Application Of Immune Checkpoint Inhibitors Research Articles

Pulmonary sarcoidosis-like reactions induced by sintilimab in esophageal cancer: A case report.

Esophageal cancer is one of the deadliest cancers in the world, with high incidence and mortality rates ranking among the top ten in China. The efficacy of conventional treatments is limited and often accompanied by severe adverse reactions, which results in unsatisfactory outcomes. The mechanism of immune checkpoint inhibitors (ICIs) is to activate cytotoxic T cells to kill tumor cells expressing tumor antigens. The application of ICIs has profoundly changed the mode of cancer treatment. However, the use of ICIs also induces a series of adverse reactions similar to autoimmune reactions, called immune-related adverse events (irAEs). Some ICIs can cause manifestations similar to those in the development of sarcoidosis, which are called sarcoidosis-like reactions or granulomatosis. We report a 50-year-old Chinese male patient. The patient had been diagnosed with advanced esophageal squamous cell carcinoma , and was confirmed to have pulmonary sarcoidosis-like reactions associated with sintilimab, a human programmed cell death protein 1 (PD-1) inhibitor. The patient was administered corticosteroid treatment. After receiving steroid treatment, the patient's systemic and pulmonary symptoms improved rapidly. To our knowledge, this is the first report of pulmonary sarcoidosis-like reaction in a patient with esophageal squamous cell carcinoma. The patient then continued to receive 1 year of follow-up antitumor treatment after the appearance of lung pulmonary sarcoidosis-like reactions. The prognosis was good and the patient's condition is currently stable. The diagnosis of ICI-induced sarcoidosis often requires comprehensive evaluation through clinical, pathological, and radiological assessment. A subset of patients with sarcoidosis-like reactions may not require treatment unless there is organ dysfunction or severe clinical symptoms, and these reactions generally respond well to treatment. The occurrence of sarcoidosis-like reactions after immunotherapy is positively correlated with the long-term prognosis of cancer patients. However, this hypothesis requires larger prospective studies for validation.

Introduction of an Ultraviolet C-Irradiated 4T1 Murine Breast Cancer Whole-Cell Vaccine Model.

The advent of immunotherapy has revolutionized cancer treatments. However, the application of immune checkpoint inhibitors may entail severe side effects, with the risk of therapeutic resistance. The generation of chimeric antigen receptor (CAR) T-cells or CAR-NK cells requires specialized molecular laboratories, is costly, and is difficult to adapt to the rapidly growing number of cancer patients. To provide a simpler but effective immune therapy, a whole-cell tumor vaccine protocol was established based on ultraviolet C (UCV)-irradiated 4T1 triple-negative breast cancer cells. The apoptosis of tumor cells after UVC irradiation was verified using resazurin and Annexin V/propidium iodide flow cytometric assays. Protective immunity was achieved in immunized BALB/c mice, showing partial remission. Adoptive transfer of splenocytes or plasma from the mice in remission showed a protective effect in the naive BALB/c mice that received a living 4T1 tumor cell injection. 4T1-specific IgG antibodies were recorded in the plasma of the mice following immunization with the whole-cell vaccine. Interleukin-2 (IL-2) and oligonucleotide 2006 (ODN2006) adjuvants were used for the transfer of splenocytes from C57BL/6 mice into cyclophosphamide-treated BALB/c mice, resulting in prolonged survival, reduced tumor growth, and remission in 33% of the cases, without the development of the graft-versus-host disease. Our approach offers a simple, cost-effective whole-cell vaccine protocol that can be administered to immunocompetent healthy organisms. The plasma or the adoptive transfer of HLA-matching immunized donor-derived leukocytes could be used as an immune cell therapy for cancer patients.

Mediators and mechanisms of immune checkpoint inhibitor-associated myocarditis: Insights from mouse and human.

The broad application of immune checkpoint inhibitors (ICIs) has led to significant gains in cancer outcomes. By abrogating inhibitory signals, ICIs promote T cell targeting of cancer cells but can frequently trigger autoimmune manifestations, termed immune-related adverse events (irAEs), affecting essentially any organ system. Among cardiovascular irAEs, immune-related myocarditis (irMyocarditis) is the most described and carries the highest morbidity. The currently recommended treatment for irMyocarditis is potent immunosuppression with corticosteroids and other agents, but this has limited evidence basis. The cellular pathophysiology of irMyocarditis remains poorly understood, though mouse models and human data have both implicated effector CD8+ T cells, some of which are specific for the cardiomyocyte protein α-myosin. While the driving molecular signals and transcriptional programs are not well defined, the involvement of chemokine receptors such as CCR5 and CXCR3 has been proposed. Fundamental questions regarding why only approximately 1% of ICI recipients develop irMyocarditis and why irMyocarditis carries a much worse prognosis than other forms of lymphocytic myocarditis remain unanswered. Further work in both murine systems and with human samples are needed to identify better tools for diagnosis, risk-stratification, and treatment.

Isolated adrenocorticotropic hormone deficiency following immune checkpoint inhibitors treatment often occurs in polyglandular endocrinopathies

BackgroundWith the increasing application of immune checkpoint inhibitors (ICI) in cancer therapy, the occurrence of isolated adrenocorticotropic hormone deficiency (IAD), as an adverse effect, is also on the rise. Nevertheless, there are only a few studies regarding IAD induced by ICI. This study aimed at investigating the characteristics of IAD induced by ICI and its relationship with other endocrine adverse events.MethodsA retrospective study was conducted in the Endocrinology Department from January 2019 to August 2022 to investigate characteristics of patients with IAD. Clinical features, laboratory findings and treatment information were collected. All patients underwent a follow-up of 3-6-month.Results28 patients with IAD were enrolled. All patients received treatment with anti-PD-1/ PD-L1. The median occurrence time of IAD was 24 (18–39) weeks after initiation of ICI treatment. Over half of the patients (53.5%) had an additional endocrinopathy, including primary hypothyroidism and fulminant type 1 diabetes mellitus (FT1DM), while other types of endocrinopathies were not identified. The interval between the occurrences of two gland damages was between 4 and 21 weeks or simultaneous. Primary hypothyroidism (46.4%) was more prevalent than FT1DM (7.1%). Fatigue and nausea were common symptoms, with a frequent occurrence of hyponatremia. All patients continued on oral glucocorticoids during follow-up.ConclusionsIAD induced by ICI could manifest independently, or more frequently in combination with hypothyroidism or FT1DM. This damage could happen at any point of ICI treatment. Given that IAD can be life-threatening, it is critical to evaluate pituitary function dynamically in patients undergoing immunotherapy.

New developments in the mechanism and application of immune checkpoint inhibitors in cancer therapy (Review).

The use of immune checkpoint inhibitors (ICIs) has been demonstrated in the treatment of numerous types of cancer and ICIs have remained a key focus of cancer research. However, improvements in survival rates only occur in a subset of patients, due to the complexity of drug resistance. Therefore, further investigations are required to identify predictive biomarkers that distinguish responders and non‑responders. Combined therapeutics involving ICIs and other modalities demonstrate potential in overcoming resistance to ICIs; however, further preclinical and clinical trials are required. Concurrently, prompt recognition and intervention of immune‑related adverse events are crucial to optimize the use of ICIs in clinical treatment. The present study aimed to review the current literature surrounding the mechanisms and application of ICIs, with the aim of providing a theoretical basis for clinicians.

Neoadjuvant tislelizumab plus nab-paclitaxel and carboplatin followed by adjuvant tislelizumab in patients with early triple-negative breast cancer.

602 Background: Triple-negative breast cancer (TNBC) is the subtype with the least favorable outcomes. However, TNBC is associated with higher immune cell abundance than other subtypes, making it a good candidate for immunotherapy. Neoadjuvant chemotherapy is the preferred treatment approach for early TNBC. Emerging evidence shows that additional immune checkpoint inhibitors (ICI) in neoadjuvant therapy significantly increases pathological complete response (pCR) and event-free survival in early TNBC. Treatment regimens of paclitaxel and carboplatin (TP) is class I recommendation for TNBC neoadjuvant therapy, the application of ICI with TP regimens is worth exploring. Methods: In this multicenter, open-label, phase II study, patients with untreated, histologically confirmed TNBC in stage II-III (per AJCC 8th edition) were enrolled. Patients received six cycles of neoadjuvant therapy with tislelizumab at 200 mg once every 3 weeks plus nab-paclitaxel (125 mg/m2 on days 1 and 8) and carboplatin (at a dose based on an area under the concentration 2 on days 1 and 8) every 3 weeks. Patients who either completed or discontinued the neoadjuvant treatment would undergo definitive surgery. After surgery, the patients received adjuvant tislelizumab every 3 weeks for up to 12 cycles. The primary endpoint was the rate of pCR (ypT0/Tis ypN0). The secondary endpoints included 1-, 2-, 3-year event free survival rates and overall survival rates. Based on the Simon’s Two-Stage design, if > 13 of 32 patients achieved pCR, the enrollment would proceed to full accrual of 62 patients as planned. If > 29 of 62 patients achieved pCR, we would deem the study to have met the primary endpoint. Results: From Mar 2021 to Jan 2022, 32 patients were enrolled; 18 of them achieved pCR, and therefore the study proceeded to complete the enrollment of 62 patients. At the data cut-off of Oct 13, 2022, 62 patients were enrolled, among which 50 patients received neoadjuvant treatment and underwent definitive surgery. The median age was 50 years. 36 (72.0%) patients had stage II breast cancer at diagnosis. 31 of the 50 patients achieved pCR (ypT0/Tis ypN0), and the pCR rate was 62.0% (95% CI, 47.2-75.4). Patients with immune cell PD-L1 expression ≥10% had numerically higher pCR rate (81.8% vs 53.6%) than those with PD-L1 expression ≥1%. All 50 (100%) patients reported any grade of neoadjuvant treatment-related adverse events (TRAEs). Grade ≥3 TRAEs occurred in 27 (54%) patients. The rate of immune-related adverse events (irAEs) was 34% (17/50), with the common occurring (10%) irAE of hypothyroidism (n = 8, 16%). 2 (4.9%) patients experienced grade ≥3 irAEs. Severe adverse events were reported in 5 (10%) patients. Conclusions: The study has met its primary endpoint. Tislelizumab plus nab-paclitaxel and carboplatin achieved a higher pCR and was generally well tolerated in the neoadjuvant treatment of early TNBC. Clinical trial information: ChiCTR2100041675 .

Clinical analysis of combined immunotherapy in patients with malignant pleural mesothelioma

Objective: To observe the present situation, efficacy and safety of immunotherapy in patients with malignant pleural mesothelioma (MPM). Methods: The data of 39 patients with MPM in two centers from 2016 to 2021 were collected and the efficacy and safety were evaluated. According to the application of immune checkpoint inhibitors (ICIs), these patients, whose median clinical follow-up amounting to 18.97 months, were divided into immunotherapy group (19 cases) and control group (20 cases). Kaplan-Meier method and Log-rank test were used for the survival analysis. Results: The objective response rate (ORR) and the disease control rate (DCR) in the immunotherapy group is 21.05% and 79.0% respectively, compared with 10.0% and 55.0% in the control group; and the difference was not statistically significant (P>0.05). The median overall survival (OS) in the immunotherapy group was significantly longer than that in the control group (14.53 months vs 7.07 months, P=0.015), but there was no significant difference in the median progression free survival (PFS) between two groups (4.80 months vs 2.03 months, P=0.062). Single factor survival analysis showed that the nature of pleural effusion, pathological subtype and the efficacy of immunotherapy were related to both PFS and OS of the patients with MPM (P<0.05). The incidence of adverse reactions in immunotherapy group was 89.5% (17 out of 19 cases), and the most common adverse event was hematological toxicity (9 cases), followed by nausea and vomiting (7 cases), fatigue (6 cases) and skin damage (6 cases). Five patients had immune checkpoint inhibitors (ICIs) related adverse reactions with grade 1-2. Conclusions: Patients with MPM have begun to receive immunotherapy in more than 2-line mainly combined chemotherapy in the real world, and the median treatment line is 2-line. Either combined with chemotherapy or anti-angiogenesis therapy, ICI inhibitors have significant efficacy, controllable adverse events and good clinical value.

Genomic profiling of radiation-induced sarcomas reveals the immunological characteristics and its response to immune checkpoint blockade.

Radiation-induced sarcomas (RISs) have poor prognosis and lack effective treatments. Its genome and tumor microenvironment are not well characterized and need further exploration. Here, we perform whole exome (WES) and mRNA sequencing (mRNA-seq) on patient with RISs and primary sarcomas (WES samples 46 vs 48, mRNA-seq samples 16 vs 8, mainly in head and neck), investigate the anti-tumor effect of PD-1 blockade in RIS-PDX models, and analyze clinical data of RIS patients treated with chemotherapy alone or combined with an anti-PD-1 antibody. Compared to primary sarcomas, RISs manifested different pattern of copy number variations, significantly higher number of predicted strong MHC-binding neoantigens, and significantly increased immune cell infiltration. Clinical data showed that the combinatorial use of chemotherapy and PD-1 blockade achieved a higher overall response rate (ORR) (36.67% vs 8.00%, p = 0.003), longer overall survival (31.9 months vs 14.8 months, p = 0.014) and longer progression free survival (4.7 months vs 9.5 months, p = 0.032) in RIS patients compared to single chemotherapy. Elevated genomic instability and higher immune cell infiltrations was found in RISs than primary sarcomas. Moreover, higher efficacy of chemotherapy plus PD-1 blockade was observed in animal experiment and clinical practice. These evidence indicated the promising application of immune checkpoint inhibitors in the treatment of RISs.

Biomarkers and factors in small cell lung cancer patients treated with immune checkpoint inhibitors: A meta-analysis.

The aim of this meta-analysis was to summarize the available results of immunotherapy predictors for small cell lung cancer (SCLC) and to provide evidence-based information for their potential predictive value of efficacy. We searched PubMed, EMBASE, Web of Science, The Cochrane Library, and ClinicalTrials (from January 1, 1975 to November 1, 2021). The hazard ratios (HR) and its 95% confidence intervals (CIs) and tumor response rate of the included studies were extracted. Eleven studies were eventually included and the pooled results showed that programmed cell death ligand 1 (PD-L1) positive: objective response rate (ORR) (relative risk [RR]=1.39, 95% CI [0.48, 4.03], p=0.54), with high heterogeneity (p=0.05, I2 = 56%); disease control rate [DCR] (RR=1.31, 95% CI [0.04, 38.57], p=0.88), with high heterogeneity (p=0.04, I2 = 75%); overall survival (OS) (HR=0.89, 95% CI [0.74, 1.07], p=0.22); and progression-free survival (PFS) (HR=0.83, 95% CI [0.59, 1.16], p=0.27), with high heterogeneity (p=0.005, I2 = 73.1%). TMB-High (TMB-H): OS (HR=0.86, 95% CI [0.74, 1.00], p=0.05); PFS (HR=0.71, 95% CI [0.6, 0.85], p< 0.001). Lactate dehydrogenase (LDH) >upper limit of normal (ULN): OS (HR=0.95, 95% CI [0.81, 1.11], p=0.511). Asian patients: OS (HR=0.87, 95% CI [0.72, 1.04], p=0.135); White/Non-Asian patients: OS (HR=0.83, 95% CI [0.76, 0.90], p < 0.001). Liver metastasis patients: OS (HR=0.93, 95% CI [0.83, 1.05], p=0.229); PFS (HR=0.84, 95% CI [0.67, 1.06], p=0.141). Central nervous system (CNS) metastasis patients: OS (HR=0.91, 95% CI [0.71, 1.17], p=0.474); PFS (HR=1.03, 95% CI [0.66, 1.60], p=0.903). The available research results do not support the recommendation of PD-L1 positive and TMB-H as predictors for the application of immune checkpoint inhibitors (ICIs) in SCLC patients. LDH, baseline liver metastasis and CNS metastasis may be used as markers/influencing factors for predicting the efficacy of ICIs in SCLC patients. Non-Asian SCLC patients had better efficacy with ICIs in our results.

Could Inhibiting the DNA Damage Repair Checkpoint Rescue Immune-Checkpoint-Inhibitor-Resistant Endometrial Cancer?

Endometrial cancer (EC) is increasingly undermining female health worldwide, with poor survival rates for advanced or recurrent/metastatic diseases. The application of immune checkpoint inhibitors (ICIs) has opened a window of opportunity for patients with first-line therapy failure. However, there is a subset of patients with endometrial cancer who remain insensitive to immunotherapy alone. Therefore, it is necessary to develop new therapeutic agents and further explore reliable combinational strategies to optimize the efficacy of immunotherapy. DNA damage repair (DDR) inhibitors as novel targeted drugs are able to generate genomic toxicity and induce cell death in solid tumors, including EC. Recently, growing evidence has demonstrated the DDR pathway modulates innate and adaptive immunity in tumors. In this review, we concentrate on the exploration of the intrinsic correlation between DDR pathways, especially the ATM-CHK2-P53 pathway and the ATR-CHK1-WEE1 pathway, and oncologic immune response, as well as the feasibility of adding DDR inhibitors to ICIs for the treatment of patients with advanced or recurrent/metastatic EC. We hope that this review will offer some beneficial references to the investigation of immunotherapy and provide a reasonable basis for "double-checkpoint inhibition" in EC.

Effect of age on the risk of immune-related adverse events in patients receiving immune checkpoint inhibitors.

Identifying patients at increased risk of immune-related adverse events (irAEs) facilitates safe application of immune checkpoint inhibitors (ICIs). This retrospective study aimed to determine the effect of age on the risk of irAEs in patients receiving ICIs and to identify potential mechanisms underlying age-related irAE risk differences. We analyzed reports of FDA Adverse Event Reporting System from July 1, 2014, to September 30, 2021. The information component ratio (ICΔ) was used to compare the irAE risk between older adults (> 65years) and younger adults (25-65years), of which the 95% confidential interval lower limit (ICΔ025) exceeding zero indicated significantly increased risk. We found that older adults had a significantly higher overall irAE risk than younger adults (ICΔ025 0.38), which was observed in almost all organ systems. We further analyzed the correlation between age-related irAE risks and age-related transcriptional changes to identify potential genes and pathways underlying age-related irAE risk differences. We found that genes significantly correlated with ICΔ were enriched in processes including extracellular matrix organization, regulation of myeloid leukocyte mediated immunity, and regulation of c-Jun N-terminal kinase (JNK) cascade. In addition, single-cell RNA sequencing analysis confirmed that genes involved in collagen-containing extracellular matrix and JNK cascade were significantly upregulated in myeloid cells from ICI-associated colitis tissues compared with ICI-treated colon tissues without colitis. In conclusion, older adults receiving ICIs have higher irAE risks than younger adults. Upregulation of genes involved in JNK cascade and collagen-containing extracellular matrix in myeloid cells may contribute to increased irAE risks in older adults.

Advances in the application of immune checkpoint inhibitors in gynecological tumors.

Immune checkpoints are regulatory molecules that suppress immune effector cells, and are essential for maintaining tolerance, preventing autoimmune reactions, and minimizing tissue damage by controlling the duration and intensity of the immune responses. However, immune checkpoints are frequently upregulated during cancer and dampen the anti-tumor immune responses. Immune checkpoint inhibitors (ICIs) have been effective against multiple tumors, and have improved patients' survival outcomes. Recent clinical trials have also reported promising therapeutic effects of ICIs in some gynecological cancers. To review the current research and future directions in the treatment of gynecological malignancies, including ovarian, cervical and endometrial cancers, using ICIs. Currently, cervical and ovarian cancers are the only gynecological tumors that are treated by immunotherapeutic approaches. In addition, ICIs, chimeric antigen receptor (CAR)- and T cell receptor (TCR)-engineered T cells targeting endometrial tumors, especially those originating in the vulva and fallopian tubes, are under development. Nevertheless, the molecular mechanism underlying the effects of ICIs, especially in combination with chemotherapy, radiation therapy, anti-angiogenesis drugs and poly ADP ribose polymerase inhibitors (PARPi), needs to be elucidated. Furthermore, novel predictive biomarkers have to be identified in order to increase the therapeutic efficacy of ICIs while reducing adverse reactions.

Progress in the clinical application of immune checkpoint inhibitors in small cell lung cancer.

Small cell lung cancer (SCLC) is a refractory cancer with poor prognosis due to its aggressive malignancy and high rates of metastasis, recurrence and drug resistance. These characteristics have also greatly impeded the identification of new treatment methods and drugs. The traditional model of SCLC treatment that has been reliant on platinum combined with etoposide for decades has been superseded by the emergence of immune checkpoint inhibitors (ICIs), which have shown significant therapeutic effects and broad application prospects as a monotherapy. This has led to the evaluation of ICIs with different mechanisms of action and their use in combination with radiotherapy or a variety of molecular targeted drugs to achieve synergy, complementary advantages, and reduce adverse reactions. Here, we review the progress in the use of ICIs as a monotherapy or in combination therapy for SCLC and consider the current limitations of these approaches as well as prospects for future developments.

Applications of immune checkpoint inhibitors (ICIs) in the medical fields

ICIs are a kind of immunotherapy that works by preventing immune checkpoints from functioning normally, which are essential immune system components. ICIs are currently the most used immunotherapy regimen. Based on the patient's health, the cancer type, the length of the illness, and the dose of inhibitors the patient can tolerate, the therapy can cause side effects of indeterminate duration and varying degrees. However, the therapy remains beneficial for patients. Therefore, the effects of immunotherapy on the human body are still an issue that needs to be explored. An overview of ICIs in immunotherapy will be given in this paper, including the following concepts: (i) General information on treatments with immune checkpoint inhibitors (ii)The immunotherapy’s mechanism and application (iii) Problems and complications with ICI therapies (iv) Ways that the immunotherapy can be improved and the future direction of ICI.

Interaction between PD-L1 and soluble VEGFR1 in glioblastoma-educated macrophages

PurposeThe combined application of immune checkpoint inhibitors (ICIs) and anti-angiogenesis therapy has shown synergistic effects on glioblastoma (GBM). As important resources of PD-L1 in the tumor microenvironment (TME), tumor-associated macrophages (TAMs) have significant impact of the efficiency of ICIs. However, the effects of anti-angiogenesis agents on immune checkpoints expression are not fully understood.MethodGBM-educated macrophages were generated from circulating monocytes of healthy controls and GBM patients under the education of GBM cell line. Surface expression of PD-L1 and VEGFR1 on GBM-educated macrophages was analyzed. VEGFR1 NAb and soluble VEGFR1 (sVEGFR1) were added and their effects on PD-L1 expression on TAMs was investigated. Serum soluble PD-L1 (sPD-L1) and sVEGFR1 levels in GBM patients were measured and their correlation was analyzed.ResultThe expression intensity of PD-L1 on GBM-educated macrophages was higher and its up-regulation partially depends on VEGFR1 signaling pathway. GBM-educated macrophages secreted less levels of soluble VEGFR1 (sVEGFR1), and exogenous sVEGFR1 down-regulated PD-L1 expression intensity. PD-L1 blockade promoted the secretion of sVEGFR1. Finally, sVEGFR1 and sPD-L1 in serum of GBM patients were overexpressed, and a positive correlation was found.ConclusionThese findings reveal the interaction between PD-L1 and VEGFR1 signaling pathway in GBM-educated macrophages. VEGFR1 is involved with PD-L1 overexpression, which can be impeded by autocrine regulation of sVEGFR1. sVEGFR1 secretion by GBM-educated macrophages can be promoted by PD-L1 blockade. Taken together, these findings provide evidences for the combined application of ICIs and anti-angiogenesis therapies in the treatment of GBM.

Polyphotosensitizer-Based Nanoparticles with Michael Addition Acceptors Inhibiting GST Activity and Cisplatin Deactivation for Enhanced Chemotherapy and Photodynamic Immunotherapy.

Glutathione S-transferase (GST), which is a key enzyme in the conjugation reaction of glutathione (GSH), is overexpressed in cancer cells, leading to cisplatin deactivation and ultimately drug resistance. In addition, many tumors are immune "cold tumors," limiting the application of immune checkpoint inhibitors. Herein, a reactive oxygen species (ROS)-responsive polyphotosensitizer-based nanoparticle (NP2) with Michael addition acceptors inhibiting GST activity and cisplatin deactivation is designed. Under the 808nm light irradiation, on the one hand, the Michael addition acceptor in NP2 can react with GST and inhibit its activity, thereby decreasing the GSH conjugation and reducing the GSH-mediated deactivation of cisplatin and improving its chemotherapeutic effect. On the other hand, NP2+L induces more ROS production in prostate tumor cells, which can further induce type II immunogenic cell death (ICD) and stimulate a stronger antitumor immune response. It is found that NP2 under the 808nm light irradiation (NP2+L) can increase PD-L1 expression on the surface of prostate cancer cells. Subsequently, NP2+L combined with PD-L1 treatment is found to simultaneously enhance the efficacies of chemotherapy and photodynamic immunotherapy in prostate tumors, providing a new paradigm for the clinical multimodal treatment of tumors.

Correlation of immune makers with HPV 16 infections and the prognosis in oropharyngeal squamous cell carcinoma

ObjectivesThis study aims to investigate the association of immune markers with high risk human papillomavirus 16 (HPV 16) infection status and to evaluate the prognostic value of programmed death ligand-1 (PD-L1) in patients with oropharyngeal squamous cell carcinoma (OPSCC).Materials and methodsThis retrospective study collected 50 cases of HPV positive and HPV negative OPSCC from January 2011 to December 2015. The correlation of CD8 + tumor infiltrating lymphocytes (TILs), programmed death-1 (PD-1), and PD-L1 expression with HPV 16 infection status was analyzed via immunofluorescent staining and quantitative real-time PCR.ResultsThere was no significant difference in the baseline data between the two groups. Patients with HPV + OPSCC had better prognosis compared to HPV − patients (5-year overall survival [OS], 66% vs. 40%, P = 0.003; 5-year disease specific survival [DSS], 73% vs. 44%, P = 0.001). The expressions of immunity related makers were significantly higher in the HPV + group than the HPV − group (CD8 + TIL: P = 0.039; PD-L1: P = 0.005; PD-1: P = 0.044). Positive CD8 + TIL and PD-L1 were independent factors for better prognosis of OPSCC (DSS, P < 0.001; OS, P < 0.001, respectively). Kaplan–Meier survival analysis indicated that patients with TILs of high HPV + /CD8 + expression were more likely to have better prognosis than those with TILs of low HPV + /CD8 + expression (DSS, P < 0.001; OS, P < 0.001), TILs of high expression of HPV − /CD8 + (DSS, P = 0.010; OS, P = 0.032), and TILs of low expression of HPV − /CD8 + (DSS, P < 0.001; OS, P < 0.001). Furthermore, HPV + /PD-L1 + OPSCC patients had significant better prognosis compared to patients with HPV + /PD-L1 − (DSS, P < 0.001; OS, P = 0.004), HPV − /PD-L1 + (DSS, P = 0.010; OS, P = 0.048) and HPV − /PD-L1 − (DSS, P < 0.001; OS, P < 0.001).ConclusionsHPV + OPSCC had a significantly better prognosis, and PD-L1 expression was elevated in HPV + OPSCC. PD-L1 positivity might be related to the better prognosis of HPV + OPSCC.Clinical relevanceThis study provides a theoretical basis and baseline data for the application of immune checkpoint inhibitors in head and neck tumors.

Clinical characteristics and therapeutic effects of checkpoint inhibitor-related pneumonitis in patients with non-small cell lung cancer

BackgroundWith the application of immune checkpoint inhibitors (ICIs) in cancer treatment, more and more attention has been paid to checkpoint inhibitor-related pneumonitis (CIP), which requires a better understanding of its clinical characteristics and therapeutic effects.MethodsThe clinical and imaging data of 704 patients with non-small cell lung cancer (NSCLC) who received immunotherapy were analyzed retrospectively; the clinical characteristics of CIP were summarized, and the therapeutic regimens and effects of the patients were summarized.Results36 CIP patients were included in the research. The most common clinical symptoms were cough, shortness of breath and fever. The CT manifestations were summarized as follows: Organizing pneumonia (OP) in 14 cases (38.9%), nonspecific interstitial pneumonia (NSIP) in 14 cases (38.9%), hypersensitiviy pneumonitis(HP) in 2 cases (6.3%), diffuse alveolar damage in 1 case (3.1%) and atypical imaging manifestations in 5 cases (13.9%). 35 cases received glucocorticoid therapy, 6 patients were treated with gamma globulin and 1 patient was treated with tocilizumab. There were no deaths in CIP G1-2 patients and 7 deaths occured in CIP G3-4 patients. 4 patients were treated again with ICIs.ConclusionWe found that glucocorticoid 1–2 mg/kg was effective for most patients with moderate to severe CIP, and a few patients with hormone insensitivity needed early immunosuppressive therapy. A few patients can be rechallenged with ICIs, but CIP recurrence needs to be closely monitored.

Correlation of the gut microbiome and immune-related adverse events in gastrointestinal cancer patients treated with immune checkpoint inhibitors.

The wide application of immune checkpoint inhibitors has significantly improved the survival expectation of cancer patients. While immunotherapy brings benefits to patients, it also results in a series of immune-related adverse events (irAEs). Increasing evidence suggests that the gut microbiome is critical for immunotherapy response and the development of irAEs. In this prospective study, we recruited 95 patients with advanced/unresectable gastrointestinal cancers treated with immunotherapy and report a comprehensive analysis of the association of the gut microbiome with irAEs. Metagenome sequencing was used to analyze the differences in bacterial composition and metabolic pathways of baseline fecal samples. In summary, we identified bacterial species and metabolic pathways that might be associated with the occurrence of irAEs in gastric, esophageal, and colon cancers. Ruminococcus callidus and Bacteroides xylanisolvens were enriched in patients without severe irAEs. Several microbial metabolic pathways involved in the urea cycle, including citrulline and arginine biosynthesis, were associated with irAEs. We also found that irAEs in different cancer types and toxicity in specific organs and the endocrine system were associated with different gut microbiota profiles. These findings provide the basis for future mechanistic exploration.

Phase 2 open label study of durvalumab with neoadjuvant chemotherapy in variant histology bladder cancer.

524 Background: The immune-responsive nature of bladder cancer has made it an active area of interest for novel applications of immune checkpoint inhibitors (ICIs), with multiple ICI agents approved in the metastatic setting and ongoing perioperative trials. Variant histology urothelial carcinoma is a rare, heterogenous, and aggressive disease category associated with poor prognosis and response to standard therapies. This investigator-initiated phase 2 trial explored the addition of durvalumab to neoadjuvant chemotherapy (NAC) in the setting of variant histology MIBC. Methods: Patients with cT2-T4a, N0-N1, M0 histologically-confirmed bladder cancer of variant histology who were candidates for platinum-based NAC and radical cystectomy were eligible for the study. Enrolled patients received durvalumab with each cycle of investigator’s choice of platinum NAC (ddMVAC, cisplatin/gemcitabine, or carboplatin/gemcitabine). The primary objective was to determine the safety and tolerability of each study treatment as assessed by the total number of adverse events of grade 3 or higher, judged by the investigator as probably or definitely related to durvalumab. Secondary objective was to determine the percent of subjects post neoadjuvant chemo immunotherapy who achieve tumor stage of pT2N0M0 or better at cystectomy. Target accrual was 24 patients. Results: Six patients were enrolled (the study closed early due to low accrual). Median age was 72 years, 17% were women, 67% were white, 33% were Asian. 50% received ddMVAC and 50% received carboplatin/gemcitabine. All patients completed the planned cycles of NAC and durvalumab (4 cycles) and 5/6 proceeded to radical cystectomy (one patient declined cystectomy). Three patients experienced a Grade 3 AE that was assessed by the investigator to be related to treatment (table). One patient with sarcomatoid and glandular histology had pathological complete response and one patient with papillary and 10% squamous had pT2N0 at cystectomy. Conclusions: The addition of durvalumab to platinum NAC for patients with variant-histology muscle invasive bladder cancer demonstrates a reasonable safety and tolerability profile. Further investigation into this combination is warranted in larger scale trials. Clinical trial information: NCT03912818 . [Table: see text]