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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (28 February 2025) | Viewed by 19360

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Dr. Ivaylo B. Mihaylov

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Department of Radiation Oncology, Miller School of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
Interests: radiotherapy; radiation therapy; cancer detection; radiation oncology
Special Issues, Collections and Topics in MDPI journals

Dr. Benjamin Spieler

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Guest Editor

Department of Radiation Oncology, Miller School of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
Interests: radiotherapy; radiation therapy; radiation oncology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The goal of this Special Issue is to publish innovative research related to immunotherapy combined with radiotherapy for cancer treatment. The inclusion of additional treatment modalities, such as chemotherapy, targeted therapy, hyperthermia, etc., is also of interest. The Special Issue is open to both clinical and preclinical studies, and to different disease sites and cancer types. The clinical studies should also encompass a preclinical component in order to be considered. The clinical component of interest is the impact of therapeutics on meaningful endpoints such as progression-free and overall survival. In the preclinical setting, improving the synergy of combination therapeutics through the optimization of sequencing, dosing, timing, and fractionation is of particular interest. Both mechanistic and phenomenological studies will be considered. Submissions may be related either to tumor control/response or to normal tissue side effects resulting from treatment. Predictive modeling intended to support clinical decision-making and pertinent to disease response or normal tissue complications is an additional area of interest.

Dr. Ivaylo B. Mihaylov
Dr. Benjamin Spieler
Guest Editors

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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. Biomedicines is an international peer-reviewed open access monthly 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 2600 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

radiotherapy
immunotherapy
outcome
toxicity
normal tissue
abscopal
tumor
systemic
local
response

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Published Papers (10 papers)

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16 pages, 1254 KiB

Open AccessArticle

Prognostic Value of Hemoglobin, Albumin, Lymphocyte, Platelet (HALP) Score in Patients with Metastatic Renal Cell Carcinoma Treated with Nivolumab

by Zuzana Tomčová, Jana Obertová, Michal Chovanec, Zuzana Syčová-Milá, Katarína Štefániková, Eva Šlachtová, Monika Žák, Alexander Savka, Matej Hrnčár, Katarína Rejleková and Patrik Palacka

Biomedicines 2025, 13(2), 484; https://doi.org/10.3390/biomedicines13020484 - 16 Feb 2025

Viewed by 633

Abstract

Background: Immunotherapy based on checkpoint inhibition is widely used in the treatment of metastatic renal cell carcinoma (RCC); however, predictive and prognostic biomarkers are yet to be explored. The objective of this study was to evaluate the prognostic value of the hemoglobin, albumin, lymphocyte, platelet (HALP) score in metastatic RCC patients receiving nivolumab. Methods: We enrolled 149 individuals (including 38 females) with a median age of 62 years, who were treated with nivolumab (at a dosage of 240 mg biweekly or 480 mg every 28 days) following progression on at least one tyrosine kinase inhibitor (TKI) between 2016 and 2024. The study population was dichotomized by the median HALP score (27.53), which was calculated as hemoglobin (g/L) × albumin (g/L) × absolute lymphocyte count/platelets (g/L) at immunotherapy initiation. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method, with differences analyzed via a log-rank test. A multivariate Cox proportional hazards model was utilized for evaluation of the prognostic value of performance status, lactate dehydrogenase (LDH) levels, and HALP score. Results: At a median follow-up of 31.1 months, 122 patients had progressed on nivolumab and 87 had died. Poor performance status was associated with significantly worse PFS and OS (HR 0.20 and 0.14, respectively). Survival was worse in individuals with an LDH level higher than 1.5 times the normal range compared to those with lower LDH values (HR 0.45 for PFS and HR 0.41 for OS). Patients with low HALP scores had shorter PFS (HR 0.69) and OS (HR 0.58) versus patients with high HALP scores. In the multivariate analysis, the independent prognostic value of the HALP index for OS was revealed in a metastatic clear-cell RCC (ccRCC) population. Conclusions: The HALP score determined before nivolumab initiation as the second or third line of treatment is an independent prognostic factor of OS in metastatic ccRCC patients. Prospective validation could lead to the incorporation of this index into prognostic models for patients with RCC. Full article

(This article belongs to the Special Issue Advances in Immunotherapy and Radiation Therapy for Cancer)

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11 pages, 4145 KiB

Open AccessArticle

The Effectiveness of Atezolizumab in Metastatic Large Cell Neuroendocrine Carcinoma of the Lungs: Insights from the LANCE Pilot Study

by Georgios Evangelou, Ioannis P. Trontzas, Ioannis Gkiozos, Ioannis Vamvakaris, Christina Paraskeva, Maria Grammoustianou, Georgia Gomatou, Ioannis Tsamis, Ioannis Vathiotis, Maximillian Anagnostakis, Vasiliki Koliaraki and Kostas Syrigos

Biomedicines 2024, 12(6), 1161; https://doi.org/10.3390/biomedicines12061161 - 23 May 2024

Cited by 1 | Viewed by 1978

Abstract

Background: Large cell neuroendocrine carcinoma (LCNEC) presents significant treatment challenges due to its rarity and limited therapeutic options. The LANCE study was designed to explore the survival benefits of incorporating atezolizumab in chemotherapy for metastatic LCNEC. Methods: In this non-randomized study, patients with metastatic LCNEC were prospectively enrolled and assigned to receive either standard chemotherapy plus atezolizumab followed by maintenance with atezolizumab or standard chemotherapy alone. The primary outcomes measured were 12- and 24-month survival rates, progression-free survival (PFS), and overall survival (OS) between the two groups. Results: Of the 22 patients screened, 17 met the inclusion criteria and received either atezolizumab plus platinum-based chemotherapy (n = 10) or chemotherapy alone (n = 7). After a median follow-up of 23.3 months, the 12-month survival rate was 57.1% (95% CI: 32.6–100%) and 14.3% (95% CI: 2.33–87.7%) for the atezolizumab and the chemotherapy-only groups, respectively. The survival benefit for the atezolizumab group was sustained at 24 months (45.7% vs. 14.3%). Overall survival was significantly higher for the atezolizumab group, and PFS was non-significantly associated with the addition of atezolizumab (log-rank p = 0.04 and 0.05, respectively). Conclusions: This pilot study suggests that the addition of atezolizumab to standard platinum-based chemotherapy may provide a substantial survival benefit compared with chemotherapy alone in the first-line treatment of metastatic LCNEC. Full article

(This article belongs to the Special Issue Advances in Immunotherapy and Radiation Therapy for Cancer)

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12 pages, 1244 KiB

Open AccessArticle

Change in Splenic Volume as a Surrogate Marker for Immunotherapy Response in Patients with Advanced Urothelial and Renal Cell Carcinoma—Evaluation of a Novel Approach of Fully Automated Artificial Intelligence Based Splenic Segmentation

by Gregor Duwe, Lukas Müller, Christian Ruckes, Nikita Dhruva Fischer, Lisa Johanna Frey, Jan Hendrik Börner, Niklas Rölz, Maximilian Haack, Peter Sparwasser, Tobias Jorg, Christopher C. M. Neumann, Igor Tsaur, Thomas Höfner, Axel Haferkamp, Felix Hahn, Rene Mager and Maximilian Peter Brandt

Biomedicines 2023, 11(9), 2482; https://doi.org/10.3390/biomedicines11092482 - 7 Sep 2023

Cited by 3 | Viewed by 1900

Abstract

Background: In the treatment of advanced urothelial (aUC) and renal cell carcinoma (aRCC), biomarkers such as PD-1 and PD-L1 are not robust prognostic markers for immunotherapy (IO) response. Previously, a significant association between IO and a change in splenic volume (SV) was described for several tumour entities. To the best of our knowledge, this study presents the first correlation of SV to IO in aUC and aRCC. Methods: All patients with aUC (05/2017–10/2021) and aRCC (01/2012–05/2022) treated with IO at our academic centre were included. SV was measured at baseline, 3 and 9 months after initiation of IO using an in-house developed convolutional neural network-based spleen segmentation method. Uni- and multivariate Cox regression models for overall survival (OS) and progression-free survival (PFS) were used. Results: In total, 35 patients with aUC and 30 patients with aRCC were included in the analysis. Lower SV at the three-month follow-up was significantly associated with improved OS in the aRCC group. Conclusions: We describe a new, innovative artificial intelligence-based approach of a radiological surrogate marker for IO response in aUC and aRCC which presents a promising new predictive imaging marker. The data presented implicate improved OS with lower follow-up SV in patients with aRCC. Full article

(This article belongs to the Special Issue Advances in Immunotherapy and Radiation Therapy for Cancer)

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16 pages, 2804 KiB

Open AccessArticle

ADCY7 mRNA Is a Novel Biomarker in HPV Infection and Cervical High-Grade Squamous Lesions or Higher

by Lihua Chen, Lixiang Huang, Binhua Dong, Yu Gu, Wei Cang, Chen Li, Pengming Sun and Yang Xiang

Biomedicines 2023, 11(3), 868; https://doi.org/10.3390/biomedicines11030868 - 13 Mar 2023

Cited by 1 | Viewed by 2611

Abstract

The effect of cervical cancer immunotherapy is limited. Combination therapy will be a new direction for cervical cancer. Thus, it is essential to discover a novel and available predictive biomarker to stratify patients who may benefit from immunotherapy for cervical cancer. In this study, 563 participants were enrolled. Adenylate cyclase 7 (ADCY7) mRNA was detected by real-time quantitative PCR (qPCR) with cervical cytology specimens. The relationship between ADCY7 and cervical intraepithelial neoplasia in grade 2 and higher (CIN2+) was analyzed, and the optimal cut-off values of the relative expression of ADCY7 mRNA to predict CIN2+ were calculated. In addition, the clinical significance of ADCY7 in cervical cancer was determined by the Kaplan–Meier Cox regression based on the TCGA database. The mean ADCY7 mRNA expression increased significantly with cervical lesion development, especially compared with CIN2+ (p < 0.05). Moreover, the expression of ADCY7 increased significantly in high-risk human papillomavirus (HR-HPV) infection but not in HPV-A5/6 species. The area under the receiver operating characteristic curve (AUC) of ADCY7 was 0.897, and an optimal cut-off was 0.435. Furthermore, ADCY7 had the highest OR (OR= 8.589; 95% CI (2.281–22.339)) for detecting CIN 2+, followed by HPV genotyping, TCT, and age (OR = 4.487, OR = 2.071, and OR = 1.345; 95% CI (1.156–10.518), (0.370–8.137), and (0.171–4.694), respectively). Moreover, this study indicated that higher ADCY7 levels could be a suitable predictor for poor prognosis in cervical cancer due to immune cell infiltration. A new auxiliary predictor of CIN2+ in cervical cytology specimens is ADCY7 ≥ 0.435. Furthermore, it may be a promising prognosis predictor and potential immunotherapy target for the combined treatment of cervical cancer and possibly further block HR-HPV persistent infection. Full article

(This article belongs to the Special Issue Advances in Immunotherapy and Radiation Therapy for Cancer)

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12 pages, 1112 KiB

Open AccessArticle

Impact of Bone Metastases on Patients with Renal Cell Carcinoma or Melanoma Treated with Combotherapy Ipilimumab Plus Nivolumab

by Félix Pham, Samy Belkaid, Denis Maillet, Cyrille B. Confavreux, Stéphane Dalle and Julien Péron

Biomedicines 2022, 10(11), 2758; https://doi.org/10.3390/biomedicines10112758 - 31 Oct 2022

Cited by 6 | Viewed by 1909

Abstract

(1) Background: Ipilimumab plus nivolumab (combo-ICI) improves overall survival (OS) in patients with advanced renal cell carcinoma (RCC) or melanoma. The impact of bone metastases (BM) on survival outcomes of combo-ICI-treated patients is unknown. (2) Methods: This single-center retrospective observational study involved 36 combo-ICI-treated patients with advanced RCC and 35 with melanoma. Clinical and laboratory data preceding the initiation of combo-ICI were collected. Univariate and multivariate Cox proportional hazard models were used to assess the effect of BM on overall survival (OS) and progression-free survival (PFS). (3) Results: zNine RCC and 11 melanoma patients had baseline BM. In unadjusted analysis, baseline BM was associated with a poorer OS in the RCC cohort. Baseline BM did not have any impact on survival outcomes in melanoma patients. After adjustment on baseline performance status and on neutrophil-to-lymphocyte ratio (NLR), the impact of BM was no longer significant, but a NLR ≥ 3 was significantly associated with a poorer OS in the RCC cohort. (4) Conclusions: The presence of baseline BM seems to be associated with worse outcomes in RCC combo-ICI-treated patients, while its effect might not be independent from the inflammatory state (approximated by the NLR). BM seems to have no impact on the outcomes of melanoma combo-ICI-treated patients. Full article

(This article belongs to the Special Issue Advances in Immunotherapy and Radiation Therapy for Cancer)

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16 pages, 1409 KiB

Open AccessArticle

Efficacy and Safety of Combined Brain Stereotactic Radiotherapy and Immune Checkpoint Inhibitors in Non-Small-Cell Lung Cancer with Brain Metastases

by Judith Porte, Caroline Saint-Martin, Thomas Frederic-Moreau, Marie-Ange Massiani, Laurence Bozec, Kim Cao, Pierre Verrelle, Joelle Otz, Eric Jadaud, Mathieu Minsat, Adriana Langer, Nicolas Girard, Gilles Créhange and Arnaud Beddok

Biomedicines 2022, 10(9), 2249; https://doi.org/10.3390/biomedicines10092249 - 10 Sep 2022

Cited by 7 | Viewed by 2225

Abstract

Background: To analyze the outcomes of patients with brain metastases (BM) from non-small cell lung cancer (NSCLC) treated with immunotherapy (IT) and stereotactic radiotherapy (SRT) and to study the impact of the sequence between the two modalities. Methods: The authors reviewed the records of 51 patients with 84 BM from NSCLC treated at Institut Curie with IT and SRT. BM were categorized into three groups: ‘SRT before IT’, ‘concurrent SRT and IT’, and ‘SRT after IT.’ Regional progression-free interval (R-PFI) and overall survival (OS) were estimated using the Kaplan–Meier method. Results: After a median follow-up from SRT of 22.5 months (2.7–47.3), the 1-year and 2-year OS were 69.7% (95%CI [58.0–83.8]) and 44.0% [30.6–63.2], respectively. Concerning distant intracranial control, the 1-year and 2-year R-PFI were 40.1% [30.1–53.3] and 35.2% [25.1–49.4], respectively. Moreover, one-year R-PFI in ‘SRT before IT’, ‘concurrent SRT and IT’, and ‘SRT after IT’ groups were 24.1%, 49.6%, and 34.2%, respectively (p = 0.094). The type of therapeutic sequence did not appear to impact the risk of brain necrosis. Conclusions: The concurrent administration of SRT and IT appeared to offer the best locoregional control, without increasing the risk of toxicity, compared to patients treated with SRT before or after IT. Full article

(This article belongs to the Special Issue Advances in Immunotherapy and Radiation Therapy for Cancer)

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14 pages, 1668 KiB

Open AccessReview

Therapeutic Applications of Programmed Death Ligand 1 Inhibitors in Small Cell Lung Cancer

by Leena Nabipur, Michael Mouawad and Vishwanath Venketaraman

Biomedicines 2025, 13(2), 401; https://doi.org/10.3390/biomedicines13020401 - 7 Feb 2025

Viewed by 798

Abstract

Background: Small cell lung cancer (SCLC) is an aggressive cancer with rapid progression, limited treatment success, and high relapse rates. Chemotherapy and radiation are standard treatments but often result in chemoresistance. PD-L1 inhibitors have gained attention for their role in enhancing tumor immunity. Methods: This review summarizes clinical trials involving PD-L1 inhibitors, such as atezolizumab, durvalumab, pembrolizumab, and nivolumab, in SCLC treatment. Key trials include IMpower133, CASPIAN, KEYNOTE-604, and CheckMate 331, focusing on survival outcomes and treatment efficacy. Results: Studies such as IMpower133 and CASPIAN demonstrate improved overall survival when PD-L1 inhibitors were added to platinum-based chemotherapy. However, outcomes in trials such as KEYNOTE-604 and CheckMate 331 varied, showing the need for refined patient selection. Adverse events (AEs) associated with these treatments were also noted. PD-L1 inhibitors offer promise in SCLC treatment, but efficacy varies across trials and patient groups. Future research should focus on better patient selection and overcoming resistance mechanisms. Addressing immune-related AEs is essential for optimizing treatment strategies. Full article

(This article belongs to the Special Issue Advances in Immunotherapy and Radiation Therapy for Cancer)

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28 pages, 4916 KiB

Open AccessReview

Emerging Ocular Side Effects of Immune Checkpoint Inhibitors: A Comprehensive Review

by Kevin Y. Wu, Yoel Yakobi, Diana D. Gueorguieva and Éric Mazerolle

Biomedicines 2024, 12(11), 2547; https://doi.org/10.3390/biomedicines12112547 - 7 Nov 2024

Viewed by 1934

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, offering significant improvements in patient survival across various malignancies. However, their use is associated with a broad spectrum of immune-related adverse events (irAEs), including those affecting the eye and its surrounding structures, collectively termed ocular irAEs (OirAEs). Although rare, OirAEs (e.g., keratitis, uveitis, retinal vasculitis, etc.) can significantly impact a patient’s quality of life, leading to ocular complications if left untreated. This review provides a comprehensive overview of OirAEs associated with ICIs, including their clinical manifestations, underlying mechanisms, and current management strategies. We delve into the anterior and posterior segment adverse events, highlighting conditions such as dry eye, uveitis, and retinal disorders, as well as neuro-ophthalmic and orbital complications. Furthermore, we discuss the challenges in diagnosing and treating these conditions, particularly given the overlap with other autoimmune and paraneoplastic syndromes. Finally, we identify key knowledge gaps and suggest future research directions aimed at optimizing the management of OirAEs while maintaining the efficacy of cancer therapy. This review underscores the need for increased awareness among clinicians to prevent irreversible ocular damage and enhance patient outcomes. Full article

(This article belongs to the Special Issue Advances in Immunotherapy and Radiation Therapy for Cancer)

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15 pages, 1059 KiB

Open AccessReview

How to Manage a Patient with Ocular Metastases?

by Juliette Thariat, Laurys Boudin, Olivier Loria, Anh-Minh Nguyen, Laurent Kodjikian and Thibaud Mathis

Biomedicines 2022, 10(12), 3044; https://doi.org/10.3390/biomedicines10123044 - 25 Nov 2022

Cited by 12 | Viewed by 2931

Abstract

Ocular metastases are the most frequent ocular malignant tumors; their prevalence is estimated around 5–10% and is even higher in patients with breast or lung cancer. They represent various clinical situations, but they share the same hierarchical multidisciplinary therapeutic challenge with respect to the way systemic and local therapies should be selected in combination or sequentially in the personalized medical history of a patient. The challenges include tumor control, eye preservation, and the minimization of iatrogenic damage to sensitive tissues surrounding the tumor in order to preserve vision. These aims should further contribute to maintaining quality of life in patients with metastases. Many patients with choroidal metastases have systemic molecular treatment for their primary tumor. However, secondary resistance to systemic treatment is common and may ultimately be associated with cancer relapse, even after an initial response. Therefore, it makes sense to propose local treatment concomitantly or after systemic therapy to provide a more sustainable response. The aim of this review is to present current therapeutic strategies in ocular metastases and discuss how to tailor the treatment to a specific patient. Full article

(This article belongs to the Special Issue Advances in Immunotherapy and Radiation Therapy for Cancer)

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21 pages, 645 KiB

Open AccessSystematic Review

A Systematic Review of Pneumonitis Following Treatment with Immune Checkpoint Inhibitors and Radiotherapy

by Melina Yerolatsite, Nanteznta Torounidou, Anna-Lea Amylidi, Iro-Chrisavgi Rapti, George Zarkavelis, Eleftherios Kampletsas and Paraskevi V. Voulgari

Biomedicines 2025, 13(4), 946; https://doi.org/10.3390/biomedicines13040946 - 12 Apr 2025

Viewed by 338

Abstract

Background: Immune checkpoint inhibitors (ICIs) are increasingly included in management guidelines for various types of cancer. However, immune-related adverse events (irAEs) are an inevitable consequence of these therapies. Some of these side effects, such as pneumonitis, can be particularly serious. Additionally, the combination of ICIs with radiotherapy (RT) may further increase the risk of pneumonitis. Objective: The aim of this systematic review is to examine all available studies on pneumonitis following the use of ICIs and RT to assess its appearance and severity. Methods: We systematically searched four different databases (PubMed, Scopus, Cochrane, and DOAJ) to identify all relevant studies within our scope. Additionally, we reviewed the references of the studies we found, as well as those of other systematic reviews and meta-analyses. We assessed the risk of bias using the Cochrane Risk of Bias Tool version 2 for randomized controlled trials and the RTI Risk of Bias Item Bank for non-randomized trials. Finally, we extracted relevant data into an Excel file and presented them in tables throughout this study. Results: A total of 58 articles met our inclusion criteria, comprising 4889 patients across multiple studies and nine case reports. Due to significant heterogeneity in study methodologies and data reporting, a cumulative statistical analysis was not performed. The included studies were published between 2017 and 2025. The incidence of pneumonitis varied, with retrospective studies showing higher rates compared to randomized and non-randomized controlled trials. Case reports described a range of pneumonitis presentations, treatments, and outcomes, with corticosteroids being the primary treatment. Conclusions: The incidence of pneumonitis varied, with retrospective studies showing the highest rates compared to other study designs. Early detection and management of pneumonitis in patients receiving RT and/or ICIs are crucial for improving outcomes. Identifying high-risk patients through predictive models, radiomics, and biomarkers may help tailor treatment strategies and minimize toxicity. Further research is needed to establish the most appropriate diagnostic criteria, optimize management approaches, and refine advanced imaging and biomarker-based risk stratification to improve patient care. Interdisciplinary collaboration is essential for reducing the risk of pneumonitis and improving patient outcomes. Full article

(This article belongs to the Special Issue Advances in Immunotherapy and Radiation Therapy for Cancer)

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