Huang Lian Jie Du Decoction enhances the anti-tumor efficacy of immune checkpoint inhibitors by activating TLR7/8 signalling in melanoma.

BACKGROUND: The clinical application of immune checkpoint inhibitors (ICIs) is limited by their drug resistance, necessitating the development of ICI sensitizers to improve cancer immunotherapy outcomes. Huang Lian Jie Du Decoction (HLJD, Oren-gedoku-to in Japanese, Hwangryunhaedok-tang in Korean), a famous traditional Chinese medicinal prescription, has exhibited potential in the field of cancer treatment. This study aims to investigate the impact of HLJD on the efficacy of ICIs in melanoma and elucidate the underlying mechanisms. METHODS: The potential synergistic effects of HLJD and ICIs were investigated on the tumor-bearing mice model of B16F10 melanoma, and the tumor infiltration of immune cells was tested by flow cytometry. The differential gene expression in tumors between HLJD and ICIs group and ICIs alone group were analyzed by RNA-seq. The effects of HLJD on oxidative stress, TLR7/8, and type I interferons (IFN-Is) signaling were further validated by immunofluorescence, PCR array, and immunochemistry in tumor tissue. RESULTS: HLJD enhanced the anti-tumor effect of ICIs, significantly inhibited tumor growth, and prolonged the survival duration in melanoma. HLJD increased the tumor infiltration of anti-tumor immune cells, especially DCs, CD4+ T cells and CD8+T cells. Mechanically, HLJD activated the oxidative stress and TLR7/8 signaling pathway and IFN-Is-related genes in tumors. CONCLUSIONS: HLJD enhanced the therapeutic benefits of ICIs in melanoma, through increasing reactive oxygen species (ROS), promoting the TLR7/8 pathway, and activating IFN-Is signaling, which in turn activated DCs and T cells.

Solamargine improves the therapeutic efficacy of anti-PD-L1 in lung adenocarcinoma by inhibiting STAT1 activation.

OBJECTIVE: The effect of solamargine on lung adenocarcinoma and its effect on STAT1 signaling pathway mediated immune escape were studied through network pharmacology and in vitro and in vivo experiments. METHODS: The solamargine targets were screened using the TCMSP and the LUAD targets were screened using the GeneCard, OMIM, PharmGkb, TTD and DrugBank databases. PPI network analysis and target prediction were performed using GO and KEGG. Colony formation assay, EDU staining, wound healing, transwell assay, Hoechst and flow cytometry were used to detect the effects of solamargine on the proliferation, migration and apoptosis of LUAD. Western blotting (WB) and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to detect P-STAT1 and PD-L1 expression. And immunofluorescence was used to detect P-STAT1 expression. In vivo experiments, C57BL/6 mice were divided into control group, low concentration group, high concentration group, positive control group and combination group. Every other day, following seven consecutive doses, the size of the tumor was assessed. Finally, the expressions of P-STAT1, STAT1, PD-L1 and apoptosis index proteins were detected by WB. RESULTS: The anti-LUAD effect of solamargine was found by wound healing, colony formation assay, transwell assay, hoechst and EdU staining. The results of network pharmacological analysis showed that solamargine could suppress STAT1 expression level. Further enrichment assay of STAT1 showed that STAT1 was associated with immune-related pathways. In addition, molecular signal analysis by WB and RT-qPCR indicated that solamargine could reduce the expression levels of P-STAT1 and PD-L1 in a concentration-dependent manner. According to the results of in vivo assays, combination of solamargine and immune checkpoint inhibitors (ICIs) durvalumab could significantly inhibit the growth of Lewis transplanted tumors in C57BL/6 mice, and no toxic side effect was recoded. CONCLUSION: These results indicated that solamargine could inhibit the proliferation and promote the apoptosis of LUAD. It also could reduce the expression level of P-STAT1 protein and inhibit the expression level of PD-L1. At the same time, the combination with the ICIs can better block the expression of PD-L1 in cells, thereby inhibiting the immune escape pathway of tumor cells and achieving anti-tumor effects. This study proposed a novel combined therapeutic approach, involving the inhibition of STAT1 by solamargine in conjunction with ICIs.

The more the merrier? Evidence and efficacy of immune checkpoint- and tyrosine kinase inhibitor combinations in advanced solid cancers.

Immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) have gained therapeutical significance in cancer therapy over the last years. Due to the high efficacy of each substance group, additive or complementary effects are considered, and combinations are the subject of multiple prospective trials in different tumor entities. The majority of available data results from clinical phase I and II trials. Although regarded as well-tolerated therapies ICI-TKI combinations have higher toxicities compared to monotherapies of one of the substance classes and some combinations were shown to be excessively toxic leading to discontinuation of trials. So far, ICI-TKI combinations with nivolumab + cabozantinib, pembrolizumab + axitinib, avelumab + axitinib, pembrolizumab + lenvatinib have been approved in advanced renal cell (RCC), with pembrolizumab + lenvatinib in endometrial carcinoma and with camrelizumab + rivoceranib in hepatocellular carcinoma (HCC). Several ICI-TKI combinations are currently investigated in phase I to III trials in various other cancer entities. Further, the optimal sequence of ICI-TKI combinations is an important subject of investigation, as cross-resistances between the substance classes were observed. This review reports on clinical trials with ICI-TKI combinations in different cancer entities, their efficacy and toxicity.

The biotherapeutic Clostridium butyricum MIYAIRI 588 strain potentiates enterotropism of Rorγt+Treg and PD-1 blockade efficacy.

Immune checkpoint inhibitors (ICI) have been positioned as a standard of care for patients with advanced non-small-cell lung carcinomas (NSCLC). A pilot clinical trial has reflected optimistic association between supplementation with Clostridium butyricum MIYAIRI 588 (CBM588) and ICI efficacy in NSCLC. However, it remains to be established whether this biotherapeutic strain may be sufficient to heighten the immunogenicity of the tumor draining lymph nodes to overcome resistance to ICI. Herein, we report that supplementation with CBM588 led to an improved responsiveness to antibody targeting programmed cell death protein 1 (aPD-1). This was statistically associated with a significant decrease in α-diversity of gut microbiota from CBM588-treated mice upon PD-1 blockade. At the level of the tumor-draining lymph node, such combination of treatment significantly lowered the frequency of microbiota-modulated subset of regulatory T cells that express Retinoic Orphan Receptor gamma t (Rorγt+ Treg). Specifically, this strongly immunosuppressive was negatively correlated with the abundance of bacteria that belong to the family of Ruminococcaceae. Accordingly, the colonic expression of both indoleamine 2,3-Dioxygenase 1 (IDO-1) and interleukin-10 (IL-10) were heightened in mice with greater PD-1 blockade efficacy. The CBM588-induced ability to secrete Interleukin-10 of lamina propria mononuclear cells was heightened in tumor bearers when compared with cancer-free mice. Conversely, blockade of interleukin-10 signaling preferentially enhanced the capacity of CD8+ T cells to secrete Interferon gamma when being cocultured with CBM588-primed lamina propria mononuclear cells of tumor-bearing mice. Our results demonstrate that CBM588-centered intervention can adequately improve intestinal homeostasis and efficiently overcome resistance to PD-1 blockade in mice.

Revolutionizing gastric cancer treatment: The potential of immunotherapy.

Gastric cancer, a prevalent malignancy worldwide, ranks sixth in terms of frequency and third in fatality, causing over a million new cases and 769000 annual deaths. Predominant in Eastern Europe and Eastern Asia, risk factors include family medical history, dietary habits, tobacco use, Helicobacter pylori, and Epstein-Barr virus infections. Unfortunately, gastric cancer is often diagnosed at an advanced stage, leading to a grim prognosis, with a 5-year overall survival rate below 5%. Surgical intervention, particularly with D2 Lymphadenectomy, is the mainstay for early-stage cases but offers limited success. For advanced cases, the National Comprehensive Cancer Network recommends chemotherapy, radiation, and targeted therapy. Emerging immunotherapy presents promise, especially for unresectable or metastatic cases, with strategies like immune checkpoint inhi-bitors, tumor vaccines, adoptive immunotherapy, and nonspecific immunomodulators. In this Editorial, with regards to the article "Advances and key focus areas in gastric cancer immunotherapy: A comprehensive scientometric and clinical trial review", we address the advances in the field of immunotherapy in gastric cancer and its future prospects.

Real-world treatment outcomes of immune checkpoint inhibitors used off-label in oncology: A comprehensive cancer institution experience.

Off-label use (OLU) is quite common in oncology due to the complexity of cancer and the time-consuming regulatory process. However, outcomes of OLU in cancer treatment remain unclear. This study aimed to evaluate the overall survival (OS), event-free survival (EFS), duration of treatment (DOT), and reason for treatment discontinuation in patients receiving immune checkpoint inhibitors (ICI) as OLU for solid tumors from 2011 to 2020. The study collected data on 356 episodes (353 patients), with a median age of 64.4 years, 36.2% women, and 14.6% ECOG ≥ 2. Median OS was 15.7 (11.9-18.7) months, and median EFS was 5.4 (3.8-6.6) months. Men, patients with metastatic disease or ECOG-PS higher than 1, had worse survival outcomes. The findings derived from this study provide valuable information regarding the real-world use of ICI-OLU and contributes to enhancing the decision-making process for individuals with cancer. Further research on immunotherapy outcomes of OLU in cancer is needed.

Effect of immunotherapy-infusion time of day on survival of patients with advanced cancers: a study-level meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have become the standard of care for numerous malignancies. Emerging evidence suggests that the time of day (ToD) of ICI administration could impact the outcomes of patients with cancer. The consistency of ToD effects on ICI efficacy awaits initial evaluation. MATERIALS AND METHODS: This meta-analysis integrates progression-free survival (PFS) and overall survival (OS) data from studies with a defined 'cut-off' ToD. Hazard ratios (HRs) [95% confidence interval (CI)] of an earlier progression or death according to 'early' or 'late' ToD of ICIs were collected from each report and pooled. RESULTS: Thirteen studies involved 1663 patients (Eastern Cooperative Oncology Group performance status 0-1, 83%; males/females, 67%/33%) with non-small-cell lung cancer (47%), renal cell carcinoma (24%), melanoma (20%), urothelial cancer (5%), or esophageal carcinoma (4%). Most patients received anti-programmed cell death protein 1 or anti-programmed death-ligand 1 (98%), and a small proportion also received anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) (18%). ToD cut-offs were 13:00 or 14:00 (i.e. ICI median infusion time), for six studies, and 16:00 or 16:30 (i.e. reported threshold for weaker vaccination responses) for seven studies. Pooled analyses revealed that the early ToD groups had longer OS (HR 0.50, 95% CI 0.42-0.58; P < 0.00001) and PFS (HR 0.51, 95% CI 0.42-0.61; P < 0.00001) compared with the late ToD groups. CONCLUSIONS: Patients with selected metastatic cancers seemed to largely benefit from early ToD ICI infusions, which is consistent with circadian mechanisms in immune-cell functions and trafficking. Prospective randomized trials are needed to establish recommendations for optimal circadian timing of ICI-based cancer therapies.

Corticosteroid-resistant immune-related adverse events: a systematic review.

Immune checkpoint inhibitor (ICI) treatment has become an important therapeutic option for various cancer types. Although the treatment is effective, ICI can overstimulate the patient's immune system, leading to potentially severe immune-related adverse events (irAEs), including hepatitis, colitis, pneumonitis and myocarditis. The initial mainstay of treatments includes the administration of corticosteroids. There is little evidence how to treat steroid-resistant (sr) irAEs. It is mainly based on small case series or single case reports. This systematic review summarizes available evidence about sr-irAEs. We conducted a systematic literature search in PubMed. Additionally, we included European Society for Medical Oncology, Society for Immunotherapy of Cancer, National Comprehensive Cancer Network and American Society of Clinical Oncology Guidelines for irAEs in our assessment. The study population of all selected publications had to include patients with cancer who developed hepatitis, colitis, pneumonitis or myocarditis during or after an immunotherapy treatment and for whom corticosteroid therapy was not sufficient. Our literature search was not restricted to any specific cancer diagnosis. Case reports were also included. There is limited data regarding life-threatening sr-irAEs of colon/liver/lung/heart and the majority of publications are single case reports. Most publications investigated sr colitis (n=26), followed by hepatitis (n=21), pneumonitis (n=17) and myocarditis (n=15). There is most data for mycophenolate mofetil (MMF) to treat sr hepatitis and for infliximab, followed by vedolizumab, to treat sr colitis. Regarding sr pneumonitis there is most data for MMF and intravenous immunoglobulins (IVIG) while data regarding infliximab are conflicting. In sr myocarditis, most evidence is available for the use of abatacept or anti-thymocyte globulin (ATG) (both with or without MMF) or ruxolitinib with abatacept. This review highlights the need for prompt recognition and treatment of sr hepatitis, colitis, pneumonitis and myocarditis. Guideline recommendations for sr situations are not defined precisely. Based on our search, we recommend-as first line treatment-(1) MMF for sr hepatitis, (2) infliximab for sr colitis, followed by vedolizumab, (3) MMF and IVIG for sr pneumonitis and (4) abatacept or ATG (both with or without MMF) or ruxolitinib with abatacept for sr myocarditis. These additional immunosuppressive agents should be initiated promptly if there is no sufficient response to corticosteroids within 3 days.

Immunoneoadjuvant therapy with immune checkpoint inhibitors of gastric cancer: an emerging exemplification : Immunoneoadjuvant therapy of gastric cancer.

Advances in immune checkpoint inhibitors (ICIs) have enabled more effective treatment for individuals with various types of solid tumors. Given the improved survival benefit and acceptable safety profile of ICIs in advanced gastric cancer, there is plenty of interest in the use of ICIs in the neoadjuvant setting with curative intent. Theoretically, immunoneoadjuvant with ICIs could boost the levels of endogenous tumor antigen present in the tumor to enhance T-cell priming and further enhance systemic immunity. This systemic immune response may improve the detection and elimination of the disseminated micrometastatic tumors beyond the resected tumor, which are sources of postsurgical relapse. Numerous clinical studies have begun to explore the application of ICIs in neoadjuvant treatment of gastric cancer. This article reviews the progress in the use of ICI monotherapy and in combination with alternative therapies for the treatment of gastric cancer to aid in the development of gastric cancer immunoneoadjuvant therapy and improve the overall therapeutic benefit.

Chinese Medicine Enhancing Response Rates to Immunosuppressant PD-L1 Inhibitor and Improving the Quality of Life of Hepatocellular Carcinoma-Bearing Mice.

Background: Malignant tumors are a significant disease endangering human health. Chinese Medicine (CM) plays an important role in comprehensive and holistic tumor treatment. Objectives: We aimed to investigate whether CM combined with the immunosuppressant PD-1/PD-L1 inhibitor has a good synergistic effect and can significantly improve response rates for the immunosuppressant. Methods: We combined CM with immunosuppressant in treating six-week-old hepatocellular carcinoma-bearing mice and compared the outcomes of groups undergoing different interventions: blank group, control group, CM group, PD-L1 inhibitor group, and CM + PD-L1 inhibitor group, with ten mice in each group. The quality of life was evaluated along with the tumor inhibition effects and growth rates. Results: CM significantly reduced tumor load and improved the quality of life of cancer-bearing mice. The survival rate was 81.8% in the control group, 100% in the CM group, 90.9% in the PD-L1 inhibitor group, and 100% in the combined group in the first week. The survival rate was 45.5% in the control group, 54.5% in the CM group, 81.8% in the PD-L1 inhibitor group, and 81.8% in the combined group in the second week. 38% mice in the CM+PD-L1 inhibitor group with smaller tumor size than the average of the control group, which was much higher than other treatment groups. CM also reduced the expression of JAK2 mRNA and STAT3 mRNA, although not significantly (P > 0.05), and reduced PD-L1 mRNA in tumor tissue compared to the control group (P < 0.05). Conclusions: CM had a synergistic effect on PD-L1 inhibitors and increased response rates to PD-L1 inhibitor treatment.

Low geriatric nutritional risk index as a poor prognostic biomarker for immune checkpoint inhibitor treatment in solid cancer.

Objective: In this investigation, we focused on the geriatric nutritional risk index (GNRI), a comprehensive metric that takes into account the patient's ideal weight, actual weight, and serum albumin levels to measure malnutrition. Our primary objective was to examine the predictive value of GNRI-defined malnutrition in determining the response to immunotherapy among cancer patients. Methods: Relevant articles for this study were systematically searched in PubMed, the Cochrane Library, EMBASE, and Google Scholar up to July 2023. Our analysis evaluated overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) as clinical outcomes. Results: This analysis comprised a total of eleven articles encompassing 1,417 patients. The pooled results revealed that cancer patients with low GNRI levels exhibited shorter OS (HR: 2.64, 95% CI: 2.08-3.36, p < 0.001) and PFS (HR: 1.87, 95% CI: 1.46-2.41, p < 0.001), and lower ORR (OR: 0.46, 95% CI: 0.33-0.65, p < 0.001) and DCR (OR: 0.42, 95% CI: 0.29-0.61, p < 0.001). Sensitivity analyses confirmed that the above results were stable. Egger's and Begg's tests revealed that there was no publication bias in the above results. Conclusion: Our results imply that the GNRI is a useful predictor of immunotherapy response in cancer patients.

Supplementation with a high-glucose drink stimulates anti-tumor immune responses to glioblastoma via gut microbiota modulation.

A high-sugar diet induces lifestyle-associated metabolic diseases, such as obesity and diabetes, which may underlie the pro-tumor effects of a high-sugar diet. We supply GL261 syngeneic glioblastoma (GBM) mice with a short-term high-glucose drink (HGD) and find an increased survival rate with no evidence of metabolic disease. Modulation of the gut microbiota through HGD supplementation is critical for enhancing the anti-tumor immune response. Single-cell RNA sequencing shows that gut microbiota modulation by HGD supplementation increases the T cell-mediated anti-tumor immune response in GBM mice. We find that the cytotoxic CD4+ T cell population in GBM is increased due to synergy with anti-programmed cell death protein 1 (anti-PD-1) immune checkpoint inhibitors, but this effect depends upon HGD supplementation. Thus, we determine that HGD supplementation enhances anti-tumor immune responses in GBM mice through gut microbiota modulation and suggest that the role of HGD supplementation in GBM should be re-examined.

Efficacy and safety analysis of TACE + Donafenib + Toripalimab versus TACE + Sorafenib in the treatment of unresectable hepatocellular carcinoma: a retrospective study.

OBJECTIVE: To compare the efficacy and safety of TACE combined with Donafenib and Toripalimab versus TACE combined with Sorafenib in the treatment of unresectable hepatocellular carcinoma (HCC), aiming to guide personalized treatment strategies for HCC and improve patient prognosis. MATERIALS AND METHODS: A retrospective analysis was conducted on the clinical data of 169 patients with unresectable advanced-stage HCC who underwent treatment at the Interventional Department of Wuhan Union Hospital from January 2020 to December 2022. Based on the patients' treatment strategies, they were divided into two groups: TACE + Donafenib + Toripalimab group (N = 81) and TACE + Sorafenib group (N = 88). The primary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) of the two groups' tumors. The secondary endpoint was the occurrence of treatment-related adverse events in the two groups of patients. RESULTS: The TACE + Donafenib + Toripalimab group showed higher ORR and DCR compared to the TACE + Sorafenib group (66.7% vs. 38.6%, 82.6% vs. 68.2%, P < 0.05). The TACE + Donafenib + Toripalimab group also demonstrated longer median progression-free survival (mPFS) (10.9 months vs. 7.0 months, P < 0.001) and median overall survival (mOS) (19.6 months vs. 10.9 months, P < 0.001) compared to the TACE + Sorafenib group. When comparing the two groups, the TACE + Sorafenib group had a higher incidence of grade 3-4 hypertension (14.8% vs. 4.9%, P = 0.041), higher incidence of diarrhea (all grades) (18.2% vs. 7.4%, P = 0.042), and higher incidence of hand-foot syndrome (all grades) (26.1% vs. 12.3%, P = 0.032). CONCLUSION: TACE combined with Donafenib and Toripalimab demonstrates superior efficacy and safety in treating unresectable HCC patients. This combination therapy may serve as a feasible option to improve the prognosis of unresectable HCC patients.

Current progress, strategy, and prospects of PD-1/PDL-1 immune checkpoint biosensing platforms for cancer diagnostics, therapy monitoring, and drug screening.

Recent technological advancements in testing and monitoring instrumentation have greatly contributed to the progress in cancer treatment by surgical, chemotherapeutic and radiotherapeutic interventions. However, the mortality rate still remains high, calling for the development of new treatment strategies with higher efficacy. Extensive efforts driven in this direction have included broadening of early cancer screening and applying innovative theranostic nanotechnologies. They have been supported by platforms introduced to enable the detection and monitoring of cancer biomarkers, inhibitors, and other agents, able to slow down cancer progression and prevent metastasis. Despite of the well-recognized principles of the immune checkpoint blockade, the efficacy of immunotherapy achieved so far does not meet the well-founded expectations. For a successful cancer treatment, highly sensitive, robust, and inexpensive multiplex biosensors have to be designed to aid in the biomarkers monitoring and in the development of new inhibitors. In this review, we provide an overview of the efforts undertaken to aid in the development and monitoring of anticancer immunotherapy, based on the programmed cell-death immune checkpoint (PD-1/PDL-1) blockade, by designing biosensors for the detection of relevant cancer biomarkers and their inhibitors screening. This review also emphasizes alternative targets made by exosomes carrying PD-L1 overexpressed in cancer cells and passed into the excreted exosomes. Evaluated are also novel targeted drug delivery nanocarriers, providing simultaneous biosensing, thereby contributing to the emerging immune checkpoint cancer therapy. On the basis of the current trends and the emerging technologies, future perspectives of cancer diagnostics and treatment monitoring using biosensing platforms are projected.

Promise and Challenges of T Cell Immunotherapy for Osteosarcoma.

The cure rate for metastatic or relapsed osteosarcoma has not substantially improved over the past decades despite the exploitation of multimodal treatment approaches, allowing long-term survival in less than 30% of cases. Patients with osteosarcoma often develop resistance to chemotherapeutic agents, where personalized targeted therapies should offer new hope. T cell immunotherapy as a complementary or alternative treatment modality is advancing rapidly in general, but its potential against osteosarcoma remains largely unexplored. Strategies incorporating immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR) modified T cells, and T cell engaging bispecific antibodies (BsAbs) are being explored to tackle relapsed or refractory osteosarcoma. However, osteosarcoma is an inherently heterogeneous tumor, both at the intra- and inter-tumor level, with no identical driver mutations. It has a pro-tumoral microenvironment, where bone cells, stromal cells, neovasculature, suppressive immune cells, and a mineralized extracellular matrix (ECM) combine to derail T cell infiltration and its anti-tumor function. To realize the potential of T cell immunotherapy in osteosarcoma, an integrated approach targeting this complex ecosystem needs smart planning and execution. Herein, we review the current status of T cell immunotherapies for osteosarcoma, summarize the challenges encountered, and explore combination strategies to overcome these hurdles, with the ultimate goal of curing osteosarcoma with less acute and long-term side effects.

Systematic vitamin D supplementation is associated with improved outcomes and reduced thyroid adverse events in patients with cancer treated with immune checkpoint inhibitors: results from the prospective PROVIDENCE study.

BACKGROUND: Hypovitaminosis D can have a negative prognostic impact in patients with cancer. Vitamin D has a demonstrated role in T-cell-mediated immune activation. We hypothesized that systematic vitamin D repletion could impact clinical outcomes in patients with cancer receiving immune-checkpoint inhibitors (ICIs). METHODS: We planned a prospective observational study (PROVIDENCE) to assess serum vitamin D levels in patients with advanced cancer receiving ICIs (cohort 1 at treatment initiation, cohort 2 during treatment) and the impact of systematic repletion on survival and toxicity outcomes. In an exploratory analysis, we compared the clinical outcomes of cohort 1 with a control cohort of patients followed at the participating centers who did not receive systematic vitamin D repletion. RESULTS: Overall, 164 patients were prospectively recruited in the PROVIDENCE study. In cohort 1, consisting of 101 patients with 94.1% hypovitaminosis (≤ 30 ng/ml) at baseline, adequate repletion with cholecalciferol was obtained in 70.1% at the three months re-assessment. Cohort 2 consisted of 63 patients assessed for vitamin D at a median time of 3.7 months since immunotherapy initiation, with no patients having adequate levels (> 30 ng/ml). Even in cohort 2, systematic supplementation led to adequate levels in 77.8% of patients at the three months re-assessment. Compared to a retrospective control group of 238 patients without systematic vitamin D repletion, PROVIDENCE cohort 1 showed longer overall survival (OS, p = 0.013), time to treatment failure (TTF, p = 0.017), and higher disease control rate (DCR, p = 0.016). The Inverse Probability of Treatment Weighing (IPTW) fitted multivariable Cox regression confirmed the significantly decreased risk of death (HR 0.55, 95%CI: 0.34-0.90) and treatment discontinuation (HR 0.61, 95%CI: 0.40-0.91) for patients from PROVIDENCE cohort 1 in comparison to the control cohort. In the context of longer treatment exposure, the cumulative incidence of any grade immune-related adverse events (irAEs) was higher in the PROVIDENCE cohort 1 compared to the control cohort. Nevertheless, patients from cohort 1 experienced a significantly decreased risk of all grade thyroid irAEs than the control cohort (OR 0.16, 95%CI: 0.03-0.85). CONCLUSION: The PROVIDENCE study suggests the potential positive impact of early systematic vitamin D supplementation on outcomes of patients with advanced cancer receiving ICIs and support adequate repletion as a possible prophylaxis for thyroid irAEs.

Predictive value of prognostic nutritional index (PNI) in recurrent or unresectable hepatocellular carcinoma received anti-PD1 therapy.

BACKGROUND: Clinical trials have shown that anti-PD1 therapy, either as a monotherapy or in combination, is effective and well-tolerated in patients with recurrent or unresectable hepatocellular carcinoma (HCC). In this study, we aimed to investigate the prognostic value of immune-nutritional biomarkers in measuring the effects of anti-PD1 therapy in these patients. METHODS: We enrolled and followed up with 85 patients diagnosed with advanced HCC who underwent anti-PD1 therapy at the First Medical Centre of Chinese People's Liberation Army (PLA) General Hospital between January 2016 and January 2021. The retrospective analysis aimed to determine whether immune-nutritional biomarkers could serve as promising prognostic indices in these patients. RESULTS: In this retrospective study, patients in the PNI-high group showed a better progression-free survival (PFS) compared to those in the PNI-low group (9.5 months vs. 4.2 months, P = 0.039). Similarly, the median overall survival (OS) was longer in the PNI-high group (23.9 months, 95%CI 17.45-30.35) than in the PNI-low group (11.7 months, 95%CI 9.27-14.13) (P = 0.002). These results were consistent with sub-analyses of the anti-PD1 therapy. Furthermore, both univariate and multivariate analyses indicated that a higher pre-treatment PNI ( > = 44.91) was a significant predictive factor for favorable outcomes in this patient cohort (HR = 0.411, P = 0.023). CONCLUSION: Our study suggests that pre-treatment PNI is a critical predictive factor in patients with recurrent or unresectable HCC undergoing anti-PD1 therapy.

Chapter 3: Management of kidney injury caused by cancer drug therapy, from clinical practice guidelines for the management of kidney injury during anticancer drug therapy 2022.

Cisplatin should be administered with diuretics and Magnesium supplementation under adequate hydration to avoid renal impairment. Patients should be evaluated for eGFR (estimated glomerular filtration rate) during the treatment with pemetrexed, as kidney injury has been reported. Pemetrexed should be administered with caution in patients with a CCr (creatinine clearance) < 45 mL/min. Mesna is used to prevent hemorrhagic cystitis in patients receiving ifosfamide. Febuxostat is effective in avoiding hyperuricemia induced by TLS (tumor lysis syndrome). Preventative rasburicase is recommended in high-risk cases of TLS. Thrombotic microangiopathy could be triggered by anticancer drugs and there is no evidence of efficacy of plasma exchange therapy. When proteinuria occurs during treatment with anti-angiogenic agents or multi-kinase inhibitors, dose reductions or interruptions based on grading should be considered. Grade 3 proteinuria and renal dysfunction require urgent intervention, including drug interruption or withdrawal, and referral to a nephrologist should be considered. The first-line drugs used for blood pressure elevation due to anti-angiogenic agents are ACE (angiotensin-converting enzyme) inhibitors and ARBs (angiotensin receptor blockers). The protein binding of drugs and their pharmacokinetics are considerably altered in patients with hypoalbuminemia. The clearance of rituximab is increased in patients with proteinuria, and the correlation with urinary IgG suggests similar pharmacokinetic changes when using other antibody drugs. AIN (acute interstitial nephritis) is the most common cause of ICI (immune checkpoint inhibitor)-related kidney injury that is often treated with steroids. The need for renal biopsy in patients with kidney injury that occurs during treatment with ICI remains controversial.

Real-World Outcomes of Latinx Versus Non-Latinx Patients Treated With First-Line Immunotherapy for Metastatic Renal-Cell Carcinoma.

BACKGROUND: There are limited data regarding the impact of ethnicity among patients receiving immune checkpoint inhibitors. We evaluated real-world outcomes between Latinx and non-Latinx patients with metastatic renal-cell carcinoma (mRCC) treated with first-line nivolumab/ipilimumab within 2 different healthcare settings. METHODS: We performed a retrospective analysis of patients with mRCC who received nivolumab/ipilimumab within the Los Angeles County Department of Health Services (LAC-DHS), a safety-net healthcare system, and the City of Hope Comprehensive Cancer Center (COH), a tertiary oncology center, between January 1, 2015 and December 31, 2021. Progression-free survival (PFS) and overall survival (OS) were determined using the Kaplan-Meier method and covariates were adjusted using multivariate Cox proportional hazards regression. RESULTS: Of 94 patients, 40 patients (43%) were Latinx while the remainder were non-Latinx (44 pts [46%] White, 7 pts [7%] Asian, and 3 pts [3%] Other). Fifty (53%) and 44 (47%) patients received their care at COH and LAC-DHS, respectively. Most Latinx patients (95%) were treated at LAC-DHS, and most non-Latinx patients (89%) were treated at COH. Pooled analysis by ethnicity demonstrated significantly shorter PFS in Latinx versus non-Latinx patients (10.1 vs. 25.2 months, hazard ratios [HR] 3.61, 95% CI 1.96-6.66, P ≤ .01). Multivariate analysis revealed a HR of 3.41 (95% CI 1.31-8.84; P = .01). At a median follow-up of 11.0 months, the median OS was not reached in either arm at the time of data cutoff. CONCLUSION: Latinx patients with mRCC had a shorter PFS treated with frontline nivolumab/ipilimumab compared to their non-Latinx counterparts. No difference was observed in OS although these data were immature. Larger studies are needed to further interrogate the social and economic determinants of ethnicity on clinical outcomes in mRCC.

Focus on T cell exhaustion: new advances in traditional Chinese medicine in infection and cancer.

In chronic infections and cancers, T lymphocytes (T cells) are exposed to persistent antigen or inflammatory signals. The condition is often associated with a decline in T-cell function: a state called "exhaustion". T cell exhaustion is a state of T cell dysfunction characterized by increased expression of a series of inhibitory receptors (IRs), decreased effector function, and decreased cytokine secretion, accompanied by transcriptional and epigenetic changes and metabolic defects. The rise of immunotherapy, particularly the use of immune checkpoint inhibitors (ICIs), has dramatically changed the clinical treatment paradigm for patients. However, its low response rate, single target and high immunotoxicity limit its clinical application. The multiple immunomodulatory potential of traditional Chinese medicine (TCM) provides a new direction for improving the treatment of T cell exhaustion. Here, we review recent advances that have provided a clearer molecular understanding of T cell exhaustion, revealing the characteristics and causes of T cell exhaustion in persistent infections and cancers. In addition, this paper summarizes recent advances in improving T cell exhaustion in infectious diseases and cancer with the aim of providing a comprehensive and valuable source of information on TCM as an experimental study and their role in collaboration with ICIs therapy.