Programmed Death 1 Immunotherapy Research Articles

Lack of Reactivation of Latent Tuberculosis despite PD-1 Immunotherapy and Chemotherapy: A Case Report and Systematic Review

Background: Programmed Death 1 (PD-1) has a controversial role in the treatment of Tuberculosis (TB). Several clinical cases of TB development have been reported by administration of anti–PD-1 antibodies for patients with advanced unresectable cancers. Case presentation: In this article, we report an interesting case about a male patient with history of cured pulmonary tuberculosis and a 4-month history of repeated hemoptysis. Imaging showed one mass in the lower lobe of left lung and the other in the left upper lobe. The diagnosis of Non-Small-Ccell Lung Cancer (NSCLC) was determined by biopsy specimens in the lower lobe nodule and cured pulmonary tuberculosis determined by past medical history. He was given neoadjuvant treatment with an anti–PD-1 inhibitor and chemotherapy. He underwent surgery. Pathological examination revealed Mtb in left upper lobe nodule but previous imaging showed without reactivation and slight reduction in tubercular infection inflammation. The left lower lobe nodule was poorly differentiated carcinoma. Conclusions: Overall, the role of immune checkpoint inhibitors in patients with cancers and latent tuberculosis infection is inconclusive. Although we cannot establish whether patients with stage IIIA NSCLC and concurrent latent pulmonary tuberculosis after surgical evaluation can receive a PD-1 and chemotherapy as neoadjuvant therapy without the activation of pulmonary tuberculosis, our case endorses the need of further evaluation.

Peripheral B-cell levels predict efficacy and overall survival in advanced melanoma patients under PD-1 immunotherapy.

Aims: Programmed death-1 (PD-1) blockade is a vital therapy for solid tumors, but not all patients benefit. Identifying which patients will benefit from immunotherapy is a key focus in oncology research. Patients & Methods:This studyanalyzed the correlation between the number of peripheral lymphocytes and the efficacy and prognosis of immunotherapy in advanced malignant melanoma. Results: Patients with a partial response had significantly lower peripheral B cell levels, and patients with a lower number of B lymphocytes had a longer survival time. Conclusion: These results suggest that peripheral B cells are correlated with the efficacy of PD-1 antibody and prognosis and are thus potential biomarkers for the efficacy and prognosis of PD-1 antibody immunotherapy in malignant melanoma.

MTOR regulates T cell exhaustion and PD-1-targeted immunotherapy response during chronic viral infection.

T cell exhaustion is a state of T cell dysfunction associated with expression of programmed death 1 (PD-1). Exhausted CD8+ T cells are maintained by self-renewing stem-like T cells that provide differentiated TIM3+ cells, a part of which possesses effector-like properties. PD-1-targeted therapies enhance T cell response by promoting differentiation of stem-like T cells toward TIM3+ cells, but the role of mTOR during T cell exhaustion remains elusive. Here, we showed that mTOR inhibition has distinct outcomes during the beginning of and after the establishment of chronic viral infection. Blocking mTOR during the T cell expansion phase enhanced the T cell response by causing accumulation of stem-like T cells, leading to improved efficacy of PD-1 immunotherapy; whereas, after exhaustion progressed, mTOR inhibition caused immunosuppression, characterized by decreased TIM3+ cells and increased viral load with minimal changes in stem-like T cells. Mechanistically, a cell-intrinsic mTOR signal was vital for differentiation of stem-like T cells into the TIM3+ state in the early and late phases of chronic infection as well as during PD-1 immunotherapy. Thus, PD-1 blockade worked after cessation of mTOR inhibition, but simultaneous treatment failed to induce functional TIM3+ cells, reducing efficacy of PD-1 immunotherapy. Our data demonstrate that mTOR regulates T cell exhaustion and have important implications for combination cancer therapies with PD-1 blockade.

Impact of PD1 and PDL1 immunotherapy on non-small cell lung cancer outcomes: a systematic review

IntroductionDespite comprising many cancer diagnoses, few treatments are suitable for patients with advanced non-small cell lung cancer (aNSCLC). Trials suggest blockade of programmed death 1 (PD1) or its ligand (PDL1)...

Salvage Endoscopic Skull Base Surgery: Another Treatment Option After Immunotherapy for Recurrent Nasopharyngeal Carcinoma.

BackgroundAdvanced recurrent nasopharyngeal carcinoma (NPC) is a relatively common nasopharyngeal skull base disease for which there is no uniform treatment modality. Not all patients are satisfied with the efficacy of immunotherapy with or without chemotherapy.MethodsThis study included patients who underwent salvage endoscopic skull base nasopharyngectomy after immunotherapy between February 2017 and June 2021. Patient survival information was analyzed. Relevant publications were retrieved from five databases from December 1, 2011 to December 1, 2021. The outcomes of patients with advanced recurrent NPC who received programmed death 1 (PD-1) immunotherapy were collected and analyzed.ResultsNine patients who underwent skull base surgery, all of whom had previously undergone PD-1 immunotherapy, were included in this study. The 2-year overall survival (OS) and progression-free survival (PFS) rates of these patients were 25% and 29.2%, respectively. Eight publications involving 688 patients with advanced recurrent NPC were also included in this study. The combined complete response (CR), partial response (PR), and stable disease (SD) values were 2%, 23%, and 29%, respectively. The combined DCR included the three disease conditions, CR, PR, and SD, with a value of 53%. PD-1 monotherapy was more effective than PD-1 combination chemotherapy.ConclusionsPD-1 immunotherapy may improve the remission rate in patients with recurrent NPC. Salvage endoscopic skull base nasopharyngectomy may be another option for patients with poor immunotherapeutic outcomes. For patients with advanced recurrent NPC, better evidence-based medical data are needed to determine whether they should receive immunotherapy before or after surgery.

OX40 enhances T cell immune response to PD-1 blockade therapy in non-small cell lung cancer

Immune-checkpoint blockade is widely studied for cancer therapy. Although the co-inhibitory receptor Programmed death-1(PD-1) blockade benefits some non-small cell lung cancer (NSCLC) patients, a large portion of NSCLC patients still fail to respond to this immunotherapy, and the underlying mechanism is unclear. Thus, a synergistic therapy to enhance the effect of PD-1 is urgently needed to improve the poor outcome of NSCLC patients. Here, we demonstrated that effector memory T cells were increased and T cell response became stronger in PD-1 immunotherapy responders (n = 20) but not in non-responders (n = 10). The expression of co-stimulatory receptor OX40 was upregulated on T cells following PD-1 immunotherapy and was positively associated with the percentage of PD-1+T cells and the responsiveness of T cells. Combination treatment of antagonistic anti-PD-1 and agonistic anti-OX40 antibodies (Abs) promoted the proliferation and cytokines production of T cells from PBMCs of non-responders ex vivo. Consistently, anti-PD-1 and anti-OX40 therapy synergistically augmented T cell response in an in vivo mouse lung cancer model. Our study confirmed the antitumor effects of anti-PD-1/OX40 combination in lung cancer patients as well as in the murine lung cancer model, and the results provide a rationale for clinical trials evaluating the therapeutic effect of this combination of antibodies for NSCLC immunotherapy.

PD-L1 Expression in Metaplastic Breast Carcinoma Using the PD-L1 SP142 Assay and Concordance Among PD-L1 Immunohistochemical Assays.

Immunotherapy for the treatment of programmed death-ligand 1 (PD-L1) positive locally advanced or metastatic triple negative breast cancer may benefit patients with metaplastic breast cancer (MpBC). Previous study of PD-L1 in MpBC scored tumor cells (TCs), different from Food and Drug Administration-approved scoring methods. We sought to define PD-L1 expression in MpBCs and to evaluate concordance of 3 PD-L1 assays. Primary, treatment naive MpBC treated at our Center from 1998 to 2019 were identified. PD-L1 expression was assessed using SP142, E1L3n, and 73-10. We evaluated PD-L1 expression on tumor infiltrating immune cells (IC) and also in TCs. For each assay, we scored PD-L1 expression using ≥1% IC expression according to the IMpassion130 trial criteria and using combined positive score (CPS) ≥10 according to the KEYNOTE-355 trial cutoff. A total of 42 MpBCs were identified. Most MpBC had PD-L1 positivity in ≥1% IC with all 3 assays (95%, 95%, 86%) in contrast to a maximum 71% with a CPS ≥10. PD-L1 IC expression was comparable between the SP142 and 73-10 assays and was lowest with E1L3n. PD-L1 TC expression was lowest using SP142. The overall concordance for IC scoring was 88% while 62% had concordant CPS. For each assay, the results of the 2 scoring algorithms were not interchangeable. The SP142 assay showed distinct expression patterns between IC (granular, dot-like) and TC (membranous) while 73-10 and E1L3n showed membranous and/or cytoplasmic expression in both IC and TC. Most MpBC in our cohort were positive for PD-L1 indicating eligibility for anti-PD-L1/programmed death-1 immunotherapy.

Chemotherapy combined with antiangiogenic drugs as salvage therapy in advanced melanoma patients progressing on PD-1 immunotherapy

BackgroundThis study aimed to evaluate the effect of salvage therapy with nab-paclitaxel (nab-p) or temozolomide (TMZ) combined with antiangiogenic drugs in programmed death 1 (PD-1) inhibitor-resistant patients with unresectable metastatic melanoma. MethodsWe conducted a retrospective review of 69 metastatic melanoma patients who received nab-p or TMZ combined with antiangiogenic drugs after developing PD-1 inhibitor resistance and were treated at the Beijing Cancer Hospital between 2016 and 2019. The disease control rate (c-DCR) and progression-free survival (c-PFS) of salvage CA (chemotherapy combined with antiangiogenic drugs) regimens were investigated. Univariate and multivariate analyses were performed to evaluate the clinical pathological factors affecting the outcomes. Then, a nomogram was formulated to predict the probability of 3-month and 6-month c-PFS based on the multivariate analysis results. ResultsThe c-DCR was 63.8%, and the median c-PFS was 3.0 months. In the univariate analysis, factors associated with the c-DCR were included the melanoma subtype, baseline platelet-to-lymphocyte ratio (PLR) and best response status to PD-1 inhibitors. Factors influencing c-PFS included age, baseline lactic dehydrogenase, PLR, neutrophil-to-lymphocyte ratio (NLR), PFS duration of anti-PD-1 therapy (p-PFS), and the best response and progression pattern of PD-1 inhibitors. In the multivariate analysis, age <65 years, heterogeneous progression pattern and baseline PLR<200 were significantly associated with improved c-PFS. The concordance index (C-index) of the nomogram was equal to 0.65 (95% CI 0.566–0.734). ConclusionsCA regimens demonstrated promising effects in PD-1 inhibitor-resistant patients. The nomogram could be a valuable predictive module for salvage therapy choice in PD-1 inhibitor-resistant patients.

PD-L1 in Lung Adenocarcinoma: Insights into the Role of 18F-FDG PET/CT.

PurposeThis study aimed to evaluate the role of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) in expression of tumor programmed death ligand-1 (PD-L1) expression and prognostic significance of 18F-FDG PET/CT at different PD-L1 status in patients with lung adenocarcinoma.Patients and MethodsSeventy-three patients with primary lung adenocarcinoma who received 18F-FDG PET/CT before treatment were retrospectively included in this study. Expression of tumor PD-L1, programmed death-1 (PD-1) and glucose metabolic parameters were evaluated.ResultsTumor PD-L1 expression was positively correlated with maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), hexokinase II (HK-II) and glucose transporter 1 (GLUT-1) (P<0.0001 for all). SUVmax was a unique independent predictor of tumor PD-L1 expression, with an optimal cut-off value of 9.5. For all the patients, tumor stage (P<0.001) and SUVmax (P=0.009) were independent prognostic indicators of disease-free survival (DFS)/progression-free survival (PFS) while carcino-embryonic antigen (CEA) (P=0.003), Ki67 (P=0.042), PD-L1 (P=0.048) and TLG (P=0.004) were independent prognostic indicators of overall survival (OS). Tumor stage (P=0.004) and SUVmax (P=0.022) were independent prognostic indicators of DFS/PFS while TLG (P=0.012) and CEA (P=0.045) were independent prognostic indicators of OS in the PD-L1-positive group. In the PD-L1-negative group, tumor stage (P=0.002) and CEA (P=0.006) were unique independent prognostic indicators of DFS/PFS and OS, respectively.Conclusion18F-FDG PET/CT may potentially predict tumor PD-L1 expression and play a role in predicting prognosis of PD-L1/PD-1 immunotherapy in lung adenocarcinoma.

Neurological adverse effects due to programmed death 1 (PD-1) inhibitors

PD-1 Immunotherapy is integral in treating multiple cancers, but has been associated with neurological adverse events (nAEs). Our study was aimed at identifying the clinical spectrum of nAEs associated with pembrolizumab and nivolumab. We performed an IRB approved single-center retrospective cohort study on patients receiving either pembrolizumab or nivolumab. Patients that developed nAEs within 12months of treatment were identified. Descriptive statistics were conducted, and differences between groups were analyzed by the Chi-square or t test method. In total, 649 patients were identified. Seventeen patients (2.6%) developed nAEs. Eight of those were on pembrolizumab and nine were on nivolumab. Average age was 62.1years. Ten were males and 7 were females. Most patients had melanoma (6, 35.3%). Patients who developed nAEs more frequently had intracranial lesions at initiation of anti PD-1 therapy compared to those who did not develop nAEs (76.5% vs 27.8%; p-value < 0.001). Fifteen patients (88.2%) permanently stopped PD-1 therapy. In 8 patients, treatment termination resolved symptoms attributed to immune checkpoint blockade. The majority of patients developed grade 3 or 4 nAEs (10 patients, 58.8%), and required hospitalization (11 patients, 64.7%). Eight patients died for nAEs referable causes. Pembrolizumab and nivolumab are associated with the development of nAEs associated with increased risk of permanent discontinuation of treatment, hospitalization, and death. Melanoma patients might be at a particularly high risk of such side effects. Future studies are still required to better assess which patients benefit most from such therapies, while minimizing the risk of complications.

The Diversity of Gut Microbiome is Associated With Favorable Responses to Anti–Programmed Death 1 Immunotherapy in Chinese Patients With NSCLC

IntroductionGut microbiome affecting the responses to immune checkpoint inhibitors against advanced NSCLC has been investigated in the Western population. However, considering pre-existing genetic and gut microbiota variation, the relevance remains unknown in the East-Asian NSCLC population. This study is designed to explore the relationship between gut microbiome and clinical outcomes in Chinese patients with NSCLC who have received treatment using an anti–programmed death 1 (PD-1) blockade. MethodsThirty-seven patients with advanced NSCLC receiving treatment with nivolumab were enrolled in CheckMate 078 (NCT02613507) and CheckMate 870 (NCT03195491). Fecal samples were collected at the starting point, when patients received nivolumab, at clinical evaluation, and when disease progression was noted. 16S ribosome RNA gene sequencing was applied to assess gut microbiota profiles. Peripheral immune signatures were determined by multicolor flow cytometry in parallel. ResultsWhen subgrouping patients into responder (R) and nonresponder according to the clinical response assessed using Response Evaluation Criteria in Solid Tumor version 1.1, R patients harbored higher diversity of gut microbiome at the starting point with stable composition during the treatment. Patients with high microbiome diversity had significantly prolonged progression-free survival when compared to those with low diversity. Compositional difference was observed between the two groups as well with the enrichment of Alistipes putredinis, Bifidobacterium longum, and Prevotella copri in R whereas Ruminococcus_unclassified enriched in nonresponding patients. Analysis of systemic immune responses using multicolor flow cytometry revealed that patients with a high abundance of microbiome diversity in the gut had a greater frequency of unique memory CD8+ T cell and natural killer cell subsets in the periphery in response to anti–PD-1 therapy. ConclusionsOur results reveal strong correlation between gut microbiome diversity and the responses to anti–PD-1 immunotherapy in Chinese patients with advanced NSCLC. Patients with favorable gut microbiome (such as those with high diversity) exhibit enhanced memory T cell and natural killer cell signatures in the periphery. These findings provide important implications for the prediction and the evaluation of anti–PD-1 immunotherapy against NSCLC in the Chinese population.

Genomics of NSCLC patients both affirm PD-L1 expression and predict their clinical responses to anti-PD-1 immunotherapy

BackgroundProgrammed Death Ligand 1 (PD-L1) is a co-stimulatory and immune checkpoint protein. PD-L1 expression in non-small cell lung cancers (NSCLC) is a hallmark of adaptive resistance and its expression is often used to predict the outcome of Programmed Death 1 (PD-1) and PD-L1 immunotherapy treatments. However, clinical benefits do not occur in all patients and new approaches are needed to assist in selecting patients for PD-1 or PD-L1 immunotherapies. Here, we hypothesized that patient tumor cell genomics influenced cell signaling and expression of PD-L1, chemokines, and immunosuppressive molecules and these profiles could be used to predict patient clinical responses.MethodsWe used a recent dataset from NSCLC patients treated with pembrolizumab. Deleterious gene mutational profiles in patient exomes were identified and annotated into a cancer network to create NSCLC patient-specific predictive computational simulation models. Validation checks were performed on the cancer network, simulation model predictions, and PD-1 match rates between patient-specific predicted and clinical responses.ResultsExpression profiles of these 24 chemokines and immunosuppressive molecules were used to identify patients who would or would not respond to PD-1 immunotherapy. PD-L1 expression alone was not sufficient to predict which patients would or would not respond to PD-1 immunotherapy. Adding chemokine and immunosuppressive molecule expression profiles allowed patient models to achieve a greater than 85.0% predictive correlation among predicted and reported patient clinical responses.ConclusionsOur results suggested that chemokine and immunosuppressive molecule expression profiles can be used to accurately predict clinical responses thus differentiating among patients who would and would not benefit from PD-1 or PD-L1 immunotherapies.

Identification of candidate responders for anti-PD-L1/PD-1 immunotherapy, Rova-T therapy, or EZH2 inhibitory therapy in small-cell lung cancer.

A useful candidate for small-cell lung cancer (SCLC) therapy is immune checkpoint blockade therapy targeting programmed death-1 (PD-1) and its ligand, PD-L1. Furthermore, rovalpituzumab tesirine (Rova-T), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate, and enhancer of zeste homologue 2 (EZH2) inhibitor are expected to be the first targeted therapy for SCLC. The aim of the present study was to evaluate PD-L1, DLL3 and EZH2 expression in SCLCs to find a candidate responder to those therapies. Immunohistochemical (IHC) staining for PD-L1, DLL3 and EZH2 was performed in 20 patients with SCLC and the clinicopathological characteristics and IHC staining intensity were compared. It was demonstrated that 1/20 patients (5.0%) exhibited positive PD-L1 expression in the metastatic lesions, as well as in the primary lung tumor. DLL3 was highly expressed in 14/20 patients (70%) and EZH2 was positive in 17/20 patients (85%). None of these cases exhibited any correlation with age, sex, smoking, stage or treatment, whereas IHC staining was able to identify candidate responders to anti-PD-L1/PD-1 immunotherapy, Rova-T therapy, or EZH2 inhibitor therapy.

Association Between Programmed Death Ligand 1 Expression in Patients With Basal Cell Carcinomas and the Number of Treatment Modalities

Response to programmed death 1 (PD-1) inhibitors has been associated with programmed death ligand 1 (PD-L1) expression levels in several cancers, but PD-L1 expression and its clinical significance in basal cell carcinoma (BCC) are unknown to date. To assess PD-L1 expression in treatment-naive and treated BCCs. This investigation was a cross-sectional study at a single academic tertiary referral center. Immunohistochemical staining on formalin-fixed BCCs from a dermatology clinic were examined in masked fashion by a dermatopathologist and a dermatologist. The study dates were March 31, 2014, to June 7, 2016. Treated BCCs (including those recurrent after surgery, radiotherapy, systemic chemotherapy, or topical chemotherapy) vs treatment-naive BCCs. Percentage of tumor cells and tumor-infiltrating lymphocytes (TILs) with PD-L1 expression, intensities of expression, and association with treatment modalities. Among 138 BCCs from 62 patients (43 males and 19 females; mean [SD] age at biopsy, 61.6 [13.7] years), 89.9% (124 of 138) were positive for PD-L1 expression in tumor cells, and 94.9% (131 of 138) were positive for PD-L1 expression in TILs, defined as greater than 5% positive immunohistochemical staining in the respective cell populations. The PD-L1 immunohistochemical staining intensity of 78 treated BCCs compared with 60 treatment-naive BCCs was significantly different in tumor cells (32% vs 7%, P = .003) and TILs (47% vs 18%, P = .008) after adjusting for the age at diagnosis. In a multivariable model adjusting for age, sex, and BCC location, PD-L1 staining intensity in tumor cells increased with the number of distinct prior treatment modalities (median, 0.12; interquartile range, 0.03-0.20; P = .007). Our data suggest that PD-1 immunotherapy may have activity against BCCs, including in those that have been previously treated. This hypothesis needs to be tested in future clinical trials.