Integrating Baseline Nutritional and Inflammatory Parameters with Post-Treatment EBV DNA Level to Predict Outcomes of Patients with De Novo Metastatic Nasopharyngeal Carcinoma Receiving Chemotherapy Combination PD-1 Inhibitor.

OBJECTIVES: To develop and validate a prognostic nomogram based on baseline nutritional and inflammatory parameters for risk stratification in patients with de novo metastatic nasopharyngeal carcinoma (dmNPC) receiving chemotherapy combination programmed death-1 (PD-1) inhibitor. METHODS: This retrospective study analyzed 131 patients with dmNPC (88 and 43 in the training and validation cohorts, respectively) between March 2017 and November 2020. All these patients received chemotherapy combined with PD-1 inhibitor treatment. We identified independent risk factors using univariate and multivariate Cox regression analyses and established a nomogram to predict the progression-free survival (PFS). The predictive accuracy of the nomogram was evaluated and independently validated. RESULTS: Baseline nutritional risk index (NRI), prognostic nutritional index (PNI), systemic immune-inflammation index (SII), uric acid (UA), and post-treatment Epstein-Barr virus (EBV) DNA were used to develop a nomogram that could divide patients into favorable- and unfavorable-prognosis groups. The median PFS (mPFS) was significantly longer in the favorable-prognosis group compared to the unfavorable-prognosis group (35.10 months [95% CI: 27.36-42.84] vs. 7.23 months [95% CI: 6.50-7.97]; p = 0.001). All results were confirmed in the validation cohort. CONCLUSIONS: The proposed model improved the prognostic risk stratification for patients with dmNPC undergoing chemotherapy combined with PD-1 inhibitor treatment.

Combination immunotherapy of PEG-modified preladenant thermosensitive liposomes and PD-1 inhibitor effectively enhances the anti-tumor immune response and therapeutic effects.

Immunotherapy is a promising cancer treatment strategy. In contrast, programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors are associated with low response rates and are only useful in a small group of cancer patients. A combination of treatments may be effective for overcoming this clinical issue. Preladenant is an adenosine (ADO) receptor inhibitor that can block the ADO pathway and improve the tumor microenvironment (TME), thereby enhancing the immunotherapeutic effect of PD-1 inhibitors. However, its poor water solubility and low targeting limit its clinical applications. We designed a PEG-modified thermosensitive-liposome (pTSL) loaded with ADO small molecule inhibitor preladenant (P-pTSL) to overcome these problems and enhance the effect of PD-1 inhibitor on breast cancer immunotherapy. The prepared P-pTSL was round and uniformly distributed with a particle size of (138.9 ± 1.22) nm, PDI: 0.134 ± 0.031, and zeta potential (-10.1 ± 1.63) mV; preladenant was released slowly at 37 °C but released fast at 42 °C from P-pTSL, which was 76.52 ± 0.44%. P-pTSL has good long-term and serum stability and excellent tumor-targeting ability in mice. Moreover, the combination with PD-1 inhibitor significantly enhanced the anti-tumor effect, and the improvement of related factors in serum and lymph was more obvious under the condition of 42 °C thermotherapy in vitro.

Chang Wei Qing Decoction enhances the anti-tumor effect of PD-1 inhibitor therapy by regulating the immune microenvironment and gut microbiota in colorectal cancer.

The anti-tumor effect of anti-PD-1 antibody has long been shown to be strongly related to the tumor immune microenvironment (TIME). This study aimed to mechanistically assess whether Chang Wei Qing (CWQ) Decoction can enhance the anti-tumor effect of PD-1 inhibitor therapy. PD-1 inhibitor therapy showed the significant anti-tumor effect in patients with mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC), rather than those with mismatch repair-proficient/microsatellite stable (pMMR/MSS) CRC. Hence, immunofluorescence double-label staining was utilized to explore the difference in the TIME between dMMR/MSI-H and pMMR/MSS CRC patients. Flow cytometry was used to analyze T-lymphocytes in tumors from mice. Western blot was used to measure the expression of PD-L1 protein in mouse tumors. The intestinal mucosal barrier of mice was evaluated by hematoxylin-eosin staining and immunohistochemistry. 16S rRNA-gene sequencing was used to examine the structure of the gut microbiota in mice. Subsequently, Spearmanapos;s correlation analysis was used to analyze the relationship between the gut microbiota and tumor-infiltrating T-lymphocytes. The results showed that dMMR/MSI-H CRC patients had more CD8+T cells and higher expression of PD-1 and PD-L1 proteins. In vivo, CWQ enhanced the anti-tumor effect of anti-PD-1 antibody and increased the infiltration of CD8+ and PD-1+CD8+ T cells in tumors. Additionally, the combination of CWQ with anti-PD-1 antibody resulted in lower inflammation in the intestinal mucosa than that induced by anti-PD-1 antibody alone. CWQ and anti-PD-1 antibody co-treatment upregulated PD-L1 protein and reduced the abundance of Bacteroides in the gut microbiota but increased the abundance of Akkermansia,Firmicutes, andActinobacteria. Additionally, the proportion of infiltrated CD8+PD-1+, CD8+, and CD3+ T cells were found to be positively correlated with the abundance of Akkermansia. Accordingly, CWQ may modulate the TIME by modifying the gut microbiota and consequently enhance the anti-tumor effect of PD-1 inhibitor therapy.

The effect of nursing intervention combined with PD-1 inhibitor on platelets, white blood cells, tumor markers and quality of life in patients with lung cancer.

Tumor immunotherapy has become one of the important directions in the field of anti-tumor research. Among them, programmed death molecule-1 (PD-1) and its ligand (PD-L1) inhibitors have attracted considerable attention. This study analyzed the application effects of PD-1 inhibitors assisted nursing intervention in patients with lung cancer (LC). Sixty-eight patients with LC were divided into research group and control group randomly. Control group was treated with PD-1 inhibitor chemotherapy. Research group was treated with PD-1 inhibitors as auxiliary nursing intervention. Platelets, immune function indexes, tumor markers, and white blood cells were analyzed. Clinical efficacy was evaluated by traditional Chinese medicine (TCM) symptom score, survival quality of karnofsky performance scale (KPS) score, living quality of quality of life (QOL) score, and nausea and vomiting classification. Hemoglobin (HB), platelet (PLT) and serum white blood cells (WBC) levels in the two groups were decreased after treatment. HB, PLT and WBC levels were enhanced in research group versus control group. Moreover, carcino-embryonic antigen (CEA), carbohydrate antigen 199 (CA199) and CA125 levels in both groups were reduced after treatment. Compared with before treatment, the levels of cluster of differentiation (CD)3+, CD4+, CD4+/CD8+ in control group and the research group increased, while the CD8+ content was significantly decreased after treatment. And their content of the research group was significantly higher/lower than that of the control group. TCM symptom score, KPS score, QOL score and nausea and vomiting classification were improved in research group compared to control group. PD-1 inhibitors assisted nursing intervention can improve the living quality of patients with LC after chemotherapy.

Construction and Validation of A Predictive Model Including TCM Pathogenic Syndrome for Short-term Efficacy of PD-1 Inhibitors in Advanced Non-small Cell Lung Cancer / 肿瘤防治研究

Objective To evaluate predictive factors affecting the short-term efficacy of PD-1 inhibitors in non-small cell lung cancer (NSCLC) and to construct a prediction model. Methods From October 2019 to November 2021, 221 patients with advanced NSCLC who met the inclusion criteria and were treated with PD-1 inhibitors were prospectively enrolled. Patients who were enrolled before May 1st, 2021 were included inthe modeling group (n=149), whereas those who enrolled thereafter were included in the validation group (n=72). The general clinical data of patients, information of the four TCM diagnoses were collected, and TCM syndrome elements were identified. R software version 4.0.4 was used in constructing a nomogram clinical prediction model of objective response rate. The predictive ability and discrimination of the model were evaluated and externally validated by using a validation group. Results After two to four cycles of PD-1 inhibitor therapy in 221 patients, the overall objective response rate was 44.80%. Multivariate logistic regression analysis of the modeling group showed that the TPS score (OR=0.261, P=0.001), number of treatment lines (OR=3.749, P=0.002), treatment mode (OR=2.796, P=0.019), qi deficiency disease syndrome elements (OR=2.296, P=0.043), and syndrome elements of yin deficiency disease (OR=3.228, P=0.005) were the independent predictors of the short-term efficacy of PD-1 inhibitors. Based on the above five independent predictors, a nomogram prediction model for the short-term efficacy of PD-1 inhibitors was constructed. The AUC values of the modeling and validation groups were 0.8317 and 0.7535, respectively. The calibration curves of the two groups showed good agreement between the predicted and true values. The mean absolute errors were 0.053 and 0.039, indicating that the model has good predictive performance. Conclusion The nomogram model constructed on the basis of the syndrome elements of Qi-deficiency disease and Yin-deficiency syndrome of TCM, as well as TPS score, number of treatment lines and treatment mode, is a stable and effective tool for predicting the short-term efficacy of PD-1 inhibitors in advanced non-small cell lung cancer.

Effects of PD-1 inhibitor combined with anti-angiogenic drugs on efficacy and immune function of non-small cell lung cancer.

OBJECTIVE: To investigate the effect of PD-1 inhibitor combined with anti-angiogenic drugs on the therapeutic efficacy and immune function of patients with non-small cell lung cancer (NSCLC). METHODS: Clinical data of 60 NSCLC patients who admitted to a regional Hospital of Traditional Chinese Medicine from May 2020 to August 2021 were analyzed retrospectively. Among them, 23 patients who received sintilimab and anlotinib were in group A, 20 patients treated with sintilimab were in group B, and 17 patients intervened by anlotinib alone were in group C. The changes of clinical efficacy, objective remission rate (ORR) and disease control rate (DCR) among the three groups were compared. The levels of cluster of differentiation 4 (CD4)+, cluster of differentiation 8 (CD8)+ and CD4+/CD8+ were assessed before and 6 weeks after treatment. The progression-free survival (PFS) was calculated and the prognostic factors were analyzed by Cox regression. The adverse reactions of immunotherapy in three groups were evaluated. RESULTS: There was no obvious difference in ORR among the three groups (P>0.05). The proportion of DCR in group A was dramatically higher than that in group B and C (P<0.05). After treatment, the CD4+ and CD4+/CD8+ levels were markedly higher, while the CD8+ level in group A was lower in group A than those in the other two groups (P<0.05). There was no obvious difference in the incidence of immune-related adverse reactions among the three groups (P>0.05). The median PFS of patients was 6.03 months. Cox regression analysis revealed that Eastern Cooperative Oncology Group score, tumor metastasis and treatment regimen were independent prognostic factors affecting PFS. CONCLUSION: Sintilimab combined with anlotinib can effectively improve DCR and prolong PFS in NSCLC patients, and this regimen does not increase immune-related adverse reactions during treatment.

Reacción adversa a medicamento con signos cutáneos (erupción liquenoide) atribuibles a imatinib, y respuesta favorable al tratamiento con fototerapia UVB de banda angosta / Adverse drug reaction with skin signs (lichenoid rash) attributable to imatinib, and favorable response to treatment with narrowband UVB phototherapy

Resumen El imatinib es un agente antineoplásico que actúa como inhibidor de la tirosina-cinasa. Los efectos adversos cutáneos son, en general, leves y autolimitados. Dentro de estos, la erupción liquenoide es infrecuente y suele mejorar sólo con tratamiento tópico. Presentamos el caso de una paciente con erupción liquenoide por imatinib refractaria al tratamiento con corticoides tópicos, con respuesta favorable a terapia de luz ultravioleta B de banda estrecha. No existen casos publicados a la fecha en la literatura de erupción liquenoide por imatinib tratada con fototerapia.

Abstract Imatinib is an antineoplastic agent that acts as a tyrosine kinase inhibitor. Cutaneous adverse effects are generally mild and self-limited. The lichenoid eruption due to imatinib is rare. It usually improves just with topical treatment. We present the case of a patient with a lichenoid reaction due to imatinib, refractory to treatment with topical corticosteroids, with a favorable response to narrow-band ultraviolet B phototherapy. There are no published cases to date in the literature of lichenoid eruption due to imatinib treated with phototherapy.

Anti-PD-1 Immunotherapy and Bee Venom for Relapsed and Refractory Liposarcoma: A Case Report.

Cancer immunotherapies, including immune checkpoint inhibitors, elicit long-term clinical responses but many cancer patients do not respond. Intensive efforts are therefore underway to identify additional immune pathways that may be modulated to enhance the efficacy of existing immunotherapies. Bee venom strongly stimulates the immune system, and is used as a complementary therapy to treat cancer pain in patients with advanced tumors in China. Bee venom contains several allergenic protease inhibitors and peptides. It triggers hypersensitivity reactions; that is, it is an immune system agonist. The generation of a spontaneous T cell response against tumor-associated antigens requires innate immune activation; this drives type I interferon production. We report a patient with a relapsed and refractory liposarcoma who had undergone several operations, chemotherapies, and radiotherapies. The tumor was large. The patient had attained the maximum radiation exposure dose. The tumor was resistant to chemotherapy and was infiltrating the pericardium, lungs, and diaphragm. The patient was a poor candidate for resection. He thus received apitherapy (a combination of bee venom and acupuncture) to control pain; then apatinib (an anti-angiogenic drug) was given to inhibit tumor growth but was terminated early because the patient could not tolerate the side effects. Subsequently, a programmed death 1 inhibitor was combined with apitherapy. Bee venom served as an innate immune system agonist promoting immune cell priming and recruitment in the tumor microenvironment. The patient was finally able to undergo radical liposarcoma resection, and no evidence of recurrence was found at re-examination 16 months after surgery.

Immune checkpoint inhibitor-related dermatologic adverse events.

Immune checkpoint inhibitors have emerged as a pillar in the management of advanced malignancies. However, nonspecific immune activation may lead to immune-related adverse events, wherein the skin and its appendages are the most frequent targets. Cutaneous immune-related adverse events include a diverse group of inflammatory reactions, with maculopapular rash, pruritus, psoriasiform and lichenoid eruptions being the most prevalent subtypes. Cutaneous immune-related adverse events occur early, with maculopapular rash presenting within the first 6 weeks after the initial immune checkpoint inhibitor dose. Management involves the use of topical corticosteroids for mild to moderate (grades 1-2) rash, addition of systemic corticosteroids for severe (grade 3) rash, and discontinuation of immunotherapy with grade 4 rash. Bullous pemphigoid eruptions, vitiligo-like skin hypopigmentation/depigmentation, and psoriasiform rash are more often attributed to programmed cell death-1/programmed cell death ligand-1 inhibitors. The treatment of bullous pemphigoid eruptions is similar to the treatment of maculopapular rash and lichenoid eruptions, with the addition of rituximab in grade 3-4 rash. Skin hypopigmentation/depigmentation does not require specific dermatologic treatment aside from photoprotective measures. In addition to topical corticosteroids, psoriasiform rash may be managed with vitamin D3 analogues, narrowband ultraviolet B light phototherapy, retinoids, or immunomodulatory biologic agents. Stevens-Johnson syndrome and other severe cutaneous immune-related adverse events, although rare, have also been associated with checkpoint blockade and require inpatient care as well as urgent dermatology consultation.

Prim-O-glucosylcimifugin enhances the antitumour effect of PD-1 inhibition by targeting myeloid-derived suppressor cells.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are immunosuppressive cells that play an important role in immune evasion, PD-1/PD-L1 inhibitor tolerance and tumour progression. Therefore, MDSCs are potential targets for cancer immunotherapy. In this study, we screened an effective polymorphonuclear MDSC (PMN-MDSC) inhibitor from the Traditional Chinese Medicine Library and evaluated its synergistic antitumour effects with PD-1 inhibitor. METHODS: In the present study, we found that PMN-MDSCs accumulate heavily in the spleen and bone marrow of melanoma (B16-F10) tumour-bearing mice. Then, we determined the top 10 key proteins in the upregulated KEGG pathways of PMN-MDSCs in tumour-bearing mice through proteomics and Cytoscape analysis. The key proteins were then used as targets for the screening of PMN-MDSC inhibitors from the traditional Chinese Medicine Library (20000 compounds) through molecular docking and weight calculation of the docking score. Finally, the inhibitory effect of the inhibitor was verified through proteomics and metabolomics analysis in vitro and melanoma (B16-F10) and triple-negative breast cancer (4 T1) mouse tumour models in vivo. RESULTS: Traditional Chinese medicine saposhnikovia root extract Prim-O-glucosylcimifugin (POG) could bind well to the target proteins and inhibit the proliferation, metabolism and immunosuppressive ability of PMN-MDSCs by inhibiting arginine metabolism and the tricarboxylic acid cycle (TCA cycle). POG could also increase CD8 T-lymphocyte infiltration in the tumours and enhance the antitumour effect of PD-1 inhibitor in B16-F10 and 4 T1 mouse tumour models. CONCLUSIONS: POG was successfully screened from the traditional Chinese Medicine library as a PMN-MDSC inhibitor. POG exhibited a good synergistic antitumour effect with PD-1 inhibitor. This study provided a potential option for enhancing the efficacy of PD-1 inhibitors in clinical applications.

Nivolumab in advanced hepatocellular carcinoma: Sorafenib-experienced Asian cohort analysis.

BACKGROUND & AIMS: Nivolumab, an immune checkpoint inhibitor, is approved in several countries to treat sorafenib-experienced patients with HCC, based on results from the CheckMate 040 study (NCT01658878). Marked differences exist in HCC clinical presentation, aetiology, treatment patterns and outcomes across regions. This analysis assessed the safety and efficacy of nivolumab in the Asian cohort of CheckMate 040. METHODS: CheckMate 040 is an international, multicentre, open-label, phase I/II study of nivolumab in adults with advanced HCC, regardless of aetiology, not amenable to curative resection or local treatment and with/without previous sorafenib treatment. This analysis included all sorafenib-experienced patients in the intent-to-treat (ITT) overall population and Asian cohort. The analysis cut-off date was March 2018. RESULTS: There were 182 and 85 patients in the ITT population and Asian cohort, respectively. In both populations, most patients were older than 60 years, had BCLC (Barcelona Clinic Liver Cancer) Stage C disease, and had received previous systemic therapy. A higher percentage of Asian patients had HBV infections, extrahepatic metastases and prior therapies. Median follow-up was 31.6 and 31.3 months for the ITT and Asian patients, respectively. Objective response rates were 14% and 15% in the ITT population and Asian cohort, respectively. In the Asian cohort, patients with HBV, HCV or those who were uninfected had objective response rates of 13%, 14% and 21%, respectively. The median duration of response was longer in the ITT (19.4 months) vs. Asian patients (9.7 months). Median overall survival was similar between the ITT (15.1 months) and Asian patients (14.9 months), and unaffected by aetiology in Asian patients. The nivolumab safety profile was similar and manageable across both populations. CONCLUSION: Nivolumab safety and efficacy are comparable between sorafenib-experienced ITT and Asian patients. LAY SUMMARY: The CheckMate 040 study evaluated the safety and efficacy of nivolumab in patients with advanced hepatocellular carcinoma who were refractory to previous sorafenib treatment or chemotherapy. This subanalysis of the data showed that treatment responses and safety in patients in Asia were similar to those of the overall treatment population, providing support for nivolumab as a treatment option for these patients. Clinical trial number: NCT01658878.

Management of Persistent Pruritus and Lichenoid Reaction Secondary to Nivolumab With Narrowband Ultraviolet B Phototherapy.

Immune checkpoint inhibitors targeting the programmed cell death receptor 1 (PD-1) are increasingly used to treat several malignancies, with the most common adverse event being cutaneous toxicity. We report the case of a 68-years-old man with stage IV non-small cell lung cancer treated with nivolumab who developed a pruritic, lichenoid eruption refractory to treatment with topical or systemic steroids, who was started on narrow band ultraviolet B therapy which resolved the reaction.