analysis, the association of Immunoscore to outcome was independent (TTR: HR (Hi vs. Lo) = 0.29, (95%-CI, 0.17–0.50); p < 0.0001) of the patient’s gender, T-stage, sidedness, and microsatellite instability-status (MSI). A significant association of Immunoscore with survival was found for Stage II, high-risk Stage II, T4N0 and MSS patients. The Immunoscore also showed significant association with TTR in Stage-I (HR (Hi vs. Lo) = 0.07 (95%-CI, 0.01–0.61); P = 0.016). The Immunoscore had the strongest (69.5%) contribution χ² for influencing survival. Patients with a high Immunoscore had prolonged TTR in T4N0 tumors even for patients not receiving chemotherapy, and the Immunoscore remained the only significant parameter in multivariable analysis. CONCLUSION: In early CC, low Immunoscore reliably identifies patients at risk of relapse for whom a more intensive surveillance program or adjuvant treatment should be considered. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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17 pages, 1675 KiB

Open AccessArticle

Predictive Value of Baseline FDG-PET/CT for the Durable Response to Immune Checkpoint Inhibition in NSCLC Patients Using the Morphological and Metabolic Features of Primary Tumors

by Ken Kudura, Nando Ritz, Tim Kutzker, Martin H. K. Hoffmann, Arnoud J. Templeton, Robert Foerster, Michael C. Kreissl and Kwadwo Antwi

Cancers 2022, 14(24), 6095; https://doi.org/10.3390/cancers14246095 - 11 Dec 2022

Cited by 10 | Viewed by 1950

Abstract

Objectives: We aimed to investigate the predictive value of baseline 2-deoxy-2-[¹⁸F]fluoro-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) for durable responses to immune checkpoint inhibitors (ICIs) by linking the morphological and metabolic features of primary tumors (PTs) in nonsmall cell lung cancer (NSCLC) [...] Read more.

Objectives: We aimed to investigate the predictive value of baseline 2-deoxy-2-[¹⁸F]fluoro-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) for durable responses to immune checkpoint inhibitors (ICIs) by linking the morphological and metabolic features of primary tumors (PTs) in nonsmall cell lung cancer (NSCLC) patients. Methods: For the purpose of this single-center study, the imaging data of the patients with a first diagnosis of NSCLC and an available baseline FDG-PET/CT between 2020 and 2021 were retrospectively assessed. The baseline characteristics were collected based on clinical reports and interdisciplinary tumor board documentation. The metabolic (such as standardized uptake value SUV maximum and mean (SUV_max, SUV mean), metabolic tumor volume (MTV), total lesion glycolysis (TLG)) and morphological (such as volume, morphology, margin, and presence of lymphangiosis through imaging) features of all the PTs were retrospectively assessed using FDG-PET/CT. Overall survival (OS), progression-free survival (PFS), clinical benefit (CB) and mortality rate were used as endpoints to define the long-term response to therapy. A backward, stepwise logistic regression analysis was performed in order to define the best model for predicting lasting responses to treatment. Statistical significance was assumed at p < 0.05. Results: A total of 125 patients (median age ± standard deviation (SD) 72.0 ± 9.5 years) were enrolled: 64 men (51.2%) and 61 women (48.8%). Adenocarcinoma was by far the most common histological subtype of NSCLC (47.2%). At the initial diagnosis, the vast majority of all the included patients showed either locally advanced disease (34.4%) or metastatic disease (36.8%). Fifty patients were treated with ICIs either as a first-line (20%) or second-line (20%) therapy, while 75 patients did not receive ICIs. The median values ± SD of PT SUV_max, mean, MTV, and TLG were respectively 10.1 ± 6.0, 6.1 ± 3.5, 13.5 ± 30.7, and 71.4 ± 247.7. The median volume of PT ± SD was 13.7 ± 30.7 cm³. The PTs were most frequently solid (86.4%) with irregular margins (76.8%). Furthermore, in one out of five cases, the morphological evidence of lymphangiosis was seen through imaging (n = 25). The median follow-up ± SD was 18.93 ± 6.98 months. The median values ± SD of OS and PFS were, respectively, 14.80 ± 8.68 months and 14.03 ± 9.02 months. Age, PT volume, SUV_max, TLG, the presence of lymphangiosis features through imaging, and clinical stage IV were very strong long-term outcome predictors of patients treated with ICIs, while no significant outcome predictors could be found for the cohort with no ICI treatment. The optimal cut-off values were determined for PT volume (26.94 cm³) and SUVmax (15.05). Finally, 58% of NSCLC patients treated with ICIs had a CB vs. 78.7% of patients in the cohort with no ICI treatment. However, almost all patients treated with ICIs and with disease progression over time died (mortality in the case of disease progression 95% vs. 62.5% in the cohort without ICIs). Conclusion: Baseline FDG-PET/CT could be used to predict a durable response to ICIs in NSCLC patients. Age, clinical stage IV, lymphangiosis features through imaging, PT volume (thus PT MTV due to a previously demonstrated linear correlation), PT SUV_max, and TLG were very strong long-term outcome predictors. Our results highlight the importance of linking clinical data, as much as morphological features, to the metabolic parameters of primary tumors in a multivariate outcome-predicting model using baseline FDG-PET/CT. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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12 pages, 1935 KiB

Open AccessArticle

Obesity Influences the Expression of Key Immunomodulators in Normal Human Breast Tissue, Basal-like Breast Cancer Patients, and Cell Lines

by DeQuarius King, Muhammad G. Khodary, Temesgen Samuel, Clayton Yates and Deepa Bedi

Cancers 2022, 14(22), 5599; https://doi.org/10.3390/cancers14225599 - 15 Nov 2022

Viewed by 1972

Abstract

Among the different components of the breast cancer microenvironment are adipocytes, which are mainly composed of differentiated adipocytes and adipose progenitors. The role of obesity in tumor progression has become a key topic in clinical studies, but the mechanics of this are still [...] Read more.

Among the different components of the breast cancer microenvironment are adipocytes, which are mainly composed of differentiated adipocytes and adipose progenitors. The role of obesity in tumor progression has become a key topic in clinical studies, but the mechanics of this are still misunderstood. There is significant evidence of serum amyloid (SAA1), an acute-phase protein, being heavily expressed in inflamed, septic conditions. VTCN1 and VSIR, members of the immunoglobulin family, are key players in T-cell regulation. The present study investigates the differentially expressed genes caused by adipose-conditioned media on the novel triple-negative breast cancer cell lines MDA MB 231 and MDA MB 468. RNA sequencing of adipocyte-conditioned media (ACM)-treated MDA MB 231 and MDA MB 468 cells were analyzed and compared using the gene sequencing enrichment analysis database (GSEA). GSEA was also done on microarray data from obese, non-tumorous breast tissue patients (GSE:33526) to show significantly upregulated immunomodulators. Obesity was also shown to influence gene expression related to immune sensing and evasion in a dataset analysis of basal-like obese patients (GSE:79858). We showed obesity significantly upregulated immunomodulators related to immune suppression in non-tumorous, basal-like patients, as well as in novel basal-like TNBC cell lines. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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14 pages, 2532 KiB

Open AccessArticle

Next-Generation Antisense Oligonucleotide of TGF-β2 Enhances T Cell-Mediated Anticancer Efficacy of Anti-PD-1 Therapy in a Humanized Mouse Model of Immune-Excluded Melanoma

by Hong Kyu Lee, Cho-Won Kim, Dohee Ahn, Ryeo-Eun Go, Youngdong Choi and Kyung-Chul Choi

Cancers 2022, 14(21), 5220; https://doi.org/10.3390/cancers14215220 - 25 Oct 2022

Cited by 3 | Viewed by 2324

Abstract

Anti-programmed death-1 (PD-1) immunotherapy is one of the most promising therapeutic interventions for treating various tumors, including lung cancer, bladder cancer, and melanoma. However, only a subset of patients responds to anti-PD-1 therapy due to complicated immune regulation in tumors and the evolution [...] Read more.

Anti-programmed death-1 (PD-1) immunotherapy is one of the most promising therapeutic interventions for treating various tumors, including lung cancer, bladder cancer, and melanoma. However, only a subset of patients responds to anti-PD-1 therapy due to complicated immune regulation in tumors and the evolution of resistance. In the current study, we investigate the potential of a novel transforming growth factor-beta2 (TGF-β2) antisense oligonucleotide (ngTASO), as a combination therapy with an anti-PD-1 antibody in melanoma. This study was conducted in a melanoma-bearing human immune system mouse model that recapitulates immune-excluded phenotypes. We observed that the TGF-β2 blockade by ngTASO in combination with PD-1 inhibition downregulated the tumor intrinsic β-catenin, facilitated the infiltration of CD8+ cytotoxic lymphocytes (CTLs) in the tumor, and finally, enhanced the antitumor immune potentials and tumor growth delays. Blockade of TGF-β2 combined with PD-1 inhibition also resulted in downregulating the ratio of regulatory T cells to CTLs in the peripheral blood and tumor, resulting in increased granzyme B expression. In addition, co-treatment of ngTASO and anti-PD-1 augmented the PD-L1 expression in tumors, which is associated with an improved response to anti-PD-1 immunotherapy. These results indicate that the combination of ngTASO and anti-PD-1 exerts an enhanced T cell-mediated antitumor immune potential. Hence, co-inhibition of TGF-β2 and PD-1 is a potentially promising immunotherapeutic strategy for immune-excluded melanoma. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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14 pages, 3021 KiB

Open AccessArticle

Combination of a Novel Fusion Protein CD3εζ28 and Bispecific T Cell Engager Enhances the Persistance and Anti-Cancer Effects of T Cells

by Feng Yu, Yang Gao, Yan Wu, Anran Dai, Xiaoyan Wang, Xiangzhi Zhang, Guodong Liu, Qinggang Xu and Dongfeng Chen

Cancers 2022, 14(19), 4947; https://doi.org/10.3390/cancers14194947 - 9 Oct 2022

Cited by 2 | Viewed by 2290

Abstract

Bi-specific T cell engager (BiTE), an artificial bi-functional fusion protein, has shown promising therapeutic potential in preclinical and clinical studies. However, T cells cannot be sufficiently activated by BiTE, most likely due to lacking co-stimulatory signal. We reasoned that incorporating co-stimulatory signal might [...] Read more.

Bi-specific T cell engager (BiTE), an artificial bi-functional fusion protein, has shown promising therapeutic potential in preclinical and clinical studies. However, T cells cannot be sufficiently activated by BiTE, most likely due to lacking co-stimulatory signal. We reasoned that incorporating co-stimulatory signal might have the potential to enhance the T cell activation mediated by BiTE. We, therefore, designed a chimeric fusion protein, named as CD3εζ28, which consists of the CD3ε extracellular region, the CD28 costimulatory signal and the intracellular region of CD3ζ in tandem. T cells genetically modified to express both CD3εζ28 and GFP (T-CD3εζ28-GFP) were generated by retroviral transduction. The results from in vitro experiments showed that T-CD3εζCD28-GFP cells had superior cytotoxic effects on tumor cells in presence of BiTE compared with control T cells, as evidenced by IL-2 and IFN-γ production, T cell proliferation and sequential killing assay. In vivo, T-CD3εζCD28-GFP cells showed superior anti-tumor effects in Hela-BiTE. EGFRvIII xenograft tumor model, as evaluated by tumor growth rate and T cell persistence in comparison with control T cells. In order to further confirm these findings, we generated T cells modified to express both CD3εζCD28 on cell surface and BiTE.CD19 by autocrine manner (T-CD3εζCD28-BiTE.19). The superior anti-tumor effects of T-CD3εζCD28-BiTE.19 cells could also be evidenced by the similar in vitro and in vivo experiments; thus, incorporating co-stimulatory signal may be an effective approach to improve the effector function of T cells mediated by BiTE. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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19 pages, 2837 KiB

Open AccessArticle

Clinical Performance of the Consensus Immunoscore in Colon Cancer in the Asian Population from the Multicenter International SITC Study

by Bernhard Mlecnik, Toshihiko Torigoe, Gabriela Bindea, Boryana Popivanova, Mingli Xu, Tomonobu Fujita, Shoichi Hazama, Nobuaki Suzuki, Hiroaki Nagano, Kiyotaka Okuno, Yoshihiko Hirohashi, Tomohisa Furuhata, Ichiro Takemasa, Prabhudas Patel, Hemangini Vora, Birva Shah, Jayendrakumar B. Patel, Kruti N. Rajvik, Shashank J. Pandya, Shilin N. Shukla, Yili Wang, Guanjun Zhang, Takayuki Yoshino, Hiroya Taniguchi, Carlo Bifulco, Alessandro Lugli, Jiun-Kae Jack Lee, Inti Zlobec, Tilman T. Rau, Martin D. Berger, Iris D. Nagtegaal, Elisa Vink-Börger, Arndt Hartmann, Carol I. Geppert, Julie Kolwelter, Susanne Merkel, Robert Grützmann, Marc Van den Eynde, Anne Jouret-Mourin, Alex Kartheuser, Daniel Léonard, Christophe Remue, Julia Wang, Prashant Bavi, Michael H. A. Roehrl, Pamela S. Ohashi, Linh T. Nguyen, SeongJun Han, Heather L. MacGregor, Sara Hafezi-Bakhtiari, Bradly G. Wouters, Giuseppe V. Masucci, Emilia Andersson, Eva Zavadova, Michal Vocka, Jan Spacek, Lubos Petruzelka, Bohuslav Konopasek, Pavel Dundr, Helena Skalova, Kristyna Nemejcova, Gerardo Botti, Fabiana Tatangelo, Paolo Delrio, Gennaro Ciliberto, Michele Maio, Luigi Laghi, Fabio Grizzi, Florence Marliot, Tessa Fredriksen, Bénédicte Buttard, Lucie Lafontaine, Pauline Maby, Amine Majdi, Assia Hijazi, Carine El Sissy, Amos Kirilovsky, Anne Berger, Christine Lagorce, Christopher Paustian, Carmen Ballesteros-Merino, Jeroen Dijkstra, Carlijn Van de Water, Shannon van Lent-van Vliet, Nikki Knijn, Ana-Maria Mușină, Dragos-Viorel Scripcariu, Francesco M. Marincola, Paolo A. Ascierto, Bernard A. Fox, Franck Pagès, Yutaka Kawakami and Jérôme Galon Show full author list Hide full author list

Cancers 2022, 14(18), 4346; https://doi.org/10.3390/cancers14184346 - 6 Sep 2022

Cited by 7 | Viewed by 3636

Abstract

BACKGROUND: In this study, we evaluated the prognostic value of Immunoscore in patients with stage I–III colon cancer (CC) in the Asian population. These patients were originally included in an international study led by the Society for Immunotherapy of Cancer (SITC) on 2681 [...] Read more.

BACKGROUND: In this study, we evaluated the prognostic value of Immunoscore in patients with stage I–III colon cancer (CC) in the Asian population. These patients were originally included in an international study led by the Society for Immunotherapy of Cancer (SITC) on 2681 patients with AJCC/UICC-TNM stages I–III CC. METHODS: CD3+ and cytotoxic CD8+ T-lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The association of Immunoscore with prognosis was evaluated for time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS). RESULTS: Immunoscore stratified Asian patients (n = 423) into different risk categories and was not impacted by age. Recurrence-free rates at 3 years were 78.5%, 85.2%, and 98.3% for a Low, Intermediate, and High Immunoscore, respectively (HR[Low-vs-High] = 7.26 (95% CI 1.75−30.19); p = 0.0064). A High Immunoscore showed a significant association with prolonged TTR, OS, and DFS (p < 0.05). In Cox multivariable analysis stratified by center, Immunoscore association with TTR was independent (HR[Low-vs-Int+High] = 2.22 (95% CI 1.10–4.55) p = 0.0269) of the patient’s gender, T-stage, N-stage, sidedness, and MSI status. A significant association of a High Immunoscore with prolonged TTR was also found among MSS (HR[Low-vs-Int+High] = 4.58 (95% CI 2.27−9.23); p ≤ 0.0001), stage II (HR[Low-vs-Int+High] = 2.72 (95% CI 1.35−5.51); p = 0.0052), low-risk stage-II (HR[Low-vs-Int+High] = 2.62 (95% CI 1.21−5.68); p = 0.0146), and high-risk stage II patients (HR[Low-vs-Int+High] = 3.11 (95% CI 1.39−6.91); p = 0.0055). CONCLUSION: A High Immunoscore is significantly associated with the prolonged survival of CC patients within the Asian population. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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21 pages, 2617 KiB

Open AccessArticle

Store-Operated Ca²⁺ Entry Is Up-Regulated in Tumour-Infiltrating Lymphocytes from Metastatic Colorectal Cancer Patients

by Pawan Faris, Agnese Rumolo, Laura Tapella, Matteo Tanzi, Alessia Metallo, Filippo Conca, Sharon Negri, Konstantinos Lefkimmiatis, Paolo Pedrazzoli, Dmitry Lim, Daniela Montagna and Francesco Moccia

Cancers 2022, 14(14), 3312; https://doi.org/10.3390/cancers14143312 - 7 Jul 2022

Cited by 6 | Viewed by 2463

Abstract

(1) Background: Store-operated Ca²⁺ entry (SOCE) drives the cytotoxic activity of cytotoxic T lymphocytes (CTLs) against cancer cells. However, SOCE can be enhanced in cancer cells due to an increase in the expression and/or function of its underlying molecular components, i.e., STIM1 [...] Read more.

(1) Background: Store-operated Ca²⁺ entry (SOCE) drives the cytotoxic activity of cytotoxic T lymphocytes (CTLs) against cancer cells. However, SOCE can be enhanced in cancer cells due to an increase in the expression and/or function of its underlying molecular components, i.e., STIM1 and Orai1. Herein, we evaluated the SOCE expression and function in tumour-infiltrating lymphocytes (TILs) from metastatic colorectal cancer (mCRC) patients. (2) Methods: Functional studies were conducted in TILs expanded ex vivo from CRC liver metastases. Peripheral blood T cells from healthy donors (hPBTs) and mCRC patients (cPBTs) were used as controls. (3) Results: SOCE amplitude is enhanced in TILs compared to hPBTs and cPBTs, but the STIM1 protein is only up-regulated in TILs. Pharmacological manipulation showed that the increase in SOCE mainly depends on tonic modulation by diacylglycerol kinase, which prevents the protein kinase C-dependent inhibition of SOCE activity. The larger SOCE caused a stronger Ca²⁺ response to T-cell receptor stimulation by autologous mCRC cells. Reducing Ca²⁺ influx with BTP-2 during target cell killing significantly increases cytotoxic activity at low target:effector ratios. (4) Conclusions: SOCE is enhanced in ex vivo-expanded TILs deriving from mCRC patients but decreasing Ca²⁺ influx with BTP-2 increases cytotoxic activity at a low TIL density. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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8 pages, 769 KiB

Open AccessArticle

Exploring Real World Outcomes with Nivolumab Plus Ipilimumab in Patients with Metastatic Extra-Pulmonary Neuroendocrine Carcinoma (EP-NEC)

by Amr Mohamed, Namrata Vijayvergia, Matthew Kurian, Lisa Liu, Pingfu Fu and Satya Das

Cancers 2022, 14(11), 2695; https://doi.org/10.3390/cancers14112695 - 30 May 2022

Cited by 6 | Viewed by 3467

Abstract

Background: Dual utilization of the immune checkpoint inhibitors (ICPIs) nivolumab plus ipilimumab has demonstrated clinical promise in the treatment of patients with refractory high-grade neuroendocrine neo-plasms (NENs) in phase II clinical trials (DART SWOG 1609 and CA209), while single agent ICPIs have [...] Read more.

Background: Dual utilization of the immune checkpoint inhibitors (ICPIs) nivolumab plus ipilimumab has demonstrated clinical promise in the treatment of patients with refractory high-grade neuroendocrine neo-plasms (NENs) in phase II clinical trials (DART SWOG 1609 and CA209), while single agent ICPIs have largely been ineffective for these types of tumors. While both trials demonstrated promising results in high grade NENs, there was no adequate description of the association between tumor differentiation (high-grade well-differentiated neuroendocrine tumor vs poorly-differentiated extra-pulmonary neuroendocrine carcinoma (EP-NEC) and ICPI outcomes in the DART SWOG 1609 trial. Our study reports on the effectiveness and toxicity profile of dual ICPIs in a real world second-line EP-NEC patient population. Methods: Data on metastatic EP-NEC patients, treated with either ICPIs (single and dual ICPIs) or chemo-therapy in the second-line setting, were retrieved from databases of three comprehensive cancer centers. Associations between treatment characteristics and outcomes, including progression-free survival (PFS) and overall survival (OS), were evaluated. Results: From 2007 to 2020, we identified 70 patients with metastatic EP-NEC (predominantly of gastro-enteropancreatic origin), of whom 42 patients (23 males, 19 females, median age 62 years old) were eligible for the final analysis. All patients were refractory to platinum etoposide doublet chemotherapy in the first-line setting. The median PFS for patients who received dual ICPIs (11 patients), single agent ICPI (8 patients), and cytotoxic chemotherapy (23 patients) was 258 days, 56.5 days, and 47 days, respectively (p = 0.0001). Median overall survival (OS) for those groups was not reached (NR), 18.7 months, and 10.5 months, respectively (p = 0.004). There were no significant differences in treatment outcomes in patients according to tumor mismatch repair (MMR) or tumor mutational burden (TMB) status. Grade 3–4 adverse events (AEs) were reported in 11.1% of the patients who received dual ICPIs; however, none of these AEs led to permanent treatment discontinuation. Conclusions: In the second-line setting, patients with EP-NECs treated with dual ICPIs (nivolumab plus ipilimumab) experienced improved PFS and OS compared to patients treated with single agent ICPI or cytotoxic chemotherapy. These results echo some of the current evidence for ICPIs in grade 3 NENs and need to be validated in future prospective studies. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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12 pages, 1972 KiB

Open AccessArticle

In Silico Designed Gain-of-Function Variants of Complement C2 Support Cytocidal Activity of Anticancer Monoclonal Antibodies

by Aleksandra Urban, Alan Majeranowski, Grzegorz Stasiłojć, Patrycja Koszałka, Anna Felberg, Michał Taszner, Jan M. Zaucha and Marcin Okrój

Cancers 2022, 14(5), 1270; https://doi.org/10.3390/cancers14051270 - 1 Mar 2022

Cited by 6 | Viewed by 2553

Abstract

The molecular target for the classical complement pathway (CP) is defined by surface-bound immunoglobulins. Therefore, numerous anticancer monoclonal antibodies (mAbs) exploit the CP as their effector mechanism. Conversely, the alternative complement pathway (AP) is spontaneously induced on the host and microbial surfaces, but [...] Read more.

The molecular target for the classical complement pathway (CP) is defined by surface-bound immunoglobulins. Therefore, numerous anticancer monoclonal antibodies (mAbs) exploit the CP as their effector mechanism. Conversely, the alternative complement pathway (AP) is spontaneously induced on the host and microbial surfaces, but complement inhibitors on host cells prevent its downstream processing. Gain-of-function (GoF) mutations in the AP components that oppose physiological regulation directly predispose carriers to autoimmune/inflammatory diseases. Based on the homology between AP and CP components, we modified the CP component C2 so that it emulates the known pathogenic mutations in the AP component, factor B. By using tumor cell lines and patient-derived leukemic cells along with a set of clinically approved immunotherapeutics, we showed that the supplementation of serum with recombinant GoF C2 variants not only enhances the cytocidal effect of type I anti-CD20 mAbs rituximab and ofatumumab, but also lowers the threshold of mAbs necessary for the efficient lysis of tumor cells and efficiently exploits the leftovers of the drug accumulated in patients’ sera after the previous infusion. Moreover, we demonstrate that GoF C2 acts in concert with other therapeutic mAbs, such as type II anti-CD20, anti-CD22, and anti-CD38 specimens, for overcoming cancer cells resistance to complement attack. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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16 pages, 3407 KiB

Open AccessArticle

HER2/neu-Based Peptide Vaccination-Pulsed with B-Cell Epitope Induced Efficient Prophylactic and Therapeutic Antitumor Activities in TUBO Breast Cancer Mice Model

by Muhammad Luqman Nordin, Abdin Shakirin Mohamad Norpi, Pei Yuen Ng, Khatijah Yusoff, Nadiah Abu, Kue Peng Lim and Fazren Azmi

Cancers 2021, 13(19), 4958; https://doi.org/10.3390/cancers13194958 - 1 Oct 2021

Cited by 13 | Viewed by 3629

Abstract

Breast cancer is the most common invasive cancer diagnosed among women. A cancer vaccine has been recognized as a form of immunotherapy with a prominent position in the prevention and treatment of breast cancer. The majority of current breast cancer vaccination strategies aim [...] Read more.

Breast cancer is the most common invasive cancer diagnosed among women. A cancer vaccine has been recognized as a form of immunotherapy with a prominent position in the prevention and treatment of breast cancer. The majority of current breast cancer vaccination strategies aim to stimulate antitumor T-cell responses of the HER2/neu oncogene, which is abnormally expressed in breast cancer cells. However, the role of the B-cell humoral response is often underappreciated in the cancer vaccine design. We have advanced this idea by elucidating the role of B-cells in cancer vaccination by designing a chimeric antigenic peptide possessing both cytotoxic T lymphocytes (GP2) and B-cell (P4) peptide epitopes derived from HER2/neu. The chimeric peptide (GP2–P4) was further conjugated to a carrier protein (KLH), forming a KLH–GP2–P4 conjugate. The immunogenicity of KLH–GP2–P4 was compared with KLH–GP2 (lacking the B-cell epitope) in BALB/c mice. Mice immunized with KLH–GP2–P4 elicited more potent antigen-specific neutralizing antibodies against syngeneic TUBO cells (cancer cell line overexpressing HER2/neu) that was governed by a balanced Th1/Th2 polarization in comparison to KLH–GP2. Subsequently, these immune responses led to greater inhibition of tumor growth and longer survival in TUBO tumor-bearing mice in both prophylactic and therapeutic challenge experiments. Overall, our data demonstrated that the B-cell epitope has a profound effect in orchestrating an efficacious antitumor immunity. Thus, a multi-epitope peptide vaccine encompassing cytotoxic T-lymphocytes, T-helper and B-cell epitopes represents a promising strategy in developing cancer vaccines with a preventive and therapeutic modality for the effective management of breast cancer. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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33 pages, 15019 KiB

Open AccessArticle

Pan-Cancer Analysis of Prognostic and Immune Infiltrates for CXCs

by Long Li, Wenchao Yao, Sen Yan, Xianghui Dong, Zhenyi Lv, Qingxu Jing, Qiang Wang, Biao Ma, Chenjun Hao, Dongbo Xue and Dawei Wang

Cancers 2021, 13(16), 4153; https://doi.org/10.3390/cancers13164153 - 18 Aug 2021

Cited by 12 | Viewed by 3780

Abstract

Background: CXCs are important genes that regulate inflammation and tumor metastasis. However, the expression level, prognosis value, and immune infiltration of CXCs in cancers are not clear. Methods: Multiple online datasets were used to analyze the expression, prognosis, and immune regulation of CXCs [...] Read more.

Background: CXCs are important genes that regulate inflammation and tumor metastasis. However, the expression level, prognosis value, and immune infiltration of CXCs in cancers are not clear. Methods: Multiple online datasets were used to analyze the expression, prognosis, and immune regulation of CXCs in this study. Network analysis of the Amadis database and GEO dataset was used to analyze the regulation of intestinal flora on the expression of CXCs. A mouse model was used to verify the fact that intestinal bacterial dysregulation can affect the expression of CXCs. Results: In the three cancers, multiple datasets verified the fact that the mRNA expression of this family was significantly different; the mRNA levels of CXCL3, 8, 9, 10, 14, and 17 were significantly correlated with the prognosis of three cancers. CXCs were correlated with six types of immuno-infiltrating cells in three cancers. Immunohistochemistry of clinical samples confirmed that the expression of CXCL8 and 10 was higher in three cancer tissues. Animal experiments have shown that intestinal flora dysregulation can affect CXCL8 and 10 expressions. Conclusion: Our results further elucidate the function of CXCs in cancers and provide new insights into the prognosis and immune infiltration of breast, colon, and pancreatic cancers, and they suggest that intestinal flora may influence disease progression through CXCs. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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17 pages, 3832 KiB

Open AccessArticle

Rapid Response to the Combination of Lenvatinib and Pembrolizumab in Patients with Advanced Carcinomas (Lung Adenocarcinoma and Malignant Pleural Mesothelioma)

by Walid Shalata, Muhammed Iraqi, Baisali Bhattacharya, Vered Fuchs, Laila C. Roisman, Ahron Yehonatan Cohen, Ismaell Massalha, Alexander Yakobson, Manu Prasad, Moshe Elkabets, Angel Porgador and Nir Peled

Cancers 2021, 13(14), 3630; https://doi.org/10.3390/cancers13143630 - 20 Jul 2021

Cited by 11 | Viewed by 4324

Abstract

The new era of cancer treatments has made immune checkpoint inhibitors (ICIs) and emerging multikinase inhibitors (TKIs) the standards of care, thus drastically improving patient prognoses. Pembrolizumab is an anti-programmed cell death-1 antibody drug, and lenvatinib is a TKI with preferential antiangiogenic activity. [...] Read more.

The new era of cancer treatments has made immune checkpoint inhibitors (ICIs) and emerging multikinase inhibitors (TKIs) the standards of care, thus drastically improving patient prognoses. Pembrolizumab is an anti-programmed cell death-1 antibody drug, and lenvatinib is a TKI with preferential antiangiogenic activity. We present, to our knowledge, the first reported series of cases consisting of patients with metastatic non–small cell lung cancer and malignant pleural mesothelioma who were treated with several types of chemotherapy combinations and ICIs followed by disease progression. They were subsequently treated with combined immunotherapy and TKI treatment, resulting in a near complete response within a very short time. Clinical responses were supported by in vitro testing of each patient’s lymphocytic response to pembrolizumab after pre-exposure of target cancer cells to lenvatinib. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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Review

Jump to: Research, Other

18 pages, 523 KiB

Open AccessReview

Double Guard Efficiency and Safety—Overcoming Resistance to Immunotherapy by Blocking or Stimulating Several Immune Checkpoints in Non-Small Cell Lung Cancer Patients

by Ewa Kalinka, Kamila Wojas-Krawczyk and Paweł Krawczyk

Cancers 2023, 15(13), 3499; https://doi.org/10.3390/cancers15133499 - 5 Jul 2023

Cited by 3 | Viewed by 2597

Abstract

Immunotherapy is one of the leading systemic therapies in non-small cell cancer (NSCLC) patients, but it is not effective in an important proportion of them due to primary or secondary resistance mechanisms. Clinicians do not have the tools to predict immunotherapy resistance, and [...] Read more.

Immunotherapy is one of the leading systemic therapies in non-small cell cancer (NSCLC) patients, but it is not effective in an important proportion of them due to primary or secondary resistance mechanisms. Clinicians do not have the tools to predict immunotherapy resistance, and thus, many patients still fail initial treatment. One of the scientific concepts to avoid resistance and/or offer the patient effective salvage second-line treatment is the dual immunologic checkpoint blockade. We aimed to review published and available data on combination immunotherapy in terms of mechanisms, efficacy, and safety data on many different dual blockades. We discussed the potential of combined CTLA-4 (Cytotoxic T Lymphocyte Antigen 4), PD-1 (Programmed Death 1) or PD-L1, TIGIT, LAG-3, TIM-3, macrophage leukocyte immunoglobulin-like receptor B2 (LILRB2/ILT4), S15-mediated immune suppression (SIGLEC-15), CD137, ICOS, and OX40 inhibitors in NSCLC treatment. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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15 pages, 1002 KiB

Open AccessReview

Chemo-Immunotherapy: A New Trend in Cancer Treatment

by Christian Sordo-Bahamonde, Seila Lorenzo-Herrero, Ana P. Gonzalez-Rodriguez, Alejandra Martínez-Pérez, Juan P. Rodrigo, Juana M. García-Pedrero and Segundo Gonzalez

Cancers 2023, 15(11), 2912; https://doi.org/10.3390/cancers15112912 - 25 May 2023

Cited by 41 | Viewed by 7642

Abstract

Chemotherapy has been the basis of advanced cancer treatment for decades. This therapy has largely been considered immunosuppressive, yet accumulated preclinical and clinical evidence shows that certain chemotherapeutic drugs, under defined conditions, may stimulate antitumor immunity and potentiate immune checkpoint inhibitor (ICI)-based therapy. [...] Read more.

Chemotherapy has been the basis of advanced cancer treatment for decades. This therapy has largely been considered immunosuppressive, yet accumulated preclinical and clinical evidence shows that certain chemotherapeutic drugs, under defined conditions, may stimulate antitumor immunity and potentiate immune checkpoint inhibitor (ICI)-based therapy. Its effectiveness has been highlighted by recent regulatory approvals of various combinations of chemotherapy with ICIs in several tumors, particularly in some difficult-to-treat cancers. This review discusses the immune modulatory properties of chemotherapy and how they may be harnessed to develop novel chemo-immunotherapy combinations. It also highlights the key determinants of the success of chemo-immunotherapy and provides an overview of the combined chemo-immunotherapies that have been clinically approved. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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20 pages, 711 KiB

Open AccessReview

Immune Checkpoint Inhibitors Combined with Targeted Therapy: The Recent Advances and Future Potentials

by Bin Li, Juan Jin, Duancheng Guo, Zhonghua Tao and Xichun Hu

Cancers 2023, 15(10), 2858; https://doi.org/10.3390/cancers15102858 - 22 May 2023

Cited by 34 | Viewed by 6803

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of cancer and have been widely approved for use in the treatment of diverse solid tumors. Targeted therapy has been an essential part of cancer treatment for decades, and in most cases, a special [...] Read more.

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of cancer and have been widely approved for use in the treatment of diverse solid tumors. Targeted therapy has been an essential part of cancer treatment for decades, and in most cases, a special drug target is required. Numerous studies have confirmed the synergistic effect of combining ICIs with targeted therapy. For example, triple therapy of PD-L1 inhibitor atezolizumab plus BRAF inhibitor vemurafenib and MEK inhibitor cobimetinib has been approved as the first-line treatment in advanced melanoma patients with BRAF^V600 mutations. However, not all combinations of ICIs and targeted therapy work. Combining ICIs with EGFR inhibitors in non-small-cell lung cancer (NSCLC) with EGFR mutations only triggered toxicities and did not improve efficacy. Therefore, the efficacies of combinations of ICIs and different targeted agents are distinct. This review firstly and comprehensively covered the current status of studies on the combination of ICIs mainly referring to PD-1 and PD-L1 inhibitors and targeted drugs, including angiogenesis inhibitors, EGFR/HER2 inhibitors, PARP inhibitors and MAPK/ERK signaling pathway inhibitors, in the treatment of solid tumors. We discussed the underlying mechanisms, clinical efficacies, side effects, and potential predictive biomarkers to give an integrated view of the combination strategy and provide perspectives for future directions in solid tumors. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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23 pages, 356 KiB

Open AccessReview

The Role of Immunotherapy or Immuno-Chemotherapy in Non-Small Cell Lung Cancer: A Comprehensive Review

by Shehab Mohamed, Luca Bertolaccini, Domenico Galetta, Francesco Petrella, Monica Casiraghi, Filippo de Marinis and Lorenzo Spaggiari

Cancers 2023, 15(9), 2476; https://doi.org/10.3390/cancers15092476 - 26 Apr 2023

Cited by 3 | Viewed by 1998

Abstract

Many new treatment modalities for non-small-cell carcinoma (NSCLC) have been described in the last two decades. Surgical resections remain the gold standard for early stages and may be considered for locally advanced tumors. Medical treatment has changed drastically in recent years, especially for [...] Read more.

Many new treatment modalities for non-small-cell carcinoma (NSCLC) have been described in the last two decades. Surgical resections remain the gold standard for early stages and may be considered for locally advanced tumors. Medical treatment has changed drastically in recent years, especially for advanced stages, for which the development of immunotherapy and molecular targeted therapy significantly increased survival and quality of life. The addition of radical surgical resection following immunotherapy or immuno-chemotherapy is feasible and safe with low surgical-related mortality and morbidity in selected patients with initially unresectable NSCLC. However, data from multiple ongoing trials with overall survival as the primary endpoint should be awaited before this strategy is introduced into the standard of care. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

20 pages, 1754 KiB

Open AccessReview

CAR-T: What Is Next?

by Yi-Ju Chen, Bams Abila and Yasser Mostafa Kamel

Cancers 2023, 15(3), 663; https://doi.org/10.3390/cancers15030663 - 21 Jan 2023

Cited by 93 | Viewed by 12164

Abstract

The year 2017 was marked by the Food and Drug Administration (FDA) approval of the first two chimeric antigen receptor-T (CAR-T) therapies. The approved indications were for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and for the treatment of [...] Read more.

The year 2017 was marked by the Food and Drug Administration (FDA) approval of the first two chimeric antigen receptor-T (CAR-T) therapies. The approved indications were for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and for the treatment of patients up to 25 years of age with acute lymphoblastic leukemia (ALL) that is refractory or in a second or later relapse. Since then, extensive research activities have been ongoing globally on different hematologic and solid tumors to assess the safety and efficacy of CAR-T therapy for these diseases. Limitations to CAR-T therapy became apparent from, e.g., the relapse in up to 60% of patients and certain side effects such as cytokine release syndrome (CRS). This led to extensive clinical activities aimed at overcoming these obstacles, so that the use of CAR-T therapy can be expanded. Attempts to improve on efficacy and safety include changing the CAR-T administration schedule, combining it with chemotherapy, and the development of next-generation CAR-T therapies, e.g., through the use of CAR-natural killer (CAR-NK) and CAR macrophages (CAR-Ms). This review will focus on new CAR-T treatment strategies in hematologic malignancies, clinical trials aimed at improving efficacy and addressing side effects, the challenges that CAR-T therapy faces in solid tumors, and the ongoing research aimed at overcoming these challenges. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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20 pages, 1353 KiB

Open AccessReview

Immunotherapy: Review of the Existing Evidence and Challenges in Breast Cancer

by Yun Hu, Yan Li, Zhangcheng Yao, Fenglin Huang, Hongzhou Cai, Hanyuan Liu, Xiaoyi Zhang and Junying Zhang

Cancers 2023, 15(3), 563; https://doi.org/10.3390/cancers15030563 - 17 Jan 2023

Cited by 4 | Viewed by 2541

Abstract

Breast cancer (BC) is a representative malignant tumor that affects women across the world, and it is the main cause of cancer-related deaths in women. Although a large number of treatment methods have been developed for BC in recent years, the results are [...] Read more.

Breast cancer (BC) is a representative malignant tumor that affects women across the world, and it is the main cause of cancer-related deaths in women. Although a large number of treatment methods have been developed for BC in recent years, the results are sometimes unsatisfying. In recent years, treatments of BC have been expanded with immunotherapy. In our article, we list some tumor markers related to immunotherapy for BC. Moreover, we introduce the existing relatively mature immunotherapy and the markers’ pathogenesis are involved. The combination of immunotherapy and other therapies for BC are introduced in detail, including the combination of immunotherapy and chemotherapy, the combined use of immunosuppressants and chemotherapy drugs, immunotherapy and molecular targeted therapy. We summarize the clinical effects of these methods. In addition, this paper also makes a preliminary exploration of the combination of immunotherapy, radiotherapy, and nanotechnology for BC. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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21 pages, 1234 KiB

Open AccessReview

Tumor Infiltrating Lymphocyte (TIL) Therapy for Solid Tumor Treatment: Progressions and Challenges

by Yueshui Zhao, Jian Deng, Shuangfeng Rao, Sipeng Guo, Jing Shen, Fukuan Du, Xu Wu, Yu Chen, Mingxing Li, Meijuan Chen, Xiaobing Li, Wanping Li, Li Gu, Yuhong Sun, Zhuo Zhang, Qinglian Wen, Zhangang Xiao and Jing Li

Cancers 2022, 14(17), 4160; https://doi.org/10.3390/cancers14174160 - 27 Aug 2022

Cited by 59 | Viewed by 10787

Abstract

Over the past decade, immunotherapy, especially cell-based immunotherapy, has provided new strategies for cancer therapy. Recent clinical studies demonstrated that adopting cell transfer of tumor-infiltrating lymphocytes (TILs) for advanced solid tumors showed good efficacy. TIL therapy is a type of cell-based immunotherapy using [...] Read more.

Over the past decade, immunotherapy, especially cell-based immunotherapy, has provided new strategies for cancer therapy. Recent clinical studies demonstrated that adopting cell transfer of tumor-infiltrating lymphocytes (TILs) for advanced solid tumors showed good efficacy. TIL therapy is a type of cell-based immunotherapy using the patient’s own immune cells from the microenvironment of the solid tumor to kill tumor cells. In this review, we provide a comprehensive summary of the current strategies and challenges in TIL isolation and generation. Moreover, the current clinical experience of TIL therapy is summarized and discussed, with an emphasis on lymphodepletion regimen, the use of interleukin-2, and related toxicity. Furthermore, we highlight the clinical trials where TIL therapy is used independently and in combination with other types of therapy for solid cancers. Finally, the limitations, future potential, and directions of TIL therapy for solid tumor treatment are also discussed. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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23 pages, 18438 KiB

Open AccessReview

Mitochondrial DNA on Tumor-Associated Macrophages Polarization and Immunity

by Yaxin Guo, Hsiang-i Tsai, Lirong Zhang and Haitao Zhu

Cancers 2022, 14(6), 1452; https://doi.org/10.3390/cancers14061452 - 11 Mar 2022

Cited by 11 | Viewed by 5378

Abstract

As the richest immune cells in most tumor microenvironments (TMEs), tumor-associated macrophages (TAMs) play an important role in tumor development and treatment sensitivity. The phenotypes and functions of TAMs vary according to their sources and tumor progression. Different TAM phenotypes display distinct behaviors [...] Read more.

As the richest immune cells in most tumor microenvironments (TMEs), tumor-associated macrophages (TAMs) play an important role in tumor development and treatment sensitivity. The phenotypes and functions of TAMs vary according to their sources and tumor progression. Different TAM phenotypes display distinct behaviors in terms of tumor immunity and are regulated by intracellular and exogenous molecules. Additionally, dysfunctional and oxidatively stressed mitochondrial-derived mitochondrial DNA (mtDNA) plays an important role in remodeling the phenotypes and functions of TAMs. This article reviews the interactions between mtDNA and TAMs in the TME and further discusses the influence of their performance on tumor genesis and development. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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14 pages, 630 KiB

Open AccessReview

Safety of Immune Checkpoint Inhibitor Resumption after Interruption for Immune-Related Adverse Events, a Narrative Review

by Marion Allouchery, Clément Beuvon, Marie-Christine Pérault-Pochat, Pascal Roblot, Mathieu Puyade and Mickaël Martin

Cancers 2022, 14(4), 955; https://doi.org/10.3390/cancers14040955 - 14 Feb 2022

Cited by 14 | Viewed by 2766

Abstract

Immune checkpoint inhibitors (ICIs) have become the standard of care for several types of cancer due to their superiority in terms of survival benefits in first- and second-line treatments compared to conventional therapies, and they present a better safety profile (lower absolute number [...] Read more.

Immune checkpoint inhibitors (ICIs) have become the standard of care for several types of cancer due to their superiority in terms of survival benefits in first- and second-line treatments compared to conventional therapies, and they present a better safety profile (lower absolute number of grade 1–5 adverse events), especially if used in monotherapy. However, the pattern of ICI-related adverse events is totally different, as they are characterized by the development of specific immune-related adverse events (irAEs) that are unique in terms of the organs involved, onset patterns, and severity. The decision to resume ICI treatment after its interruption due to irAEs is challenged by the need for tumor control versus the risk of occurrence of the same or different irAEs. Studies that specifically assess this point remain scarce, heterogenous and mostly based on small samples of patients or focused only on the recurrence rate of the same irAE after ICI resumption. Moreover, patients with grade ≥3 irAEs were excluded from many of these studies. Herein, we provide a narrative review on the field of safety of ICI resumption after interruption due to irAE(s). Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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15 pages, 2349 KiB

Open AccessReview

Changing the Treatment Paradigm for Hepatocellular Carcinoma Using Atezolizumab plus Bevacizumab Combination Therapy

by Masatoshi Kudo

Cancers 2021, 13(21), 5475; https://doi.org/10.3390/cancers13215475 - 30 Oct 2021

Cited by 17 | Viewed by 4887

Abstract

Atezolizumab plus bevacizumab combination therapy was approved worldwide for use in 2020. A 30% objective response rate with 8% complete response (CR) was achieved in a phase 3 IMbrave150 trial. Here, the change in the treatment strategy for hepatocellular carcinoma (HCC) using atezolizumab [...] Read more.

Atezolizumab plus bevacizumab combination therapy was approved worldwide for use in 2020. A 30% objective response rate with 8% complete response (CR) was achieved in a phase 3 IMbrave150 trial. Here, the change in the treatment strategy for hepatocellular carcinoma (HCC) using atezolizumab plus bevacizumab combination therapy is reviewed. The phase 3 IMbrave150 clinical trial was successful because of the direct antitumor effect of bevacizumab, which shifted the suppressive immune microenvironment to a responsive immune microenvironment, in addition to its synergistic effects when combined with atezolizumab. The analysis of CR cases was effective in patients with poor conditions, particularly tumor invasion in the main portal trunk (Vp4), making the combination therapy a breakthrough for HCC treatment. The response rate of the combination therapy was 44% against intermediate-stage HCC. Such a strong tumor-reduction effect paves the way for curative conversion (ABC conversion) therapy and, therefore, treatment strategies for intermediate-stage HCC may undergo a significant shift in the future. As these treatment strategies are effective in maintaining liver function, even in elderly patients, the transition frequency to second-line treatments could also be improved. These strategies may be effective against nonalcoholic steatohepatitis-related hepatocellular carcinoma and WNT/β-catenin mutations to a certain degree. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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Other

Jump to: Research, Review

25 pages, 7510 KiB

Open AccessSystematic Review

by Wen Lei, Mixue Xie, Qi Jiang, Nengwen Xu, Ping Li, Aibin Liang, Ken H. Young and Wenbin Qian

Cancers 2021, 13(15), 3912; https://doi.org/10.3390/cancers13153912 - 3 Aug 2021

Cited by 31 | Viewed by 5437

Abstract

Chimeric antigen receptors T (CAR-T) cell therapy of cancer is a rapidly evolving field. It has been shown to be remarkably effective in cases of hematological malignancies, and its approval by the FDA has significantly increased the enthusiasm for wide clinical usage and [...] Read more.

Chimeric antigen receptors T (CAR-T) cell therapy of cancer is a rapidly evolving field. It has been shown to be remarkably effective in cases of hematological malignancies, and its approval by the FDA has significantly increased the enthusiasm for wide clinical usage and development of novel CAR-T therapies. However, it has also challenged physicians and investigators to recognize and deal with treatment-associated toxicities. A total of 2592 patients were included from 84 eligible studies that were systematically searched and reviewed from the databases of PubMed, de, the American Society of Hematology and the Cochrane Library. The meta-analysis and subgroup analysis by a Bayesian logistic regression model were used to evaluate the incidences of therapy-related toxicities such as cytokine release syndrome (CRS) and neurological symptoms (NS), and the differences between different targets and cancer types were analyzed. The pooled all-grade CRS rate and grade ≥ 3 CRS rate was 77% and 29%, respectively, with a significantly higher incidence in the hematologic malignancies (all-grade: 81%; grade ≥ 3: 29%) than in solid tumors (all-grade: 37%; grade ≥ 3: 19%). The pooled estimate NS rate from the individual studies were 40% for all-grade and 28% for grade ≥ 3. It was also higher in the hematologic subgroup than in the solid tumors group. The subgroup analysis by cancer type showed that higher incidences of grade ≥ 3 CRS were observed in anti-CD19 CAR-T therapy for ALL and NHL, anti-BCMA CAR-T for MM, and anti-CEA CAR-T for solid tumors, which were between 24–36%, while higher incidences of grade ≥ 3 NS were mainly observed in CD19-ALL/NHL (23–37%) and BCMA-MM (12%). Importantly, subgroup analysis on anti-CD19 CAR-T studies showed that young patients (vs. adult patients), allologous T cell origin (vs. autologous origin), gamma retrovirus vector, and higher doses of CAR-T cells were associated with high-grade CRS. On the other hand, the patients with NHL (vs ALL), administered with higher dose of CAR-T, and adult patients (vs. young patients) had an increased incidence of grade ≥ 3 NS events. This study offers a comprehensive summary of treatment-related toxicity and will guide future clinical trials and therapeutic designs investigating CAR T cell therapy. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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