Combination Immunotherapy Research Articles

Combinatory Immunotherapy for Glioblastoma Treatment

AbstractDespite advancements in the treatment of glioblastoma, it faces challenges due to tumor heterogeneity, the blood‐brain barrier, recurrence, immune evasion, and conventional strategies, leading to low survival and a poor prognosis. Therefore, it is crucial to develop novel, useful treatment strategies for improving brain distribution to overcome blood‐brain barriers (BBB) and help the treatment of glioblastoma. Conventional immunotherapy like checkpoint inhibitors, CAR‐T cell therapy, monoclonal antibodies, cancer vaccines, and adoptive cell transfer often suffers from low therapeutic outcomes because the singular therapy generally has shortcomings, such as the cold immune microenvironment of brain tumors. In contrast, the emerging combinatory immunotherapy integrated with chemo‐immunotherapy, photothermal‐immunotherapy, and radio‐immunotherapy has shown great promise to modulate tumoral immune microenvironment and boost treatment outcomes. This review discusses the immune microenvironment of GBM, its impact on immunological effects, current immunotherapy methods, and advanced studies. It also introduces combinational GBM immunotherapy with traditional cancer therapies like chemo‐immunotherapy, surgery‐immunotherapy, photothermal‐immunotherapy, and radiotherapy‐immunotherapy. In the future, it is anticipated that this article will provide beneficial information and a path for the strategy of innovative, efficient combination immunotherapy in the treatment of glioblastoma.

An analysis of the clinical significance of the TKI-resistant gene ZNF687 for hepatocellular carcinoma patients.

Novel treatments such as monotherapy and combined immunotherapy significantly extend overall survival (OS) for hepatocellular carcinoma (HCC) patients, but HCC is susceptible to treatment resistance during long-term therapy. The resistance mechanism to targeted drugs in HCC remains ambiguous, making research on HCC drug resistance targets crucial for the development of precision medicine. To investigate the transcriptional features, biological functions and potential clinical value of the tyrosine kinase inhibitor (TKI)-resistant gene ZNF687 in HCC. The TKI-resistant genes of HCC were identified using clustered regularly interspaced short palindromic repeats (CRISPR) in vitro screening. Then, the dependence of HCC cell lines on ZNF687 was investigated in silico. We collected global mRNA datasets of HCC tissue, integrated the mRNA expression characteristics of ZNF687 in HCC and explored the impact of ZNF687 on HCC patient prognoses using the Kaplan-Meier method (in silico). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analyses were then conducted, and a connectivity map and molecular docking technology were applied to find the underlying agent opposing ZNF687. In vitro, the guide RNA corresponding to ZNF687 was weakly detected in HCC cells, and ZNF687 deficiency was found to inhibit growth in HCC cell lines. ZNF687 mRNA was overexpressed and had a high discriminatory ability for HCC in 2,975 HCC samples, contrasting with 2,340 non-HCC samples. Moreover, an excessive ZNF687 transcript level was related to a worse overall survival (OS) prognosis. Histone modification, spliceosome, transcription coregulator activity, and nucleocytoplasmic transport were the most significant pathways for ZNF687 differential-related gene enrichment. Chaetocin was found to be a candidate compound and presented a strong affinity to ZNF687. ZNF687 represents a TKI-resistant and growth-dependent gene for HCC, the overexpression of which indicates poor OS for HCC patients. Additionally, ZNF687 is expected to be a druggable target for overcoming TKI resistance, and chaetocin may be a candidate therapeutic compound for ZNF687.

Narrative review on efficacy and safety of anti-angiogenesis in combination with immunotherapy in the treatment of breast cancer.

Breast cancer was the second frequently diagnosed cancer in 2022 among all cancers. Besides classical chemotherapy and radiation, immunotherapy and targeted therapy are both identical treatment options for patients with advanced breast cancer. Immunotherapy is a therapeutic approach to control and eliminate tumors by restarting and maintaining the tumor-immunity cycle and restoring the body's normal anti-tumor immune response. Immunotherapy alone or in combination with other therapies has been shown to be clinically beneficial in a variety of solid tumors with a manageable safety profile. However, immunotherapy alone cannot fully satisfy the therapeutic needs for patients with breast cancer. Therefore, there is an urgent need for immunotherapy to be combined with other therapeutic approaches to increase treatment efficacy. We systematically searched PubMed database for relevant studies published over the past 5 years. Articles were screened for eligibility and key data extracted. We assess the current breast cancer treatment landscape, summarizing efficacy and safety of recent immunotherapy, chemotherapy combined with immunotherapy, immunotherapy combined with anti-angiogenic therapy. In the treatment of breast cancer, aiming to promote further research and applications of this novel treatment regimen in patients with breast cancer. Since anti-angiogenic therapy can reprogramme the tumor immune microenvironment, immunotherapy in combination with anti-angiogenic therapy might have a synergistic effect, igniting a new hope for immunotherapy for breast cancer patients. The review's conclusions offer insightful information on the state of breast cancer treatment today. In the end, improving clinical practice and pertinent research for immunotherapy combination therapy will contribute to bettering patient outcomes, raising quality of life, and creating more potent treatments. This review emphasizes the potential of immunotherapy combinations, especially with anti-angiogenic therapeutic regimens, as a viable strategy for the treatment of breast cancer through a thorough study of the literature. To improve treatment approaches, lessen side effects for patients, and find trustworthy biomarkers to forecast response to immunotherapy combo medicines, further research is necessary.

The Trend of the Treatment of Advanced Hepatocellular Carcinoma: Combination of Immunotherapy and Targeted Therapy.

Hepatocellular carcinoma (HCC) is a common type of tumor worldwide. The development of systemic treatment of advanced HCC has remained stagnant for a considerable period. During the last years, a series of new treatment regimens based on the combination of immunotherapeutic drugs and targeted drugs have been gradually developed, increased the objective response rate (ORR), overall survival (OS), and progression free survival (PFS) of HCC patients. Among the different combination therapy groups, atezolizumab plus bevacizumab and sintilimab plus IBI-305 seem to have unique advantages, while head-to-head comparisons are still needed. A comprehensive understanding of the developments, the ongoing clinical trials and the mechanisms of combination of immunotherapy and targeted therapy might lead to the development of new combination strategies and solving current challenges such as the molecular biomarkers, the clinical administration order of drugs and the second-line treatments after combination therapy.

SPI1+CD68+ macrophages as a biomarker for gastric cancer metastasis: a rationale for combined antiangiogenic and immunotherapy strategies

BackgroundTumor-associated macrophages (TAMs) have been demonstrated to be associated with tumor progression. However, the different subpopulations of TAMs and their roles in gastric cancer (GC) remain poorly understood. This study...

Pancreatic cancer is feeling the heat.

Pancreatic adenocarcinoma (PDAC) is considered an immunologically 'cold' tumor that fails to attract or support effector T cells. Most PDACs are resistant to immune checkpoint blockade due to the complex signaling pathways that exist within its tumor microenvironment. Recent advances in genomic and proteomic technology advances are finally uncovering the complex inflammatory cellular and intercellular signals that require modulation and reprogramming. The goal is to 'turn up the heat' on PDACs with combination immunotherapies that incorporate T cell activating agents and immune modulatory agents, and successfully eradicate tumors. Here, we discuss progress and promising new research that is moving the field toward this goal.

Improved outcomes of palliative radiotherapy combined with immune checkpoint inhibitors in recurrent or metastatic cervical cancers

BackgroundImmunotherapy provides a remarkable survival advantage for patients with recurrent or metastatic cervical cancer (R/M CC). However, the role of immunotherapy in combination with radiotherapy in R/M CC remains unclear. MethodsWe retrospectively analyzed factors affecting immunotherapy effectiveness in patients with R/M CC. Clinical outcomes including tumor response and patient survival were assessed. Kaplan-Meier curves with the log-rank test were employed to compare survival data. Cox regression analysis was utilized to investigate prognostic factors. ResultsA total of 65 R/M CC patients treated with immune checkpoint inhibitors were eligible for analysis. We found that immunotherapy combined with palliative radiotherapy showed a significant positive correlation with complete response (OR = 6.31; 95 %CI: 1.74–22.91; p = 0.005). The 36-month progression-free survival (PFS) rate (73.7 % vs 33.8 %, p = 0.0048) and 36-month overall survival (OS) rate (85.7 % vs 38.7 %, p = 0.0043) were also prominently increased. We further demonstrated that patients prolonged 36-month PFS rate (69.9 % vs 15.2 %; p < 0.001) and 36-month OS rate (64.6 % vs 39.7 %; p = 0.032) when they had more than 4 cycles of immunotherapy. Meanwhile, our findings showed that patients with only recurrence had longer 36-month OS rate (77.7 % vs 44.4 % vs 40.1 %; p = 0.024) compared to those with only metastasis and both. We also observed that patients with squamous carcinoma had higher 2-year PFS rate (57.9 % vs 14.6 %; p = 0.042) than those with other pathological subtypes (adenocarcinoma, adenosquamous carcinoma and neuroendocrine carcinoma). ConclusionsThe combination of immunotherapy and palliative radiotherapy increased complete response rates and improved survivals in recurrent or metastatic cervical cancer patients.

Immune checkpoint inhibitor combinations for patients with advanced endometrial cancer: a network meta-analysis and cost-utility analysis

BackgroundImmune checkpoint inhibitor combinations show significant survival advantages compared with chemotherapy for patients with advanced endometrial cancer.ObjectiveTo compare the efficacy, safety, and cost-effectiveness of different immunotherapy combinations for clinician and...

A combination of protein phosphatase 2A inhibition and checkpoint immunotherapy: a perfect storm.

Immune checkpoint blockade has emerged as a potent new tool in the war on cancer. However, only a subset of cancer patients benefit from this therapeutic modality, sparking a search for combination therapies to increase the fraction of responding patients. We argue here that inhibition of protein phosphatase 2A (PP2A) is a promising approach to increase responses to immune checkpoint blockade and other therapies that rely on the presence of tumor-reactive Tcells. Inhibition of PP2A increases neoantigen expression on tumor cells, activates the cGAS/STING pathway, suppresses regulatory Tcells, and increases cytotoxic Tcell activation. In preclinical models, inhibition of PP2A synergizes with immune checkpoint blockade and emerging evidence indicates that patients who have tumors with mutations in PP2A respond better to immune checkpoint blockade. Therefore, inhibition of PP2A activity may be an effective way to sensitize cancer cells to immune checkpoint blockade and cell-based therapies using tumor-reactive Tcells.

Real-world experience of lenvatinib-based therapy in patients with advanced hepatocellular carcinoma.

Given the significant advancements in the management of hepatocellular carcinoma (HCC) and the emergence of novel treatment approaches, establishing reliable predictors has become crucial for optimizing patient selection and therapeutic sequencing in HCC. In this study, we aimed to investigate the prognostic factors and treatment efficacy associated with lenvatinib-based therapy. We retrospectively enrolled 53 patients receiving lenvatinib monotherapy, and 19 patients receiving lenvatinib plus immune checkpoint inhibitor combination therapy as their first-line systemic treatment for unresectable HCC at a single medical center. We employed univariate and multivariate Cox regression analyses to ascertain the factors influencing survival in these cohorts. For lenvatinib monotherapy and the combination therapy, the objective response rates were 30.2% and 63.2%, respectively (P=0.03); the median progression-free survival (PFS) durations were 7 months [95% confidence interval (CI): 4.5-9.5] and 12 months (95% CI: 6.4-17.6), respectively (P=0.74); and the median overall survival (OS) was not reached in either group (P=0.93). Although patients receiving the combination therapy had a greater treatment response, no significant survival differences were observed between the lenvatinib monotherapy and combination therapy subgroups, even after inverse probability of treatment weighting (IPTW). Patients who received lenvatinib monotherapy could be stratified based on a combination of albumin-bilirubin (ALBI) grade (either grade 1 or 2a) and a neutrophil-lymphocyte ratio (NLR) of ≤5.8. Compared to the other subgroups combined, those who met both of these criteria exhibited PFS with a hazard ratio (HR) of 0.382 (95% CI: 0.168-0.871; P=0.02), corresponding to 11 and 5 months, respectively; and an OS (HR: 0.198, 95% CI: 0.043-0.920; P=0.04) of not reached versus 12 months, respectively, according to multivariate Cox regression analysis. In our study cohort, there were no statistically significant differences observed in the survival rates between patients treated with lenvatinib monotherapy and those treated with a combination of lenvatinib and immunotherapy. The incorporation of ALBI grade and NLR facilitates the stratification of survival outcomes in patients with unresectable HCC undergoing lenvatinib monotherapy.

Oral Heterojunction Coupling Interventional Optical Fiber Mediates Synergistic Therapy for Orthotopic Rectal Cancer.

Catalytic therapy has shown great potential for clinical application. However, conventional catalytic therapies rely on reactive oxygen species (ROS) as "therapeutic drugs," which have limitations in effectively inhibiting tumor recurrence and metastasis. Here, a biomimetic heterojunction catalyst is developed that can actively target orthotopic rectal cancer after oral administration. The heterojunction catalyst is composed of quatrefoil star-shaped BiVO4 (BVO) and ZnIn2S4 (ZIS) nanosheets through an in situ direct growth technique. Poly-norepinephrine and macrophage membrane coatings afford the biomimetic heterojunction catalyst (BVO/ZIS@M), which has high rectal cancer targeting and retention abilities. The coupled optical fiber intervention technology activates the multicenter coordination of five catalytic reactions of heterojunction catalysts, including two reduction reactions (O2→·O2 - and CO2→CO) and three oxidation reactions (H2O→·OH, GSH→GSSG, and LA→PA). These catalytic reactions not only induce immunogenic death in tumor cells through the efficient generation of ROS/CO and the consumption of GSH but also specifically lead to the use of lactic acid (LA) as an electron donor to improve catalytic activity and disrupt the LA-mediated immunosuppressive microenvironment, mediating synergistic catalysis and immunotherapy for orthotopic rectal cancer. Therefore, this optical fiber intervention triggered the combination of heterojunction catalytic therapy and immunotherapy, which exhibits prominent antitumor effects.

PULSAR Effect: Revealing potential synergies in combined radiation therapy and immunotherapy via differential equations

PULSAR (personalized ultrafractionated stereotactic adaptive radiotherapy) is a form of radiotherapy method where a patient is given a large dose or “pulse” of radiation a couple of weeks apart rather than daily small doses. The tumor response is then monitored to determine when the subsequent pulse should be given. Pre-clinical trials have shown better tumor response in mice that received immunotherapy along with pulses spaced 10 days apart. However, this was not the case when the pulses were 1 or 4 days apart. Therefore, a synergistic effect between immunotherapy and PULSAR is observed when the pulses are spaced out by a certain number of days. In our study, we aimed to develop a mathematical model that can capture the synergistic effect by considering a time-dependent weight function that takes into account the spacing between pulses. We determined feasible parameters by fitting murine tumor volume data of six treatment groups via simulated annealing algorithm. Applying these parameters to the model we simulated 4000 trials with varying sequencing of pulses. These simulations indicated that if pulses were spaced apart by at least 9 days the tumor volume was about 200 mm3 to 250 mm3 smaller when treated with PULSAR combined with immunotherapy. We successfully demonstrate that our model is simple to implement and can generate tumor volume data that is consistent with the pre-clinical trial data. Our model has the potential to aid in the development of clinical trials of PULSAR therapy.

Systemic anti-cancer treatment and healthcare utilization at end of life: A SEER Medicare analysis.

276 Background: Use of chemotherapy at end-of-life (EOL) is associated with adverse quality of life, higher costs, increased hospitalizations (HL), emergency department (ED), and intensive care unit (ICU) utilization and lower hospice (HP) use. While EOL chemotherapy use has declined in recent years, EOL immunotherapy use has increased. It is unknown how the trend of increased immunotherapy use at the EOL is associated with healthcare utilization. We evaluated the association between types of systemic anticancer therapy (SACT) within 30 days of death and hospitalizations, emergency department, intensive care unit, and hospice use. Methods: We identified patients in the SEER-Medicare database with a diagnosis date of 2005-2019 and death date of 2015-2020 with the following cancers: breast, colorectal, lung, prostate, bladder, cervix, kidney, leukemia, liver, lymphoma, myeloma, ovarian, pancreas, skin, and uterine. EOL SACT was defined as SACT received within 30 days of death, categorized as combination chemo-immunotherapy, immunotherapy, and chemotherapy. We analyzed associations between EOL SACT use (overall and by type), and healthcare utilization in the last 30-days of life (ED, HL, ICU, and HP) with chi-square tests and multivariable regression, controlling for sociodemographic and cancer covariates. Results: Of 499,607 beneficiaries, 37,595 (7.5%) received SACT within 30 days of death. Compared to no EOL SACT, any SACT use was associated with higher ED [75.5% vs 50.8%], HL [71.0% vs 48.7%] and ICU (35.7% vs 23.3%) and lower HP enrollment (46.1% vs 59.3%) and number of days in HP (2.4 vs 6.5 days) (all p &lt;0.001, table). After adjusting for covariates, patients with EOL SACT were more likely to have HL (odds ratio [OR], 2.43; 95% confidence interval [CI], 2.38-2.49), ED visits (OR, 2.87; 95% CI, 2.80-2.94), and ICU stay (OR, 1.66; 95% CI, 1.62-1.70), and less likely to receive HP care (OR, 0.62; 95% CI: 0.61-0.64)-compared to no SACT use; All subtypes of EOL SACT were significantly more likely to have ED, HL, and ICU use and less likely to use HP than those with No EOL SACT (p-values &lt;0.001). Conclusions: All types SACT within 30 days of death were associated increased healthcare use compared with no EOL SACT, with combination chemo-immunotherapy having the highest ED, hospitalizations and ICU use and lowest hospice enrollment and duration. Healthcare utilization. Combination Chemo-Immunotherapy(n=5,171) Immunotherapy(n = 11,397) Chemotherapy(n = 21,027) Any SACT(n = 37,595) No SACT(n = 462,012) P -value* ED Visit (%) 76.9 73.7 76.1 75.5 50.8 &lt;.001 Hospitalizations (%) 72.5 67.7 72.5 71.0 48.7 &lt;.001 ICU use (%) 40.4 32.1 36.5 35.7 23.3 &lt;.001 Hospice use (%) 38.8 50.2 45.8 46.1 59.3 &lt;.001 Number of days Hospice (Days, Mean ± standard deviation) 1.7 ± 3.0 2.7 ± 3.9 2.4 ± 3.9 2.4 ± 3.8 6.5 ± 7.8 &lt;.001 *P-values for statistical difference between each individual SACT subgroup and No SACT and Any SACT and No SACT group.

Prise en charge diagnostique et thérapeutique du mésothéliome pleural en 2024

Pleural mesothelioma (PM) is a quite rare tumor, usually due to previous asbestos exposure. Its global prognosis is poor, without validated curative treatment to date. Diagnosis relies ideally on thoracoscopy with pleural biopsies, ± combined with (immediate) talc pleurodesis. Surgery with curative intent, included with multimodal treatment and restrained to highly selected patients, was recently rechallenged. As frontline treatment, standard pemetrexed/platinum-based chemotherapy was lightly improved by addition of bevacizumab. It is currently challenged by the immunotherapy combination of Nivolumab + Ipilimumab, and perhaps soon by combinations of chemotherapy + immunotherapy. No standard treatment is firmly validated beyond first line treatment, even if anti-PD-1/PD-L1 ± anti-CTLA-4 checkpoint inhibitors also exhibited some interesting results in this setting, in phase II and III clinical trials. Therefore, the search of new treatments, strategies and biomarkers is a crucial goal, and recruitment of patients in clinical trials strongly encouraged. Other immunotherapies alone or combined with standard treatments and/or targeted therapies, multimodal strategies are currently assessed. In France, the national network of expert centers for PM management, “NETMESO” (labelled by INCa), aims at proposing an optimal management to all patients systematically discussed in regional (± national) MTB dedicated to PM, and at stimulating clinical and translational research in collaboration with its partners including patients advocating associations.1877-1203/© 2024 SPLF. Published by Elsevier Masson SAS. All rights reserved.

A Phase 1 Trial of Trebananib, an Angiopoietin 1 and 2 Neutralizing Peptibody, Combined with Pembrolizumab in Patients with Advanced Ovarian and Colorectal Cancer.

Ovarian cancers and microsatellite stable (MSS) colorectal cancers (CRC) are insensitive to anti-PD1 immunotherapy, and new immunotherapeutic approaches are needed. Preclinical data suggests a relationship between immunotherapy resistance and elevated angiopoietin 2 levels. We performed a phase 1 dose-escalation study of pembrolizumab and the angiopoietin 1/2 inhibitor trebananib (NCT03239145). This multicenter trial enrolled patients with metastatic ovarian cancer or MSS CRC. Trebananib was administered intravenously weekly for 12 weeks with 200 mg intravenous pembrolizumab every 3 weeks. The toxicity profile of this combination was manageable, and the protocol-defined highest dose level (trebananib 30 mg/kg weekly plus pembrolizumab 200 mg every 3 weeks) was declared the maximum tolerated dose. The objective response rate for all patients was 7.3% (90% confidence interval: 2.5-15.9%). Three patients with MSS CRC had durable responses for ≥3 years. One responding patient's CRC harbored a POLE mutation. The other two responding patients had left-sided CRCs with no baseline liver metastases, and genomic analysis revealed that they both had KRAS wild-type, ERBB2 amplified tumors. After development of acquired resistance, biopsy of one patient's KRAS wild-type, ERBB2 amplified tumor showed a substantial decline in tumor-associated T cells and an increase in immunosuppressive intratumoral macrophages. Future studies are needed to carefully assess whether clinicogenomic features, such as lack of liver metastases, ERBB2 amplification, and left-sided tumors, can predict increased sensitivity to PD1 immunotherapy combinations.

Evidence for the evolving role of neoadjuvant and perioperative immunotherapy in resectable non-small cell lung cancer.

The treatment of early-stage non-small cell lung cancer (NSCLC) is becoming increasingly complex. Standard of care management for the past decade has been adjuvant chemotherapy following curative intent resection regardless of nodal status or tumour profile. With the increased incorporation of immunotherapy in NSCLC, especially in the locally advanced, unresectable, or metastatic settings, multiple studies have sought to assess its utility in early-stage disease. While there are suboptimal responses to neoadjuvant chemotherapy alone, there is a strong rationale for the use of neoadjuvant immunotherapy in tumour downstaging, based upon the concept of enhanced T cell priming at the time of a high tumour antigen burden, and demonstrated clinically in other solid tumours, such as melanoma. In the NSCLC cancer setting, currently over 20 combinations of chemoimmunotherapy in the neoadjuvant and perioperative setting have been studied with results variable. Multiple large phase III studies have demonstrated that neoadjuvant chemoimmunotherapy combinations result in significant advances in pathological response, disease free and overall survival which has led to practice change across the world. Currently, combination immunotherapy regimens with novel agents targeting alternate immunomodulatory pathways are now being investigated. Given this, the landscape of treatment in resectable early-stage NSCLC has become increasingly complex. This review outlines the literature of neoadjuvant and perioperative immunotherapy and discusses its potential benefits and complexities and ongoing considerations into future research.

Meta-analysis of platinum chemotherapy combinations with immunotherapy in metastatic urothelial carcinoma.

The therapeutic landscape for metastatic urothelial carcinoma (mUC) has evolved significantly due to the development of innovative combination treatments, including enfortumab vedotin-pembrolizumab (EVP). Despite these advancements, the limited availability of EVP means that platinum-based chemotherapy regimens continue to serve as the primary treatment modality for many patients with mUC. We evaluated the effect of the type of platinum chemotherapy used in combination with immunotherapy (IO) on treatment outcomes in mUC. The meta-analysis showed that cisplatin-gemcitabine plus IO combination and carboplatin-gemcitabine plus IO combination improve progression-free survival compared to platinum-gemcitabine therapy (hazard ratio [HR] = 0.71, 95% CI: 0.62-0.82; P < .0001 and HR = 0.85, 95% CI: 0.73-0.98; P < .03, respectively). However, only the cisplatin-gemcitabine plus IO combination showed overall survival (OS) benefit (HR = 0.80, 95% CI: 0.69-0.93; P < .003). In comparison to the platinum-gemcitabine combination, neither the cisplatin-gemcitabine plus IO nor the carboplatin-gemcitabine plus IO combinations demonstrated an objective response rate (ORR) benefit. In summary, combining cisplatin-gemcitabine with immunotherapy offers significant overall survival benefits in mUC. The exact mechanisms-whether cisplatin's immunomodulatory effects or patient demographic differences-are yet to be determined, necessitating further research to understand these outcomes better.

Customizable Lyophilized Agent for Radiotherapy Imaging and TherapY (CLARITY).

Smart radiotherapy biomaterials (SRBs) include seed and liquid biomaterials designed to be employed as fiducial markers during radiotherapy while also delivering therapeutic drug payloads to enhance treatment outcomes. In this study, we investigate a novel Customizable Lyophilized Agent for Radiotherapy Imaging and TherapY (CLARITY) biomaterial, which can be loaded with immunoadjuvants (anti-CD40 monoclonal antibody or Caflanone (FBL-03G)) at the point of care. The CLARITY biomaterial was investigated in an animal model of pancreatic cancer using C57BL6 mice. Mice were imaged before and at different points of time post-treatment to evaluate the potential of CLARITY biomaterial to provide imaging contrast similar to fiducials. This study also used cadavers to assess CLARITY's potential to provide imaging contrast in humans. Results showed imaging contrast from computed tomography (CT) and magnetic resonance imaging (MRI) modalities for up to 30 days post-treatment, demonstrating potential for use as fiducials. A significant increase in survival (***, p = 0.0006) was observed for mice treated with CLARITY biomaterial loaded with immunoadjuvant for up to 10 weeks post-treatment compared to those without treatment. These initial results demonstrate the potential of CLARITY biomaterial to serve as a smart multifunctional radiotherapy biomaterial and provide the impetus for further development and optimization as a point-of-care technology for combination radiotherapy and immunotherapy.

The immunotherapy-based combination associated score as a robust predictor for outcome and response to combination of immunotherapy and VEGF inhibitors in renal cell carcinoma

BackgroundOver the past decade, the realm of immunotherapy-based combination therapy has witnessed rapid growth for renal cell carcinoma (RCC), however, success has been constrained thus far. This limitation primarily stems from the absence of biomarkers essential for identifying patients likely to derive benefits from such treatments. MethodsIn this study, the immunotherapy-based combination associated score (IBCS) was established using single-sample gene set enrichment analysis (ssGSEA) based on the genes identified in the key modules extracted by weighted correlation network analysis (WGCNA) in the IMmotion151 dataset, a randomized, global phase III trial. ResultsHigh IBCS patients showed better responses to immunotherapy-based combinations and had longer progression-free survival (PFS). Further transcriptomic analysis revealed that IBCS was negatively correlated to TIDE score, identifying a subset of RCC patients characterized by enrichment of T-effector and moderate cell-cycle/angiogenesis gene expression. Our analysis of hub genes unveiled a novel molecule that could potentially serve as a target antigen in RCC. Validation through multiplex immunofluorescence assays on tissue microarrays (TMAs) containing 180 samples confirmed the pivotal role of this hub gene in immunoregulation. Furthermore, we developed an independent risk score model, which is significant for prognostic evaluation and patient stratification. Notably, we devised a forecasting nomogram using this risk score model, surpassing the IMDC score (a widely accepted risk score for predicting survival in patients undergoing VEGF-targeted therapy) in prognostic accuracy for patients treated with immunotherapy-based combinations. ConclusionThis study has collectively developed an immunotherapy-based combination associated score, pinpointed effective biomarkers for prognostic and responsiveness of kidney cancer patients to immunotherapy-based combinations, and delved into their potential biological mechanisms, offering promising targets for further exploration.

Non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) is one of the most frequent cancer types and is responsible for the majority of cancer-related deaths worldwide. The management of NSCLC has improved considerably, especially in the past 10 years. The systematic screening of populations at risk with low-dose CT, the implementation of novel surgical and radiotherapeutic techniques and a deeper biological understanding of NSCLC that has led to innovative systemic treatment options have improved the prognosis of patients with NSCLC. In non-metastatic NSCLC, the combination of various perioperative strategies and adjuvant immunotherapy in locally advanced disease seem to enhance cure rates. In metastatic NSCLC, the implementation of novel drugs might prolong disease control together with preserving quality of life. The further development of predictive clinical and genetic markers will be essential for the next steps in individualized treatment concepts.