Severe Immune-related Adverse Effects Research Articles

Baricitinib protects ICIs-related myocarditis by targeting JAK1/STAT3 to regulate Macrophage polarization

PurposeThe emergence of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, but these drugs can also cause severe immune-related adverse effects (irAEs), including myocarditis. Researchers have become interested in exploring ways to mitigate this side effect, and one promising avenue is the use of baricitinib, a Janus kinase inhibitor known to have anti-inflammatory properties. This study aimed to examine the potential mechanism by which baricitinib in ICIs-related myocarditis. MethodsTo establish an ICIs-related myocarditis model, BALB/c mice were administered murine cardiac troponin I (cTnI) peptide and anti-mouse programmed death 1 (PD-1) antibodies. Subsequently, baricitinib was administered to the mice via intragastric administration. Echocardiography, HE staining, and Masson staining were performed to evaluate myocardial functions, inflammation, and fibrosis. Immunofluorescence was used to detect macrophages in the cardiac tissue of the mice.In vitro experiments utilized raw264.7 cells to induce macrophage polarization using anti-PD-1 antibodies. Different concentrations of baricitinib were applied to assess cell viability, and the release of pro-inflammatory cytokines was measured. The activation of the JAK1/STAT3 signaling pathway was evaluated through western blot analysis. ResultsBaricitinib demonstrated its ability to improve cardiac function and reduce cardiac inflammation, as well as fibrosis induced by ICIs. Mechanistically, baricitinib treatment promoted the polarization of macrophages towards the M2 phenotype. In vitro and in vivo experiments showed that anti-PD-1 promoted the release of inflammatory factors. However, treatment with baricitinib significantly inhibited the phosphorylation of JAK1 and STAT3. Additionally, the use of RO8191 reversed the effects of baricitinib, further confirming our findings. ConclusionBaricitinib demonstrated its potential as a protective agent against ICIs-related myocarditis by modulating macrophage polarization. These findings provide a solid theoretical foundation for the development of future treatments for ICIs-related myocarditis.

Core-shell nanomedicine based on multifunctional tetrahedral DNA nanostructures for synergistic enhancement of tumor chemodynamic/chemo-immunotherapy

Immune checkpoint blockade therapy has made great strides in cancer treatment, but conventional immune checkpoint blockade antibodies often lead to overactivation of the immune system and severe immune-related adverse effects. Herein, we report the design of a nanomedicine (denoted as CPD@M−TDN) based on multifunctional tetrahedral DNA nanostructures (M−TDN). In this system, a bimetallic metal–organic framework (Cu/ZIF-8) is synthesized as the core; doxorubicin-loaded polydopamine acts as a shell to reduce the immunogenicity of the nanomaterials in peripheral blood. Finally, the CpG oligodeoxynucleotides and PD-L1 aptamer-based M−TDN are coupled to the core–shell structure nanomedicine through the biotin-avidin-system. Under the acidic tumor microenvironment, the decomposition of Cu/ZIF-8 and the release of copper ions and doxorubicin can lead to immunogenic death of tumor cells through chemodynamic/chemotherapy. Furthermore, the M−TDN has the dual effects of weakening the immunosuppressive microenvironment with PD-L1 aptamer and promoting dendritic cell activation with the immunostimulant CpG. Overall, the developed CPD@M−TDN can effectively enhance the response rate to immunotherapy and has excellent potential in the field of integrated tumor treatment.

Advances in efficacy prediction and monitoring of neoadjuvant immunotherapy for non-small cell lung cancer.

The use of immune checkpoint inhibitors (ICIs) has become mainstream in the treatment of non-small cell lung cancer (NSCLC). The idea of harnessing the immune system to fight cancer is fast developing. Neoadjuvant treatment in NSCLC is undergoing unprecedented change. Chemo-immunotherapy combinations not only seem to achieve population-wide treating coverage irrespective of PD-L1 expression but also enable achieving a pathological complete response (pCR). Despite these recent advancements in neoadjuvant chemo-immunotherapy, not all patients respond favorably to treatment with ICIs plus chemo and may even suffer from severe immune-related adverse effects (irAEs). Similar to selection for target therapy, identifying patients most likely to benefit from chemo-immunotherapy may be valuable. Recently, several prognostic and predictive factors associated with the efficacy of neoadjuvant immunotherapy in NSCLC, such as tumor-intrinsic biomarkers, tumor microenvironment biomarkers, liquid biopsies, microbiota, metabolic profiles, and clinical characteristics, have been described. However, a specific and sensitive biomarker remains to be identified. Recently, the construction of prediction models for ICI therapy using novel tools, such as multi-omics factors, proteomic tests, host immune classifiers, and machine learning algorithms, has gained attention. In this review, we provide a comprehensive overview of the different positive prognostic and predictive factors in treating preoperative patients with ICIs, highlight the recent advances made in the efficacy prediction of neoadjuvant immunotherapy, and provide an outlook for joint predictors.

Impact of sarcopenia indexes on survival and severe immune acute toxicity in metastatic non-small cell lung cancer patients treated with PD-1 immune checkpoint inhibitors

Sarcopenia has long been associated with higher toxicity induced by anti-cancer treatments and shorter survival in patients with solid tumors. The creatinine-to-cystatin ratio (CC ratio, serum creatinine/cystatin C×100) and the sarcopenia index (SI, serum creatinine×cystatin C (CysC)-based glomerular filtration rate (eGFRCysC)) are have been reported to be correlated with skeletal muscle mass. The aim of this study is to assess primarily whether the CC ratio and the SI could predict mortality in metastatic non-small cell lung cancer (NSCLC) patients treated with PD-1 inhibitors, and secondarily their impact on severe immune-related adverse effects (irAEs). From the prospective CERTIM cohort, we analyzed retrospectively stage IV NSCLC patients, who received PD-1 inhibitors between June 2015 and November 2020 in Cochin Hospital (Paris, France). We assessed sarcopenia measuring skeletal muscle area (SMA) by computed tomography and handgrip strength (HGS) by a hand dynamometer. In total, 200 patients were analyzed. The CC ratio and the IS were significantly correlated with SMA and HGS: rCC/SMA=0.360, rSI/SMA=0.407, rCC/HGS=0.331, rSI/HGS=0.370. In multivariate analysis of overall survival, a lower CC ratio (HR 1.73, P=0.033) and a lower SI (HR 1.89, P=0.019) were independent predictors of poor prognosis. In univariate analysis of severe irAEs, CC ratio (OR 1.01, P=0.628) and SI (OR 0.99, P=0.595) were not associated with a higher risk of severe irAEs. In metastatic NSCLC patients treated with PD-1 inhibitors, a lower CC ratio and a lower SI are independent predictors of mortality. However, they are not associated with severe irAEs.

PD-L1 Aptamer-Functionalized Metal-Organic Framework Nanoparticles for Robust Photo-Immunotherapy against Cancer with Enhanced Safety.

Immune checkpoint blockade has become a paradigm-shifting treatment modality to combat cancer, while conventional administration of immune checkpoint inhibitors, such as anti-PD-L1 antibody (α-PD-L1), often shows unsatisfactory immune responses and lead to severe immune-related adverse effects (irAEs). Herein, we develop a PD-L1 aptamer-based spherical nucleic acids (SNAs), which consists of oxaliplatin (OXA) encapsulated in a metal-organic framework nanoparticle core and a dense shell of aptPD-L1 (denoted as M@O-A). Upon light irradiation, this nanosystem enables concurrent photodynamic therapy (PDT), chemotherapy, and enhanced immunotherapy in one shot to inhibit both primary colorectal tumors and untreated distant tumors in mice. Notably, M@O-A shows scarcely any systemic immunotoxicity in a clinical irAEs-mimic transgenic mouse model. Collectively, this study presents a novel strategy for priming robust photo-immunotherapy against cancer with enhanced safety.

A genomic instability-related lncRNA model for predicting prognosis and immune checkpoint inhibitor efficacy in breast cancer.

Breast cancer has overtaken lung cancer as the most frequently diagnosed cancer type and is the leading cause of death for women worldwide. It has been demonstrated in published studies that long non-coding RNAs (lncRNAs) involved in genomic stability are closely associated with the progression of breast cancer, and remarkably, genomic stability has been shown to predict the response to immune checkpoint inhibitors (ICIs) in cancer therapy, especially colorectal cancer. Therefore, it is of interest to explore somatic mutator-derived lncRNAs in predicting the prognosis and ICI efficacy in breast cancer patients. In this study, the lncRNA expression data and somatic mutation data of breast cancer patients from The Cancer Genome Atlas (TCGA) were downloaded and analyzed thoroughly. Univariate and multivariate Cox proportional hazards analyses were used to generate the genomic instability-related lncRNAs in a training set, which was subsequently used to analyze a testing set and combination of the two sets. The qRT-PCR was conducted in both normal mammary and breast cancer cell lines. Furthermore, the Kaplan–Meier and receiver operating characteristic (ROC) curves were applied to validate the predictive effect in the three sets. Finally, the Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm was used to evaluate the association between genomic instability-related lncRNAs and immune checkpoints. As a result, a six-genomic instability-related lncRNA signature (U62317.4, MAPT-AS1, AC115837.2, EGOT, SEMA3B-AS1, and HOTAIR) was identified as the independent prognostic risk model for breast cancer patients. Compared with the normal mammary cells, the qRT-PCR showed that HOTAIR was upregulated while MAPT-AS1, EGOT, and SEMA3B-AS1 were downregulated in breast cancer cells. The areas under the ROC curves at 3 and 5 years were 0.711 and 0.723, respectively. Moreover, the patients classified in the high-risk group by the prognostic model had abundant negative immune checkpoint molecules. In summary, this study suggested that the prognostic model comprising six genomic instability-related lncRNAs may provide survival prediction. It is necessary to identify patients who are suitable for ICIs to avoid severe immune-related adverse effects, especially autoimmune diseases. This model may predict the ICI efficacy, facilitating the identification of patients who may benefit from ICIs.

Computational discovery of small drug-like compounds as potential inhibitors of PD-1/PD-L1 interactions

The programmed cell death ligand protein 1 (PD-L1) is a strong immunosuppressive molecule that inactivates tumor-specific T cells by binding to the programmed cell death- 1 protein (PD-1). Cancer immunotherapy based on the monoclonal antibodies targeting the PD-1/PD-L1 pathway has demonstrated therapeutic responses without precedent over a wide range of cancers. However, the antibody-based immunotherapies have several limitations such as high production cost or the induction of severe immune-related adverse effects. Small-molecule inhibitors of the PD-1/PD-L1 pathway are a promising alternative or complementary therapeutic to antibodies. Currently, the field of developing anti-PD-1/PD-L1 small-molecule inhibitors is intensively explored. In the present study a pharmacophore model was generated based on previously developed compounds and their atomistic structures with the PD-L1 dimer. Structure-based affinity-based virtual screening of small-molecule inhibitors of the PD-1/PD-L1 pathway according to the pharmacophore model followed by a screening in terms of drug-likeness resulted in ten hit compounds of high affinity towards the PD-L1 dimer and the satisfaction to all of the drug-likeness rules. Molecular dynamics (MD) simulations showed that nine of ten compounds formed stable complexes with the PD-L1 dimer as evidenced by the analysis of MD trajectories. Molecular mechanics Poisson- Boltzmann surface area (MM-PBSA) calculation revealed very low binding energies (<-46 kcal/mol) for the interactions of these ligands with the PD-L1 dimer, suggesting that identified compounds may serve as good scaffolds for the design of novel agents of antitumor immunotherapy able to target the PD-1/PD-L1 interaction Communicated by Ramaswamy H. Sarma

Rechallenge with immune checkpoint inhibitors beyond severe toxicities, an utopia?

e14601 Background: Immunotherapy (IO) has substantially improved clinical outcomes in different types of tumours. Its use has been associated with so-called immune-related adverse effects (IrAEs), some of them, potentially severe and/or fatal. Current guidelines recommend discontinuation of IO in severe IrAEs (grades 3/4). Therefore, there is very limited evidence about the safety of “rechallenge” or re-treatment with IO in patients who have experienced severe toxicities. The objective of this study is to describe the toxicities experienced by patients treated with IOs in our unit and identify the recurrence rate of these rEAIs in those patients in whom immunotherapy is re-administered. Methods: We carried out a retrospective analysis of patients treated with IO from January 2015 to April 2021. As inclusion criteria, we selected the condition that the patients have had at least one tumour reevaluation after the IO was started. We have collected clinical and epidemiological variables, efficacy (mesured by RECIST 1.1 and iRECIST criteria) and, as well as recorded toxicity data (mesured by CTCAE V4.3). Results: 220 patients have received some IO drug between the indicated periods. The characteristics of the patients are shown in the attached table. 66% of patients treated with IO have received anti-PD-1/PD-L1 therapy as monotherapy. 60% (134/220) of patients experienced at least 1 IrAE. Of the IrAEs, only 20% were grade 3/4. Only 34 (25%) of the 134 patients who experienced any toxicity required IO stop. Of these 34, only 17 patients achieved retreatment with IO after resolution of initial toxicity. In 14 of the 17 patients who underwent rechallenge, IO was permanently discontinued due to recurrence of the same IrAEs. The IrAE that recurs most frequently after rechallenge was colitis (35% of cases), followed by nephritis (28%). 41% of the patients who experienced toxicity had an objective response to their disease, compared to only 9% in those who did not present any IrAE, which was statistically significant (p&lt;0.05%). Conclusions: In our serie, rechallange with IO after toxicity was associated with the appearance of the same IrAE, which is consistent with what has been published in other series. We are doing further analyses in order to explore IO toxicity deeply, increasing the number of patients which have received immune checkpoint inhibitors.[Table: see text]

Injectable Hydrogel as a Unique Platform for Antitumor Therapy Targeting Immunosuppressive Tumor Microenvironment

Cancer immunotherapy can boost the immune response of patients to eliminate tumor cells and suppress tumor metastasis and recurrence. However, immunotherapy resistance and the occurrence of severe immune-related adverse effects are clinical challenges that remain to be addressed. The tumor microenvironment plays a crucial role in the therapeutic efficacy of cancer immunotherapy. Injectable hydrogels have emerged as powerful drug delivery platforms offering good biocompatibility and biodegradability, minimal invasion, convenient synthesis, versatility, high drug-loading capacity, controlled drug release, and low toxicity. In this review, we summarize the application of injectable hydrogels as a unique platform for targeting the immunosuppressive tumor microenvironment.

Early Use of High-Dose Glucocorticoid for the Management of irAE Is Associated with Poorer Survival in Patients with Advanced Melanoma Treated with Anti-PD-1 Monotherapy.

Programmed cell death receptor-1 (PD-1) inhibitors are frontline therapy in advanced melanoma. Severe immune-related adverse effects (irAEs) often require immunosuppressive treatment with glucocorticoids (GCCs), but GCC use and its correlation with patient survival outcomes during anti-PD-1 monotherapy remains unclear. In this multicenter retrospective analysis, patients treated with anti-PD-1 monotherapy between 2009 and 2019 and detailed GCC use, data were identified from five independent cohorts, with median follow-up time of 206 weeks. IrAEs were tracked from the initiation of anti-PD-1 until disease progression, initiation of a new therapy, or last follow-up. Correlations between irAEs, GCC use, and survival outcomes were analyzed. Of the entire cohort of 947 patients, 509 (54%) developed irAEs. In the MGH cohort [irAE(+) n = 90], early-onset irAE (within 8 weeks of anti-PD-1 initiation) with high-dose GCC use (≥60-mg prednisone equivalent once a day) was independently associated with poorer post-irAE PFS/OS (progression-free survival/overall survival) [post-irAE PFS: HR, 5.37; 95% confidence interval (CI), 2.10-13.70; P < 0.001; post-irAE OS: HR, 5.95; 95% CI, 2.20-16.09; P < 0.001] compared with irAEs without early high-dose GCC use. These findings were validated in the combined validation cohort [irAE(+) n = 419, post-irAE PFS: HR, 1.69; 95% CI, 1.04-2.76; P = 0.04; post-irAE OS: HR, 1.97; 95% CI, 1.15-3.39; P = 0.01]. Similar findings were also observed in the 26-week landmark analysis for post-irAE-PFS but not for post-irAE-OS. A sensitivity analysis using accumulated GCC exposure as the measurement achieved similar results. Early high-dose GCC use was associated with poorer PFS and OS after irAE onset. Judicious use of GCC early during anti-PD-1 monotherapy should be considered. Further prospective randomized control clinical trials designed to explore alternative irAE management options are warranted.

SAT-493 A Case of Profound Hypothyroidism Secondary to Immune Check Point Inhibitors

Background: The discovery of immune check-point inhibitors (ICI) revolutionized cancer treatment. CTLA-4, anti-PD-1 and anti-PD-L1 monoclonal antibodies have been approved in recent years. However, the advantageous clinical outcomes can also be associated with potentially severe immune related adverse effects (irAEs) such as hypophysitis, thyroiditis, type 1 diabetes mellitus, and adrenal insufficiency [1]. We report to highlight the importance of awareness of irAEs and collaboration of endocrinology and oncology specialties in managing oncology patients with ICI in an underserved community hospital in Brooklyn, NY.Clinical case: 62 years old woman with unremarkable thyroid history presented with chronic mid-chest pain and dysphagia in 2016 found to have a mass in middle third of esophagus. Biopsies revealed invasive squamous cell carcinoma (T3N0). She underwent radiotherapy and esophagectomy.On 1/2018, surveillance imaging detected a new tracheobronchial angle lymph node, which was confirmed as hypermetabolic and likely malignant by PET scan. Patient received additional 5 cycles of radiotherapy followed with 5 cycles of chemotherapy with Oxaliplatin and Capecitabine. Since post-chemotherapy PET scan showed local recurrence, patient was started on PD1 inhibitor, Pembrolizumab 200 mg Q3 week. After 3 doses patient developed cold intolerance, weight gain and low mood. Her TSH was 173 uIU/ml (0.27-0.42), FT4 <0.1 ng/dL (0.9-1.8) and referred to endocrine clinic. Repeat TSH was 190 uIU/ml, FT4 0.2 ng/dL, TPOAbs 619 IU/ml (<35) and TSI<0.1 IU/L (<0.55). Adrenal insufficiency was ruled out and started on levothyroxine 50 mcg in the morning, increased to 75 mcg. After 2 months of levothyroxine use, TSH was 11.8 uIU/ml and FT4 1.3. Pembrolizumab therapy is restarted shortly after.Conclusion: National Comprehensive Cancer Network guideline for management of immunotherapy related toxicities recommends routine monitoring of TSH and FT4 at baseline and every 4-6 weeks during immunotherapy, follow up every 12 weeks and TPO antibodies if TSH is high. This patient’s clinical symptoms of hypothyroidism might be confused by nonspecific symptoms of underlying malignancy. Combination radiotherapy and immunotherapy place this patient at higher risk of developing hypothyroidism. This case showed the successful collaboration of endocrinology and oncology team in giving vulnerable patient an optimized care with good clinical outcome.

Efficacy and Toxicity of Immune -Checkpoint Inhibitors in Patients With Preexisting Autoimmune Disorders.

Immunotherapy is an important armamentarium for cancer treatment nowadays. Apart from their significant effectiveness in controlling disease they also generate potential severe immune related adverse effects. Preexistence of immune related conditions may eventually predispose to the development of more severe complication and extreme caution have been taken in treating these patients. We performed a literature review searching for case reports and case series in order to offer evidence-based data for clinical management of these patients. Preexisting serological-only immune abnormalities or presence of a predisposing genetic background does not seem to confer significant risk but existing data is scarce. Most patients with preexistent autoimmune diseases can probably treated with checkpoint inhibitors as they seem to have at least the same response rate as the general cancer population. Under treatment, a significant part of them (at least 30%) can experience a flare of their baseline disease which can sometime be severe. Life-threatening cases seems rare and disease flare can be generally managed with steroids. The volume of available data is more important for rheumatologic diseases than for inflammatory bowel diseases were more caution should be observed. However, it has to be kept in mind that new immune related adverse effects (IrAE) are seen with a similar frequency as the flare of the baseline disease. Both flare-up's and newly developed IrAE are generally manageable with a careful clinical follow-up and prompt therapy.

1304P - Significance of severe immune-related adverse effects (irAE) on patients with advanced tumors treated with immune checkpoint inhibitors being admitted for secondary toxicity: Clinical relevance and next steps

BackgroundDisruption of the immune system using immune checkpoint inhibitors (ICI) can result in a multitude of immune-related adverse effects (irAE). While irAEs have been well-reported in clinical trials, the impact and magnitude in the real world is unclear. MethodsData was collected on patients with advanced malignancy who experienced a suspected irAE requiring admission to an academic hospital (02/11-10/18). Each case was comprehensively reviewed by a minimum of two reviewers, including one sub-specialist. ResultsFrom 2011-2018, there were 632 hospitalizations for suspected irAEs, and the majority (59.7%; N=377) were confirmed irAEs from immunotherapy: PD1 (N=194, 51.5%), CTLA4 (N=92, 24.4%), CTLA4 + PD1 (N=76, 20.2%), PLD1 (N=15, 4.0%). The most common irAEs were gastrointestinal (37.4%), pulmonary (14.9%), hepatic (13.5%), endocrine (16.2%), neurologic (9.0%), cardiac (6.9%), dermatologic (5.6%), rheumatologic (2.9%), hematologic (2.1%), renal (1.9%), and allergy (1.1%). 10.3% of admissions had multiple toxicities. Median length of stay was 5 days (IQR, 3-8). Majority of patients (89.1%) required continuation of immunosuppressive medication on discharge. Inpatient toxicity led to ICI discontinuation in 78.1% of admissions. Overall, there were 11.3 irAE admissions per 100 patients treated with ICI and 2.1 irAE admissions per 100 ICI administrations. ConclusionsirAEs from ICI can result in prolonged hospitalizations, need for immunosuppression, and ICI discontinuation, which can have detrimental effects on oncologic outcomes. Consequently, there is a critical need for coordinated multidisciplinary approach, comprehensive provider education, and translational research programs for early detection and intervention. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Predictable early onset high-dose-glucocorticoid-associated-irAE and its predictive role in anti-PD-1 monotherapy treated advanced melanoma patients.

9544 Background: Though uncommon, a subgroup of patients with melanoma develop early-onset severe immune-related adverse effects (irAEs) that require immunosuppressive treatment with high-dose glucocorticoids (HD-GCCs). We aimed to examine the impact of early onset HD-GCC-associated-irAE (EO-HGA-irAE) in the setting of anti-PD-1 monotherapy initiation on prognosis and to develop a predictive scoring system. Methods: Clinical data was collected retrospectively from advanced melanoma patients treated with anti-PD-1 monotherapy at Massachusetts General Hospital from Sept 2009 to Dec 2017. The relationship between EO-HGA-irAE and PFS (defined as time from anti-PD-1 monotherapy initiation to PD) was assessed using 8-week conditional landmark analysis (Kaplan-Meier curves, log-rank test) and time-dependent COX regression model (multivariate analysis). Demographic characteristics and baseline routine laboratory variables were collected and correlated with occurrence of EO-HGA-irAE using logistic regression modeling. Best cutoff values were identified using ROC curve (Youden index) to dichotomize continuous variables. Results: Among 146 patients, 13 (8.9%) developed EO-HGA-irAE. In 8-week landmark analysis, median PFS was 2.9 (95% CI, 2.8-3.0) and 17.5 (95% CI, 10.8-24.2) months (P = .001) for patients with and without EO-HGA-irAE, respectively. Multivariate analysis revealed that EO-HGA-irAE was independently correlated with significantly higher risk of disease progression with hazard ratio of 2.4 (95% CI 1.4-4.0) (P = .001). Potential predictive variables (P &lt; .25 for continuous variables, P &lt; .1 for dichotomous variables) in favor of the occurrence of EO-HGA-irAE included age, baseline glucose, and neutrophil, eosinophil, and WBC count. After dichotomization and further validation using a logistic regression model, a scoring system (score range 0-3) composed of 3 dichotomized predictors, including age, baseline glucose, and baseline neutrophil count was developed with odds ratio of 3.4 (95% CI, 1.6-8.8) (P = .001). The probabilities of patients scoring 0,1,2,3 of developing EO-HGA-irAE were 1.1%, 3.5%, 11.1%, and 29.9%, respectively. Conclusions: Development of EO-HGA-irAE is correlated with shorter PFS in advanced melanoma patients treated with anti-PD-1 monotherapy. A scoring system based on age and simple, easily accessible, routinely tested biomarkers can be used to help predict the risk of EO-HGA-irAE occurrence. Validation with a larger sample size is required.

Nanoengineered Immune Niches for Reprogramming the Immunosuppressive Tumor Microenvironment and Enhancing Cancer Immunotherapy.

Cancer immunotherapies that harness the body's immune system to combat tumors have received extensive attention and become mainstream strategies for treating cancer. Despite promising results, some problems remain, such as the limited patient response rate and the emergence of severe immune-related adverse effects. For most patients, the therapeutic efficacy of cancer immunotherapy is mainly limited by the immunosuppressive tumor microenvironment (TME). To overcome such obstacles in the TME, the immunomodulation of immunosuppressive factors and therapeutic immune cells (e.g., T cells and antigen-presenting cells) should be carefully designed and evaluated. Nanoengineered synthetic immune niches have emerged as highly customizable platforms with a potent capability for reprogramming the immunosuppressive TME. Here, recent developments in nano-biomaterials that are rationally designed to modulate the immunosuppressive TME in a spatiotemporal manner for enhanced cancer immunotherapy which are rationally designed to modulate the immunosuppressive TME in a spatiotemporal manner for enhanced cancer immunotherapy are highlighted.

Structure-Function Analysis of Immune Checkpoint Receptors to Guide Emerging Anticancer Immunotherapy.

The modulation of immune checkpoint receptors has been one of the most successful, exciting, and explored approaches for cancer immunotherapy. Currently, several immune checkpoint modulators, mainly monoclonal antibodies, are showing remarkable results. However, the failure to show a response in most patients and the induction of severe immune-related adverse effects are the major drawbacks. Novel approaches concerning the development of immune modulatory small molecules have emerged as an alternative. Nevertheless, the lack of structural information about immune checkpoint receptors has hindered the rational design of those small-molecule modulators by preventing the use of methodologies such as computer-aided drug design. Herein, we provide an overview and critical analysis of the structural and dynamic details of immune checkpoint receptors (cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and glucocorticoid-induced TNFR-related protein (GITR)) and their interaction with known modulators. This knowledge is essential to advance the understanding of their binding mode and guide the design of novel effective targeted anticancer medicines.

Severe immune-related adverse effects (irAE) requiring hospital admission in patients treated with immune checkpoint inhibitors for advanced malignancy: Temporal trends and clinical significance.

3096Background: Disruption of the immune system using immune checkpoint inhibitors can result in a multitude of immune-related adverse effects (irAE). While irAEs have been well-reported in clinica...

Evaluation of rare but severe immune related adverse effects in PD-1 and PD-L1 inhibitors in non-small cell lung cancer: a meta-analysis.

Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitor therapy is showing marked efficacy in advanced non-small cell lung cancer (NSCLC). Meanwhile, it is concomitant with distinctive immune-related adverse effects. We aim to describe the incidence of pneumonitis and other rare but severe immune-related adverse effects (IRAEs), as well as treatment related deaths. In addition, we analyze the differences in incidence of pneumonitis between PD-1 and PD-L1 inhibitors and standard-of-care chemotherapy. PubMed was searched up to 24 March 2017 for clinical trials of PD-1 inhibitors (nivolumab and pembrolizumab) and PD-L1 inhibitors (atezolizumab, avelumab and durvalumab) in treatment of NSCLC. Besides, references of relevant articles were screened. Finally, 22 trials were included in our study, 14 with data of pneumonitis, 19 with other severe IRAEs or treatment related deaths and 5 with control groups. Incidence of all-grade pneumonitis was 2.9% (95% CI, 2.0-4.8%) and grade 3 or higher pneumonitis 2.0% (95% CI, 1.0-2.0%). Incidence of all-grade pneumonitis in PD-1 and PD-L1 inhibitor therapy (n=1,313) was significantly higher than that in chemotherapy (n=918) (OR=2.35, 95% CI, 1.32-4.20, P=0.004), but had no significance in grade 3-5 pneumonitis. Incidence of cardiorespiratory arrest (n=537) was 1.0% (95% CI, 0-2.0%), cardiac failure (n=214) 2.0% (95% CI, 1.0-5.7%), myocardial infarction (n=402) 1.0% (95% CI, 0-3.8%), stroke (n=135) 2.0% (95% CI, 0-13.0%), disease progression (n=391) 1.0% (95% CI, 0-2.9%), pancreatitis (n=700) 1.0% (95% CI, 0-2.0%) and severe skin reactions (n=836) 2.0% (95% CI, 1.0-3.8%). Incidence of treatment related deaths was 0.7%. Immune related adverse effects can on occasion be life-threatening even though usually rare. Incidence of pneumonitis in PD-1 and PD-L1 inhibitors was significantly higher than that in chemotherapy. More studies should be conducted to investigate the incidence of these rare but life-threatening IRAEs.

Nivolumab for treating non-small cell lung cancer

Introduction: Diversion of the immune checkpoint PD-1/PD-L1 by a tumor in order to escape antitumor immunity is a hallmark of NSCLC, but offers promising new strategies. Nivolumab, a fully human monoclonal antibody, is the first PD-1 inhibitor to be approved to treat metastatic NSCLC after exciting results obtained from clinical trials.Areas covered: This review aims to:) clarify the mechanism of action and toxicities of PD-1 inhibitors; recapitulate the results from various clinical trials that have evaluated nivolumab as a monotherapy for metastatic NSCLC; discuss the clinical and translational research axes to better use this molecule; and summarize the therapeutic combinations currently under evaluation.Expert opinion: The contribution of this molecule to treat NSCLC is undeniable, making it a new standard of care after prior chemotherapy. Its toxicity profile is favorable but a good knowledge of new and potentially severe immune-related adverse effects such as endocrinopathy or interstitial pneumonitis is essential for its early detection and management. Better selection of patients is needed, particularly based on the discovery of predictive biomarkers, such as PD-L1 expression. Multiple associations with other checkpoint inhibitors, chemotherapy and targeted therapies are currently being studied and should pave the way toward new uses for this drug.