Radiotherapy combined with anti-PD-1 and TKI for primary cardiac angiosarcoma considering the joint assessment of TLSs and PD-L1: a case report.

BACKGROUND: Primary cardiac angiosarcoma(PCA) has a low incidence rate and poor prognosis. Currently, no unified clinical treatment standards are available. CASE PRESENTATION: We report the case of a 48-year-old man presenting chest tightness, breathlessness, and dyspnea. Imaging and postoperative histopathologic studies confirmed PCA and that the tumor had invaded the entire right atrium. The patient developed progressive disease (PD) during postoperative radiotherapy. We used immunotherapy combined with targeted therapy based on the results of molecular profile and evaluation of tertiary lymphoid structures (TLSs) and programmed cell death-ligand 1 (PD-L1). After treatment, the metastatic lymph nodes of the patient were reduced to a certain extent, indicating that combination therapy was effective. CONCLUSION: To the best of our knowledge, this is the first report of radiotherapy combined with anti-PD-1 and tyrosine kinase inhibitors(TKI) for PCA. In addition, this is the first report on immunotherapy for PCA based on new evaluation methods, including TLSs, PD-L1, and genomic profile.

Assessment of PD-1 and PD-L1 tissue expression levels in lichen planus patients: a case-control study.

Programmed cell death protein-1 (PD-1) is an immune checkpoint protein, PD-1 interaction with PD ligand-1 (PD-L1) is essential for maintaining immunological tolerance. The study aimed to study and compare the levels of PD-1 and PD-L1 in lesional and nonlesional skin of lichen planus (LP) patients and compare these levels to normal healthy controls to assess their role in the pathogenesis of LP. This case-control study involved 30 patients with LP and 30 healthy age-and sex-matched controls. After clinical assessment of the severity by LP severity index score (LPSI), skin biopsies were taken from lesional and nonlesional skin of LP patients and from normal skin in healthy controls for assessment of the tissue levels of PD-1 and PD-L1 by ELISA. The tissue levels of both PD-1 and PD-L1 were significantly higher in healthy controls than in both lesional and nonlesional skin of LP patients (P < 0.001). Also, significantly higher PD-l and PD-L1 levels in nonlesional skin than in lesional skin of LP patients were reported (P < 0.001). No significant correlations were found between lesional and nonlesional PD-1, PD-L1 levels, or LPSI score. Based on the fact that PD-1/PD-L1 interaction is important to maintain tolerance and protection against autoimmune diseases, in addition to our study results that revealed lower levels of PD-1/PD-L1 in LP skin than in healthy skin, we can conclude that PD-1/PDL-1 may be incriminated in the pathogenesis of LP. ClinicalTrials.govID: NCT04892381.

Exploring the Cost Effectiveness of a Whole-Genome Sequencing-Based Biomarker for Treatment Selection in Patients with Advanced Lung Cancer Ineligible for Targeted Therapy.

OBJECTIVE: We aimed to perform an early cost-effectiveness analysis of using a whole-genome sequencing-based tumor mutation burden (WGS-TMB), instead of programmed death-ligand 1 (PD-L1), for immunotherapy treatment selection in patients with non-squamous advanced/metastatic non-small cell lung cancer ineligible for targeted therapy, from a Dutch healthcare perspective. METHODS: A decision-model simulating individual patients with metastatic non-small cell lung cancer was used to evaluate diagnostic strategies to select first-line immunotherapy only or the immunotherapy plus chemotherapy combination. Treatment was selected using PD-L1 [A, current practice], WGS-TMB [B], and both PD-L1 and WGS-TMB [C]. Strategies D, E, and F take into account a patient's disease burden, in addition to PD-L1, WGS-TMB, and both PD-L1 and WGS-TMB, respectively. Disease burden was defined as a fast-growing tumor, a high number of metastases, and/or weight loss. A threshold of 10 mutations per mega-base was used to classify patients into TMB-high and TMB-low groups. Outcomes were discounted quality-adjusted life-years (QALYs) and healthcare costs measured from the start of first-line treatment to death. Healthcare costs includes drug acquisition, follow-up costs, and molecular diagnostic tests (i.e., standard diagnostic techniques and/or WGS for strategies involving TMB). Results were reported using the net monetary benefit at a willingness-to-pay threshold of €80,000/QALY. Additional scenario and threshold analyses were performed. RESULTS: Strategy B had the lowest QALYs (1.84) and lowest healthcare costs (€120,800). The highest QALYs and healthcare costs were 2.00 and €140,400 in strategy F. In the base-case analysis, strategy A was cost effective with the highest net monetary benefit (€27,300), followed by strategy B (€26,700). Strategy B was cost effective when the cost of WGS testing was decreased by at least 24% or when immunotherapy results in an additional 0.5 year of life gained or more for TMB high compared with TMB low. Strategies C and F, which combined TMB and PD-L1 had the highest net monetary benefit (≥ €76,900) when the cost of WGS testing, immunotherapy, and chemotherapy acquisition were simultaneously reduced by at least 47%, 39%, and 43%, respectively. Furthermore, strategy C resulted in the highest net monetary benefit (≥ €39,900) in a scenario where patients with both PD-L1 low and TMB low were treated with chemotherapy instead of immunotherapy plus chemotherapy. CONCLUSIONS: The use of WGS-TMB is not cost effective compared to PD-L1 for immunotherapy treatment selection in non-squamous metastatic non-small cell lung cancer in the Netherlands. WGS-TMB could become cost effective provided there is a reduction in the cost of WGS testing or there is an increase in the predictive value of WGS-TMB for immunotherapy effectiveness. Alternatively, a combination strategy of PD-L1 testing with WGS-TMB would be cost effective if used to support the choice to withhold immunotherapy in patients with a low expected benefit of immunotherapy.

Comparison of assessment of programmed death-ligand 1 (PD-L1) status in triple-negative breast cancer biopsies and surgical specimens.

AIMS: Programmed death-ligand 1 (PD-L1) status in triple-negative breast cancer (TNBC) is important for immune checkpoint inhibitor therapies but may vary between different immunohistochemical assays, scorings and the type of specimen used for analysis. METHODS: We compared the analytical concordance of three clinically relevant PD-L1 assays (VENTANA SP142, VENTANA SP263 and DAKO 22C3 pharmDx) assessing immune cell score (IC), tumour proportion score and combined positive score (CPS) in preoperative biopsies and resection specimens of primary TNBC. PD-L1 expression was scored on virtual whole slide images and compared with expression data from corresponding surgical specimens. RESULTS: The mean PD-L1 positivity in TNBC biopsies defined as IC ≥1% and CPS ≥1 ranged between 11% and 61% with the lowest positivity for SP142 and highest for SP263. The corresponding surgical specimens showed overall higher positivity rates (53%-75%). When comparing biopsies with surgical specimens, the agreement for PD-L1 positivity with SP263 and 22C3 at IC score ≥1% and CPS ≥1 was fair (kappa 0.47-0.52) and poor for SP142 (kappa 0.15-0.19). Using CPS ≥10 cut-off, the agreement for SP263 was excellent (kappa 0.751) but poor for 22C3 (kappa 0.261). Spearman correlation coefficients ranged between 0.489 and 0.75 indicating a generally moderate to strong correlation between biopsies and surgical specimens for all assays and scores. CONCLUSIONS: We demonstrate high accordance between biopsies and surgical specimens for SP263 and 22C3 scoring but less for SP142. Generally, biopsies are suitable for PD-L1 testing in TNBC but the appropriate assay, scoring and cut-off must be considered.

Cost-effectiveness of first-line immunotherapy for advanced non-small cell lung cancer with different PD-L1 expression levels: A comprehensive overview.

BACKGROUND: Immunotherapies can substantially improve treatment efficacy, despite their high cost. A comprehensive overview of the cost-effectiveness analysis (CEA) of immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer based on different tumor proportion scores (TPSs) was conducted. METHODS: PubMed, Embase, Cochrane Central Register of Controlled Trials, Health Technology Assessment Database, and NHS Economic Evaluation databases were searched from their inception until August 24, 2022. Data relevant to the CEA results were recorded, and quality assessments conducted based on the Quality of Health Economic Studies (QHES) process. FINDINGS: Fifty-one original studies from seven countries were included. The mean QHES score was 77.0 (range: 53-95). Twenty-seven studies were classified as high-quality, and the rest as fair quality. Pembrolizumab, nivolumab, ipilimumab, atezolizumab, camrelizumab, cemiplimab, sintilimab, tislelizumab, and durvalumab were identified using three TPS categories. While nivolumab plus ipilimumab and pembrolizumab plus chemotherapy were unlikely to be cost-effective in China, the results for the US were uncertain. Atezolizumab combinations were not cost-effective in China or the US, and tislelizumab and sintilimab were cost-effective in China. For TPSs ≥ 50%, the pembrolizumab monotherapy could be cost-effective in some developed countries. Cemiplimab was more cost-effective than chemotherapy, pembrolizumab, and atezolizumab in the US. For TPSs ≥ 1%, the cost-effectiveness of pembrolizumab was controversial due to the different willingness-to-pay thresholds. CONCLUSIONS: None of the atezolizumab combination regimens were found to be cost-effective in any perspective of evaluations. Camrelizumab, tislelizumab, and sintilimab have lower ICERs compared to atezolizumab, pembrolizumab, and nivolumab in China. Cemiplimab may be a more affordable alternative to pembrolizumab or atezolizumab. However, it remains unclear which ICIs are the best choices for each country. Future CEAs are required to select comprehensive regimens alongside randomized trials and real-world studies to help verify the economics of ICIs in specific decision-making settings.

Comparative cost-effectiveness of nivolumab first-line and second-line therapy for advanced esophageal cancer in Japan.

OBJECTIVE: A model-based cost-effectiveness analysis comparing first-line and second-line nivolumab therapy for advanced esophageal cancer was performed to support public healthcare in Japan. METHODS: A partitioned survival model was developed to predict costs and outcomes. Survival data were obtained from two phase 3 clinical trials (Attraction-3 and Checkmate-648), and direct medical costs were estimated from the perspective of the Japanese National Health Insurance payer. The time horizon for the model was set to 20 years. Health outcomes were calculated and defined as quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER) were compared to those of control therapy. A sensitivity analysis was performed based on parameter settings and model uncertainties. A willingness-to-pay threshold of 15 million Japanese yen (JPY) was established. RESULTS: Compared to that of each control therapy, the ICER for nivolumab per QALY gained was 15,712,265 JPY (143,099 USD) for first-line combination therapy with chemotherapy in the overall population, 10,657,085 JPY (97,059 USD) in the population with ≥ 1% Programmed Death-Ligand 1 (PD-L1) expression, and 41,184,322 JPY (375,085 USD) for second-line nivolumab monotherapy. A probabilistic sensitivity analysis estimated that nivolumab was cost-effective as a first-line therapy for the overall population (61.5%) and for the population with ≥ 1% PD-L1 expression (76.5%), but not as second-line monotherapy (32.3%). CONCLUSION: Nivolumab is recommended as a first-line therapy in combination with chemotherapy owing to its cost-effectiveness, but not as a second-line monotherapy. Patient selection based on PD-L1 expression may help to improve the cost-effectiveness of using nivolumab as a first-line treatment.

PD-L1 Assessment in Needle Core Biopsies of Non-Small Cell Lung Cancer: Interpathologist Agreement and Potential Associated Histopathological Features.

OBJECTIVE: Immune checkpoint inhibitors are used in the treatment of non-small cell lung cancer (NSCLC). Programmed cell death-ligand 1 (PD-L1) immunohistochemistry (IHC) assessed by pathologists is subject to interobserver variability. In advanced/metastatic disease and inoperable patients, PD-L1 assessment relies on biopsy specimens, commonly needle core biopsies (NCB). We aimed to determine the interobserver agreement for PD-L1 tumor proportion score (TPS) in NSCLC NCBs and identify histopathological features that may be related to interobserver variability. MATERIAL AND METHODS: Sixty NSCLC NCBs with PD-L1 IHC were evaluated independently by four pathologists from different institutions. PD-L1 TPS was evaluated in three categories: no/low expression ( < 1%), intermediate expression (1%49%), and high expression (≥50%). Histological tumor type, necrosis, tumor-infiltrating lymphocytes, tumor length/percentage in the biopsy, and crush/squeeze artifact was evaluated. RESULTS: The statistical analysis of the three PD-L1 TPS categories demonstrated moderate agreement (Fleiss Kappa 0.477) in the no/low category, fair agreement (Fleiss Kappa 0.390) in the intermediate category, and almost perfect agreement (Fleiss Kappa 0.952) in the high category. A significant correlation (p=0.003) was found between the crush/squeeze artifact in NCB and rate of discordant TPS categories. There was no significant correlation between pathologists' agreement in the TPS categories and histological tumor type, tumor length, tumor ratio, necrosis, and tumor-infiltrating lymphocytes. CONCLUSION: Our results demonstrated moderate agreement among pathologists for the PD-L1 TPS 1% cut-off in NSCLC NCB, which is lower than that reported in resection materials. The presence of crush/squeeze artifact in NCBs is significantly related to the rate of discordant TPS categories, suggesting that PD-L1 assessment of pulmonary NCBs requires an awareness of this artifact.

Immunotherapy Guided by Immunohistochemistry PD-L1 Testing for Patients with NSCLC: A Microsimulation Model-Based Effectiveness and Cost-Effectiveness Analysis.

BACKGROUND: On the basis of immunohistochemistry PD-L1 testing results, patients with advanced non-small cell lung cancer (NSCLC) are treated differently. Theoretically, patients with high PD-L1 expression (50% or 1%) should receive PD-1 monotherapy for fewer adverse reactions and cost savings from avoiding chemotherapy; however, there is controversy surrounding the cut-off criteria (1% or 50%) for immunohistochemistry testing and threshold for PD-1 monotherapy. OBJECTIVE: This study aims to predict the effectiveness and cost-effectiveness of different immunotherapy strategies for patients with NSCLC in China from the healthcare system perspective. PATIENTS AND METHODS: A microsimulation model was developed to evaluate the effectiveness and cost-effectiveness of three treatment strategies: PD-L1 testing (1%) (PD-1 monotherapy for those with PD-L1 expression at 1% threshold, and combination with chemotherapy for others with immunohistochemistry testing), PD-L1 testing (50%) (PD-1 monotherapy for those with PD-L1 expression at 50% threshold, and combination with chemotherapy for others with immunohistochemistry testing), and No PD-L1 testing (PD-1 combined with chemotherapy without immunohistochemistry testing). The model assumed 1000 patients per strategy, with each patient entering a unique clinical path prior to receiving treatment on the basis of PD-L1 test results. Clinical inputs were derived from clinical trials. Cost and utility parameters were obtained from the database and literature. One-way probabilistic sensitivity analyses (PSA) and six scenario analyses were used to test the model's robustness. RESULTS: The study revealed a hierarchy of survival benefits across three strategies, with No PD-L1 testing demonstrating the most survival advantage, followed by PD-L1 testing (50%), and finally, PD-L1 testing (1%). The comparative analysis demonstrated that No PD-L1 testing significantly enhanced overall survival (OS) (HR 0.85, 95% CI 0.78-0.93), progression-free survival (HR 0.82, 95% CI 0.75-0.90), and progression-free2 survival (PFS2) (HR 0.91, 95% CI 0.83-0.99) when juxtaposed against PD-L1 testing (1%). However, these improvements were not as pronounced when compared with PD-L1 testing (50%), particularly in relation to PFS, PFS2, and OS. The cost-effectiveness analysis further unveiled incremental cost-utility ratios (ICUR), with No PD-L1 testing versus PD-L1 testing (50%) at $34,003 per quality-adjusted life year (QALY) and No PD-L1 testing versus PD-L1 testing (1%) at $34,804 per QALY. In parallel, the ICUR for PD-L1 testing (50%) versus PD-L1 testing (1%) stood at $35,713 per QALY. Remarkably, the PSA result under a willingness-to-pay (WTP) threshold of $10,144 per QALY, with a 100% probability, demonstrated PD-L1 testing (1%) as the most cost-effective option. CONCLUSIONS: The survival benefits of PD-1 monotherapy for high expression with PD-L1 immunohistochemistry testing are inferior to those of PD-1 combined with chemotherapy without testing, but it is found to be more cost-effective at the WTP thresholds in China and holds great potential in increasing affordability and reducing the economic burden.

Accuracy of Cytologic vs Histologic Specimens for Assessment of Programmed Cell Death Ligand-1 Expression in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Programmed cell death ligand-1 (PD-L1) expression on tumor cells, evaluated by immunohistochemistry, guides the use of immunotherapy in advanced non-small cell lung cancer (NSCLC). RESEARCH QUESTION: What is the sensitivity and specificity of PD-L1 testing performed in cytologic vs paired histologic specimens in patients with NSCLC? STUDY DESIGN AND METHODS: The MEDLINE, Embase, Web of Science, and Cochrane Library databases were searched through June 1, 2021. The primary outcome was pooled sensitivity and specificity of PD-L1 testing performed on cytologic specimens compared with the reference standard of histologic specimens, analyzed at the PD-L1 expression cutoffs (tumor proportion score) ≥ 1% and ≥ 50%. Pooled sensitivity and specificity, and associated 95% CIs, were estimated using bivariate generalized linear mixed models. RESULTS: Twenty-six articles were included, encompassing a total of 1,064 pairs of histology specimens and cytology cell blocks, and 267 pairs of histology specimens and direct smears. Among these, 946 paired specimens were acquired without interval treatment between the collection of histology and cytology samples. The pooled sensitivity and specificity of cytology specimens compared with paired histology specimens at the PD-L1 expression cutoff ≥ 1% were 0.84 (95% CI, 0.77-0.89) and 0.88 (95% CI, 0.82-0.93), respectively, whereas the pooled sensitivity and specificity at cutoff ≥ 50% were 0.78 (95% CI, 0.69-0.86) and 0.94 (95% CI, 0.91-0.96), respectively. When only paired specimens acquired without interval treatment were considered, the pooled sensitivity and specificity of cytology specimens at PD-L1 expression cutoff ≥ 1% were 0.84 (95% CI, 0.76-0.90) and 0.89 (95% CI, 0.82-0.94), respectively, whereas the pooled sensitivity and specificity at cutoff ≥ 50% were 0.80 (95% CI, 0.71-0.89) and 0.94 (95% CI, 0.91-0.96), respectively. INTERPRETATION: Cytologic specimens provide an accurate assessment of PD-L1 expression in most patients with NSCLC, at both ≥ 1% and ≥ 50% cutoffs, when compared with histologic specimens. TRIAL REGISTRATION: PROSPERO; No.: CRD42020153279; URL: https://www.crd.york.ac.uk/prospero/.

Refining PD-1/PD-L1 assessment for biomarker-guided immunotherapy: A review.

Anti-programmed cell death ligand 1 (anti-PD-L1)  immunotherapy is an increasingly crucial in cancer treatment. To date, the Federal Drug Administration (FDA) has approved four PD-L1 immunohistochemistry (IHC) staining protocols, commercially available in the form of "kits", facilitating testing for PD-L1 expression. These kits comprise four PD-L1 antibodies on two separate IHC platforms, each utilizing distinct, non-interchangeable scoring systems. Several factors, including tumor heterogeneity and the size of the tissue specimens assessed, can lead to PD-L1 status misclassification, potentially hindering the initiation of therapy. Therefore, the development of more accurate predictive biomarkers to distinguish between responders and non-responders prior to anti-PD-1/PD-L1 therapy warrants further research. Achieving this goal necessitates refining sampling criteria, enhancing current methods of PD-L1 detection, and deepening our understanding of the impact of additional biomarkers. In this article, we review potential solutions to improve the predictive accuracy of PD-L1 assessment in order to more precisely anticipate patients' responses to anti-PD-1/PD-L1 therapy, monitor disease progression and predict clinical outcomes.

PD-L1 assessment in lung cancer biopsies-pitfalls and limitations.

The programmed cell death-ligand 1 (PD-L1) protein expression on tumor cells predicts the efficacy of immunotherapy in patients with non-small cell lung cancer. However, the assessment of PD-L1 expression on tumor cells has limited power for selecting patients for immunotherapy due to intra-tumoral heterogeneity and inter-tumoral heterogeneity of PD-L1 expression, the inter-observer variability in scoring PD-L1 staining, and reproducibility. These difficulties and pitfalls in interpreting the PD-L1 assessment are discussed in detail in this review.

Systematic assessment of tumor necrosis at baseline in cervical cancer - An independent factor associated with poor outcome.

Cervical cancer (CC) is a leading challenge in oncology worldwide, with high prevalence and mortality rates in young adults, most prominent in low to middle-income countries with marginal screening facilities. From the prospectively collected BioRAIDS (NCT02428842) cohort of primary squamous CC conducted in 7 European countries, a central pathology review was carried out on 294 patients' tumors. The focus was on identification of tumor-stromal characteristics such as CD8+, CD45+, CD68+ staining cells, PD-L1 expression, tumor infiltrating lymphocytes (TILs) together with the degree of tumor necrosis. Both (FIGO-2018) stage (I-II/III-IV) as well as tumor necrosis were highly significantly associated with Progression-free Survival (PFS); with tumor necrosis scoring as most potent independent factor in a multivariable analysis (p < 0.001). Tumor necrosis can be assessed in the very first diagnostic biopsyand our data suggest that this rapid, simple and cost-effective biomarker, should be routinely assessed prior to treatment decisions.

Similar Efficacy Observed for First-Line Immunotherapy in Racial/Ethnic Minority Patients With Metastatic NSCLC.

BACKGROUND: Limited data exist on the impact of immunotherapy use in ethnic minority patients with non-small cell lung cancer (NSCLC), because they have been underrepresented in immunotherapy trials. This study aims to evaluate race/ethnicity and other demographic, socioeconomic, and clinical factors of patients with metastatic NSCLC treated with first-line immunotherapy. METHODS: A retrospective cohort study of 5,920 patients diagnosed with lung cancer treated at Montefiore Einstein Cancer Center from January 1, 2013, to June 1, 2022, was used to identify patients with metastatic NSCLC without EGFR, ALK, or ROS1 alterations who underwent first-line immunotherapy (n=248). The primary endpoint was overall survival (OS), with secondary endpoints of progression-free survival (PFS) and time to discontinuation (TTD) from the start of immunotherapy. RESULTS: Among the 248 patients, median follow-up time was 12.0 months, median age at start of treatment was 66 years, and 39.1% were non-Hispanic Black, 30.2% were Hispanic, and 30.7% were non-Hispanic White. OS (P=.39), PFS (P=.29), and TTD (P=.98) were similar among racial/ethnic groups. Patients with an ECOG performance status (PS) of <2 at the start of immunotherapy had longer OS compared with those with ECOG PS of ≥2 (P<.0001). PD-L1 expression (<50% vs ≥50%; P=.03) and body mass index (BMI) (P=.01) were also found to be associated with PFS, and ECOG PS (P<.0001) and BMI (P=.02) were associated with TTD. In a multivariate analysis of OS and PFS, ECOG PS was the only variable found to be significant. CONCLUSIONS: Our study observed similar benefits of immunotherapy in patients with metastatic NSCLC in different racial and ethnic groups. Furthermore, ECOG PS was associated with OS, and PD-L1 expression and BMI were associated with PFS and TTD. These findings help identify potential factors associated with outcomes and care while patients are undergoing immunotherapy.

Development and pharmacokinetic assessment of a fully canine anti-PD-1 monoclonal antibody for comparative translational research in dogs with spontaneous tumors.

PD-1 checkpoint inhibitors have revolutionized the treatment of patients with different cancer histologies including melanoma, renal cell carcinoma, and non-small cell lung carcinoma. However, only a subset of patients show a dramatic clinical response to treatment. Despite intense biomarker discovery efforts, no single robust, prognostic correlation has emerged as a valid outcome predictor. Immune competent, pet dogs develop spontaneous tumors that share similar features to human cancers including chromosome aberrations, molecular subtypes, immune signatures, tumor heterogeneity, metastatic behavior, and chemotherapeutic response. As such, they represent a valuable parallel patient population in which to investigate predictive biomarkers of checkpoint inhibition. However, the lack of a validated, non-immunogenic, canine anti-PD-1 antibody for pre-clinical use hinders this comparative approach and prevents potential clinical benefits of PD-1 blockade being realized in the veterinary clinic. To address this, fully canine single-chain variable fragments (scFvs) that bind canine (c)PD-1 were isolated from a comprehensive canine scFv phage display library. Lead candidates were identified that bound with high affinity to cPD-1 and inhibited its interaction with canine PD-L1 (cPD-L1). The lead scFv candidate re-formatted into a fully canine IgGD reversed the inhibitory effects of cPD-1:cPD-L1 interaction on canine chimeric antigen receptor (CAR) T cell function. In vivo administration showed no toxicity and revealed favorable pharmacokinetics for a reasonable dosing schedule. These results pave the way for clinical trials with anti-cPD-1 in canine cancer patients to investigate predictive biomarkers and combination regimens to inform human clinical trials and bring a promising checkpoint inhibitor into the veterinary armamentarium.

Assessment of PD-L1, TROP2, and nectin-4 expression in penile squamous cell carcinoma.

OBJECTIVES: There is an unmet need for therapeutically relevant biomarkers for advanced penile squamous cell carcinoma (pSCC). Proposed immunohistochemistry (IHC)-based biomarkers include programmed death-ligand 1 (PD-L1), trophoblast cell-surface antigen 2 (TROP2), and nectin-4; however, there is a paucity of data pertaining to these biomarkers. Herein, we investigated the expression of PD-L1, TROP2, and nectin-4 in a well-annotated cohort of pSCCs. METHODS: A single-institution pathology archive was queried for patients who had a partial or total penectomy for pSCC between January 2000 and December 2022. Whole-slide sections were stained with antibodies against PD-L1 (22C3), TROP2, and nectin-4. Expression in tumor cells was quantified using H-scores (0-300). Associations between IHC expression, human papilloma virus (HPV) status, clinicopathologic findings, and outcome parameters were evaluated. RESULTS: This study included 121 patients. For PD-L1, the median combined positive and H-scores were 1 and 0, respectively; 32.7 % of the cases had an H-score>0. Compared to PD-L1-negative tumors, PD-L1-positive tumors had higher pT stage and grade. The median TROP2 and nectin-4 H-scores were 230 and 140, respectively, with high TROP2 and nectin-4, defined by an H-score>200, noted in 80.7 % and 10.9 % of cases, respectively. High-risk HPV-positive cases had higher TROP2 and nectin-4 scores compared to HPV-negative cases. Patients with high TROP2 expression had significantly more disease progression, and patients with high nectin-4 expression had significantly fewer deaths due to disease. CONCLUSIONS: High expression of TROP2 and nectin-4 in pSCC support evaluation of these markers as therapeutic targets pending validation of our findings.

Preclinical assessment of CAR-NK cell-mediated killing efficacy and pharmacokinetics in a rapid zebrafish xenograft model of metastatic breast cancer.

Natural killer (NK) cells are attractive effectors for adoptive immunotherapy of cancer. Results from first-in-human studies using chimeric antigen receptor (CAR)-engineered primary NK cells and NK-92 cells are encouraging in terms of efficacy and safety. In order to further improve treatment strategies and to test the efficacy of CAR-NK cells in a personalized manner, preclinical screening assays using patient-derived tumor samples are needed. Zebrafish (Danio rerio) embryos and larvae represent an attractive xenograft model to study growth and dissemination of patient-derived tumor cells because of their superb live cell imaging properties. Injection into the organism's circulation allows investigation of metastasis, cancer cell-to-immune cell-interactions and studies of the tumor cell response to anti-cancer drugs. Here, we established a zebrafish larval xenograft model to test the efficacy of CAR-NK cells against metastatic breast cancer in vivo by injecting metastatic breast cancer cells followed by CAR-NK cell injection into the Duct of Cuvier (DoC). We validated the functionality of the system with two different CAR-NK cell lines specific for PD-L1 and ErbB2 (PD-L1.CAR NK-92 and ErbB2.CAR NK-92 cells) against the PD-L1-expressing MDA-MB-231 and ErbB2-expressing MDA-MB-453 breast cancer cell lines. Injected cancer cells were viable and populated peripheral regions of the larvae, including the caudal hematopoietic tissue (CHT), simulating homing of cancer cells to blood forming sites. CAR-NK cells injected 2.5 hours later migrated to the CHT and rapidly eliminated individual cancer cells throughout the organism. Unmodified NK-92 also demonstrated minor in vivo cytotoxicity. Confocal live-cell imaging demonstrated intravascular migration and real-time interaction of CAR-NK cells with MDA-MB-231 cells, explaining the rapid and effective in vivo cytotoxicity. Thus, our data suggest that zebrafish larvae can be used for rapid and cost-effective in vivo assessment of CAR-NK cell potency and to predict patient response to therapy.

Cost-Effectiveness Analysis of Atezolizumab versus Platinum-Based Chemotherapy as First-Line Treatment for Patients with Unresectable Advanced Non-small Cell Lung Cancer with PD-L1 Expression Status in Japan.

BACKGROUND AND OBJECTIVES: Atezolizumab has demonstrated safety and efficacy in patients with metastatic non-small cell lung cancer (NSCLC) in the IMpower110 trial. The aim of this study was to evaluate the cost-effectiveness of atezolizumab as the first-line treatment for patients with unresectable advanced NSCLC, including programmed cell death ligand-1 (PD-L1)-positive probability testing, from the perspective of healthcare costs in Japan. METHODS: A cost-effectiveness analysis model for atezolizumab, including PD-L1-positive probability testing, was used to construct a partitioned survival model with three health states. To assess the robustness, a probabilistic sensitivity analysis (PSA) was conducted. The acceptable probability was defined as the probability of willingness-to-pay (WTP) over the incremental cost-effectiveness ratio (ICER). Multiple repetitions at WTP thresholds were calculated by continuously reducing the atezolizumab price. RESULTS: The ICER per quality-adjusted life year (QALY) for atezolizumab therapy only for patients with high PD-L1 expression compared to platinum-based chemotherapy for all patients was 31,975,792 yen per QALY. This is higher than the WTP threshold of 15,000,000 yen. If the cost of atezolizumab were reduced to 54% of the original cost (563,917 yen), the strategy of using atezolizumab for patients with high PD-L1 could become more cost-effective. CONCLUSIONS: The results indicated that atezolizumab was not cost-effective compared to platinum-based chemotherapy as a first-line treatment for patients with unresectable advanced NSCLC. However, we suggest that the price of atezolizumab should be reduced to 54% of the original cost to meet the WTP threshold of 15,000,000 yen per QALY.

[Practical aspects of PD-L1 assessment in the treatment of urothelial carcinoma: Consensus of the uropathology group of the SEAP]. / Aspectos prácticos sobre la determinación de PD-L1 en el tratamiento de carcinoma urotelial. Consenso del grupo de uropatología de la SEAP.

The recent addition of novel immunotherapy drugs for the treatment of urothelial carcinoma makes it necessary the establishment of criteria to harmonize the immunohistochemical assessment of PD-L1, both as a prognostic factor and for the selection of patients to be treated. In this scenario, a group of uropathologists from the Spanish Society of Pathological Anatomy, together with a medical oncologist as an external collaborator subspecialized in uro-oncology, have prepared this document of recommendations based on the available evidence. During PD-L1 assessment it is especially relevant the selection of the sample, its processing, the immunohistochemical platform and antibody used, and the algorithm applied in the interpretation of results. All these aspects must be indicated in the results report, which should be easily interpretable in a context of rapid evolution of immunological therapies.

Preclinical safety assessment of an oncolytic herpes simplex virus type 2 expressed PD-L1/CD3 bispecific antibody.

Oncolytic virotherapy is an emerging and safe therapeutic approach based on the inherent cytotoxicity of oncolytic viruses and their ability to replicate and spread within tumors in a selective manner. We constructed a new type of oncolytic herpes simplex virus armed with Bispecific Antibody (BsAb) molecules targeting PD-L1/CD3 (oHSV2-PD-L1/CD3-BsAb) to treat human malignancies. We demonstrated the anti-tumor efficacy of oHSV2-PD-L1/CD3-BsAb. To move forward with clinical trials of oHSV2-PD-L1/CD3-BsAb, we conducted a comprehensive preclinical safety evaluation, including hemolysis test, anaphylaxis test, repeated dose toxicity test in cynomolgus monkeys, biodistribution in cynomolgus monkeys and tissue cross-reactivity of PD-L1/CD3-BsAb with human and cynomolgus monkey tissues in vitro. Our preclinical safety evaluation indicated that oHSV2-PD-L1/CD3-BsAb is safe and suitable for clinical trials. After undergoing a thorough evaluation by the United States Food and Drug Administration (FDA), oHSV2-PD-L1/CD3-BsAb has successfully obtained approval to initiate Phase I clinical trials in the United States (FDA IND: 28717).

Cost-effectiveness analysis of nivolumab plus chemotherapy vs chemotherapy for patients with unresectable advanced or metastatic HER2-negative gastric or gastroesophageal junction or esophageal adenocarcinoma in Japan.

BACKGROUND: This study aimed to evaluate the cost-effectiveness of nivolumab plus chemotherapy (NIVO + Chemo) compared with chemotherapy monotherapy (Chemo) for patients with advanced or metastatic HER2-negative gastric or gastroesophageal junction or esophageal adenocarcinoma (GC/GEJC/EAC) in Japan from the perspective of healthcare payer. METHODS: A partitioned survival analysis model was developed to predict costs and quality-adjusted life years (QALYs) for NIVO + Chemo and Chemo. The time horizon of the model was set to 38 years. An annual discount rate of 2% for both costs and QALYs was applied. Data on overall survival and progression-free survival were derived from the CheckMate649 trial. Cost parameters were estimated from a Japanese medical claims database. The incremental cost-effectiveness ratio (ICER) of NIVO + Chemo compared with Chemo was estimated. A subgroup analysis on the level of PD-L1 CPS expression was conducted. In addition, sensitivity analysis was performed to assess the uncertainty in the parameter settings. RESULTS: The incremental cost and QALY of NIVO + Chemo compared with Chemo were USD99,416 and 0.30 QALY, respectively. The ICER of NIVO + Chemo was estimated to be USD327,161 per QALY gained. The results of the subgroup analysis showed that ICER was USD247,403/QALY and USD302,183/QALY for PD-L1 CPS ≧ 5 and ≧ 1, respectively. Sensitivity analyses showed a relatively robust result that the ICER remained higher than the Japanese cancer threshold of USD75,000-150,000/QALY. CONCLUSIONS: Applying the Japanese cancer threshold of USD75,000-150,000/QALY, NIVO + Chemo was not cost-effective for patients with advanced or metastatic HER2-negative GC/GEJC/EAC in Japan from the perspective of healthcare payer.