Programmed Death-ligand 1 Therapy Research Articles

Absence of PD-L1 signaling hinders macrophage defense against Mycobacterium tuberculosis via upregulating STAT3/IL-6 pathway

The blockade of programmed death-ligand 1 (PD-L1) pathway has been clinically used in cancer immunotherapy, while its effects on infectious diseases remain elusive. Roles of PD-L1 signaling in the macrophage-mediated innate immune defense against M.tb is unclear. In this study, the outcomes of tuberculosis (TB) in wild-type (WT) mice treated with anti-PD-1/PD-L1 therapy and macrophage-specific Pdl1-knockout (Pdl1ΔΜΦ) mice were compared. Treatment with anti-PD-L1 or anti-PD-1 benefited protection against M.tb infection in WT mice, while Pdl1ΔΜΦ mice exhibited the increased susceptibility to M.tb infection. Mechanistically, the absence of PD-L1 signaling impaired M.tb killing by macrophages. Furthermore, elevated STAT3 activation was found in PD-L1-deficient macrophages, leading to increased interleukin (IL)-6 production and reduced inducible nitric oxide synthase (iNOS) expression. Inhibiting STAT3 phosphorylation partially impeded the increase in IL-6 production and restored iNOS expression in these PD-L1-deficient cells. These findings provide valuable insights into the complexity and mechanisms underlying anti-PD-L1 therapy in the context of tuberculosis.

The predictive value of PD-L1 expression in response to anti-PD-1/PD-L1 therapy for biliary tract cancer: a systematic review and meta-analysis.

Recently, anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immunotherapy offers promising results for advanced biliary tract cancer (BTC). However, patients show highly heterogeneous responses to treatment, and predictive biomarkers are lacking. We performed a systematic review and meta-analysis to assess the potential of PD-L1 expression as a biomarker for treatment response and survival in patients with BTC undergoing anti-PD-1/PD-L1 therapy. We conducted a comprehensive systematic literature search through June 2023, utilizing the PubMed, EMBASE, and Cochrane Library databases. The outcomes of interest included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) according to PD-L1 expression. Subgroup analyses and meta-regression were performed to identify possible sources of heterogeneity. A total of 30 studies was included in the final analysis. Pooled analysis showed no significant differences in ORR (odds ratio [OR], 1.56; 95% confidence intervals [CIs], 0.94-2.56) and DCR (OR, 1.84; 95% CIs, 0.88-3.82) between PD-L1 (+) and PD-L1 (-) patients. In contrast, survival analysis showed improved PFS (hazard ratio [HR], 0.54, 95% CIs, 0.41-0.71) and OS (HR, 0.58; 95% CI, 0.47-0.72) among PD-L1 (+) patients compared to PD-L1 (-) patients. Sensitivity analysis excluding retrospective studies showed no significant differences with the primary results. Furthermore, meta-regression demonstrated that drug target (PD-1 vs. PD-L1), presence of additional intervention (monotherapy vs. combination therapy), and PD-L1 cut-off level (1% vs. ≥5%) significantly affected the predictive value of PD-L1 expression. PD-L1 expression might be a helpful biomarker for predicting PFS and OS in patients with BTC undergoing anti-PD-1/PD-L1 therapy. The predictive value of PD-L1 expression can be significantly influenced by diagnostic or treatment variables. https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023434114.

Concordance among three programmed death-ligand 1 (PD-L1) scoring methods and their association with clinical outcomes of tislelizumab (TIS) monotherapy in esophageal squamous cell carcinoma (ESCC).

390 Background: Multiple scoring methods and cutoffs have been developed to evaluate tumor PD-L1 expression status in patients with ESCC, and PD-L1 expression level has been associated with the degree of response to anti-programmed cell death protein 1 (PD-1)/PD-L1 therapy. Here, we retrospectively investigated concordance between three PD-L1 scoring methods and their association with clinical outcomes in RATIONALE-302, a phase 3 study of the anti-PD-1 antibody TIS vs investigator-chosen chemotherapy (ICC) as second-line treatment for advanced unresectable/metastatic ESCC (NCT03430843). Methods: Patients enrolled in RATIONALE-302 with evaluable PD-L1 expression by the tumor area positivity (TAP) score (based on visual estimation of positive tumor cells [TCs] and tumor-associated immune cells [ICs]) using the VENTANA PD-L1 (SP263) assay were categorized at a 10% cutoff. Stained slides from those patients were rescored post hoc using both combined positive score (CPS; based on counting positive TCs and ICs) at cutoff 10 and TC (based on counting positive TCs only) score at a 1% cutoff, thresholds currently used in ESCC for anti-PD-(L)1 therapy. Concordance at these thresholds was investigated. Clinical efficacy (overall survival [OS]) for PD-L1 subgroups was assessed. Results: Of 512 pts enrolled, 364 had evaluable TAP scores (TIS, n=180; ICC, n=184), of whom 355 had evaluable post-hoc CPS and TC scores (TIS, n=175; ICC, n=180). TAP score and CPS showed high concordance in terms of overall percentage agreement (OPA; 90% [95% confidence interval (CI): 86, 93]) and Cohen’s Kappa (0.79 [95% CI: 0.72, 0.85]), while TAP and TC scores had lower concordance (OPA: 78% [95% CI: 73, 82]; Cohen’s Kappa: 0.56 [95% CI: 0.47, 0.64]). OS benefit with TIS vs ICC in PD-L1 subgroups defined by TAP, CPS, and TC score cutoffs were generally similar (Table). Conclusions: OS subgroup analysis showed comparable treatment effect by TAP score at 10% cutoff, CPS at cutoff 10, and TC score at 1% cutoff based on SP263 staining. TAP score and CPS at these cutoffs exhibited substantial concordance. The results indicate that the less time-consuming, visually estimated TAP score and CPS may be interchangeable for clinical measurement of PD-L1 expression in patients with ESCC. Clinical trial information: NCT03430843 . [Table: see text]

Effect of PD-1/ PD-L1 and statin combination therapy on gastrointestinal toxicity related to immune checkpoint inhibitors and on survival.

742 Background: Immune Checkpoint Inhibitor (ICI) therapy has greatly expanded its approval to treat a variety of malignancies with high efficacy. Inhibitors of programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) are two of the most common classes of ICI therapy. There has been significant research into medications that may have a synergistic effect with ICI therapy, notably statins due to their pro-apoptotic effect. The addition of statins to immunotherapy may also increase the risk of developing certain immune related adverse events (irAEs). We sought to investigate the effect of statin use on the development of gastrointestinal (GI) irAEs and on survival of patients on PD-1/L1 therapy. Methods: We conducted a review of select cancer patients at a tertiary cancer center who received PD-1/L1 inhibitors and statins between 2016 and 2022. The clinical characteristics and overall survival were compared to a control group who received PD-1/L1 inhibitors without statins. Results: A total of 823 patients were included in the statin group and compared to 11101 patients in the control group. In the statin group 707 received a PD-1 inhibitor, 86 received a PD-L1 inhibitor, and 30 received both checkpoint inhibitors. The included cancer types were lung cancer (44%), kidney cancer (26%), head/neck cancer (19%), and GI cancer (7.0%). The overall incidence of GI irAEs in patients receiving statins was 10.8%, which was comparable to patients without statin treatment (11.1%, p=0.83). In addition, statin treatment appeared to be associated with a more favorable survival in patients overall (p= 0.004) and also those with GI irAEs (p=0.047). Conclusions: Synergism between statins and PD-1/L1 inhibitors continues to be a developing field of interest. Our data showed the combination therapy’s survival benefit without exacerbating GI toxicity, which warrants further investigation of this treatment strategy.

Understanding immune checkpoints and PD-1/PD-L1-mediated immune resistance towards tumour immunotherapy.

Immunotherapy has emerged as a transformative approach in the treatment of various cancers, offering new hope for patients previously faced with limited treatment options. A cornerstone of cancer immunotherapy lies in targeting immune checkpoints, particularly the programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) pathway. Immune checkpoints serve as crucial regulators of the immune response, preventing excessive immune activity and maintaining self-tolerance. PD-1, expressed on the surface of T cells, and its ligand PD-L1, expressed on various cell types, including cancer cells and immune cells, play a central role in this regulatory process. Although the success rate associated with these immunotherapies is very promising, most patients still show intrinsic or acquired resistance. Since the mechanisms related to PD-1/PD-L1 resistance are not well understood, an in-depth analysis is necessary to improve the success rate of anti-PD-1/PD-L1 therapy. Hence, here we provide an overview of PD-1, its ligand PD-L1, and the resistance mechanism towards PD-1/PD-L1. Furthermore, we have discussed the plausible solution to increase efficacy and clinical response. For the following research, joint endeavours of clinicians and basic scientists are essential to address the limitation of resistance towards immunotherapy.

Regulation of post-translational modification of PD-L1 and advances in tumor immunotherapy.

The immune checkpoint molecules programmed cell death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1) are one of the most promising targets for tumor immunotherapy. PD-L1 is overexpressed on the surface of tumor cells and inhibits T cell activation upon binding to PD⁃1 on the surface of T cells, resulting in tumor immune escape. The therapeutic strategy of targeting PD-1/PD-L1 involves blocking this binding and restoring the tumor-killing effect of immune cells. However, in clinical settings, a relatively low proportion of cancer patients have responded well to PD-1/PD-L1 blockade, and clinical outcomes have reached a bottleneck and no substantial progress has been made. In recent years, PD-L1 post-translation modifications (PTMs) have gradually become a hot topic in the field of PD-L1 research, which will provide new insights to improve the efficacy of current anti-PD-1/PD-L1 therapies. Here, we summarized and discussed multiple PTMs of PD-L1, including glycosylation, ubiquitination, phosphorylation, acetylation and palmitoylation, with a major emphasis on mechanism-based therapeutic strategies (including relevant enzymes and targets that are already in clinical use and that may become drugs in the future). We also summarized the latest research progress of PTMs of PD-L1/PD-1 in regulating immunotherapy. The review provided novel strategies and directions for tumor immunotherapy research based on the PTMs of PD-L1/PD-1.

Inter-rater and intra-rater agreement of [99mTc]-labelled NM-01, a single-domain programmed death-ligand 1 (PD-L1) antibody, using quantitative SPECT/CT in non-small cell lung cancer

BackgroundImmune checkpoint inhibitors, including those against programmed cell death protein-1 (PD-1) or its ligand (PD-L1), are routinely used to treat non-small cell lung cancer (NSCLC). PD-L1 is a validated prognostic and predictive immunohistochemical biomarker of anti-PD-1/PD-L1 therapy but displays temporospatial heterogeneity of expression. Non-invasive radiopharmaceutical techniques, including technetium-99m [99mTc]-labelled anti-PD-L1 single-domain antibody (NM-01) SPECT/CT, have the potential to improve the predictive value of PD-L1 assessment. This study aims to determine the inter- and intra-rater agreement of the quantitative measurement of [99mTc]NM-01 SPECT/CT in NSCLC.MethodsParticipants (n = 14) with untreated advanced NSCLC underwent [99mTc]NM-01 SPECT/CT at baseline (n = 3) or at baseline plus 9-week follow-up (n = 11). [99mTc]NM-01 uptake (of primary lung, lymph node, thoracic and distant metastases, and healthy reference tissues) was measured using SUVmax and malignant lesion-to-blood pool ratios with Siemens xSPECT Broad Quantification software by three independent raters. Intraclass correlation coefficients (ICC) were calculated and Bland–Altman plot analysis performed to determine inter- and intra-rater agreement.ResultsThere was excellent inter-rater agreement of manual freehand SUVmax scores of primary lung tumour (T; n = 25; ICC 1.00; 95% CI 0.99–1.00), individual lymph node metastases (LN; n = 56; ICC 0.97; 95% CI 0.95–0.98), thoracic metastases (ThMet; n = 9; ICC 0.94; 95% CI 0.83–0.99) and distant metastases (DisMet; n = 21; ICC 0.91; 95% CI 0.83–0.96). The inter-rater ICCs of tumour-to-blood pool (T:BP), LN:BP, ThMet:BP and DisMet:BP measures of [99mTc]NM-01 uptake also demonstrated good or excellent agreement. Manual freehand scoring of T, LN, ThMet, DisMet and their ratios using [99mTc]NM-01 SPECT/CT following a 28-day interval was consistent for all raters with good or excellent intra-rater agreement demonstrated (ICCs range 0.86–1.00).ConclusionQuantitative assessment of [99mTc]NM-01 SPECT/CT in NSCLC, using SUVmax of malignant primary or metastatic lesions and their ratios with healthy reference tissues, demonstrated good or excellent inter- and intra-rater agreement in this study. Further validation with ongoing and future larger cohort studies is now warranted.Clinical trial registrationClinicalTrials.gov identifier no. NCT04436406 (registered 18th June 2020; available at https://clinicaltrials.gov/ct2/show/NCT04436406) and NCT04992715 (registered 5th August 2021; available at https://clinicaltrials.gov/ct2/show/NCT04992715).

Safety, tolerability, and clinical activity of selinexor in combination with pembrolizumab in treatment of metastatic non-small cell lung cancer.

In lung cancer, overexpression of nuclear export proteins can result in inactivation of critical tumor suppressor proteins and cell-cycle regulators. Selective suppression of nuclear export proteins has immunomodulatory activities. Here, clinical safety and early efficacy data are presented on the combination of pembrolizumab and an oral selective nuclear export inhibitor, selinexor, for the treatment of metastatic non-small cell lung cancer (mNSCLC). The primary objective of this prospective investigator-initiated study was to determine the safety and tolerability of selinexor in combination with pembrolizumab in patients with mNSCLC. Secondary objectives included determination of objective tumor response rate, disease control rate, and progression-free survival duration. A total of 17 patients were included in the final analysis. Fifteen (88%) received more than two lines of prior systemic therapy and 10 (59%) had prior exposure to anti-PD-1/programmed death-ligand 1 (PD-L1) therapy. The median age was 67.5years. Ten patients had grade ≥3 adverse events related to selinexor treatment. Responses to treatment occurred in patients who did and did not undergo previous anti-PD-1/PD-L1 therapy and in patients with activating driver mutations. The median overall survival and progression-free survival were 11.4months (95% CI, 3.4-19.8months) and 3.0months (95% CI, 1.7-5.7months), respectively. The overall response rate was 18% and the 6-month disease control rate was 24%. Selinexor in combination with pembrolizumab demonstrated promising antitumor activity in patients with mNSCLC, including those who had previously received anti-PD-1/PD-L1 therapy. The therapy-related toxic effects were consistent with the prior safety data for both drugs, and no overlapping toxic effects were observed. ClinicalTrials.gov identifier: NCT02419495. New strategies to prevent or reverse resistance to immune checkpoint inhibitors are under investigation. Selective inhibitors of nuclear export proteins, such as selinexor, can induce restoration of tumor-suppressing pathways and induce potent immunomodulatory activities. This article contains the clinical safety and early efficacy data on the combination of pembrolizumab and selinexor in treatment of metastatic non-small cell lung cancer.

Abstract 5199: B7-H3 & PD-L1 double-humanized BALB/c mouse: a novel animal model for preclinical studies of human B7-H3 antibodies or bispecific antibodies

Abstract Immune checkpoint molecule B7-H3, also known as CD276, is a member of the B7-CD28 family of immunomodulatory proteins. It is a type I membrane protein with sequence similarities to the extracellular domain of programmed death-ligand 1 (PD-L1). B7-H3 is highly expressed in most human cancers, but has limited distribution in normal tissues, remaining elusive of its receptor. Due to its promising safety as a dominant tumor target, various strategies have been developed to modulate the effect of B7-H3 via monoclonal antibodies, bispecific antibodies, ADC, or CAR-T. To study the effect of these therapies in an immunocompetent mouse model, we established a double humanized B7-H3 and PD-L1 mouse model on BALB/c background (BALB/c-hB7-H3/hPD-L1). In this model, the extracellular domain of murine fragments was replaced by the human counterparts while the trans-membrane and cytoplasmic domain were kept intact. When engrafted with CT26 colon cancer cells, which stably overexpress human B7-H3 and PD-L1 while endogenous murine counterparts were knocked out, the tumor growth was inhibited certain degree by anti-B7-H3 antibody (8H9 Biosimilar, 20mpk, TGI=18.56%) treatment while inhibited significantly after the monotherapy of anti-PD-L1 (Tecentriq, 3 mpk, TGI=55.89%, p<0.001). The same dosage combination of anti-B7-H3 and anti-PD-L1 had a significant inhibition on tumor growth (TGI=76.85%, p<0.001), and had a synergistic effect (CDI<0.7) compared with the monotherapy. Analysis of tumor-infiltrating lymphocytes (TILs) at the end of the efficacy study showed that the proportion of CD45+ immune cells was significantly increased in all of the treated groups. The NK cells were significantly increased and the Treg cells were significantly decreased especially in the combined treatment group. Based on the above, the B7-H3 and PD-L1 double humanized mouse model is suitable for the pre-clinical evaluation of mono or combined immune checkpoint blockade with anti-human B7-H3 and PD-L1 therapy. Citation Format: Shiying Guo, Lingyu Song, Xin Qin, Jianming Xu, Hongyan Sun, Cunxiang Ju, Hongyu Wang, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao. B7-H3 & PD-L1 double-humanized BALB/c mouse: a novel animal model for preclinical studies of human B7-H3 antibodies or bispecific antibodies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5199.

Evaluation of Programmed Death - Ligand 1 (Pd-L1) Expression in Head and Neck Squamous Cell Carcinoma.

Head and Neck Squamous Cell Carcinoma (HNSCC) is a highly frequent malignancy worldwide and is also the leading cause of death. The prognosis for individuals with HNSCC remains dismal, with a five-year survival rate of less than 50%. The novel anti-PD-L1 immunotherapy is found to be promising, and immunohistochemistry (IHC) has been established as a reliable method for patient stratification. We intend to evaluate the prognostic significance of the expression of programmed death ligand-1 (PD-L1) in HNSCC and determine its association with clinicopathological variables. A total of 50 cases of biopsy-confirmed HNSCC were studied in a tertiary hospital between Dec 2020 and June 2022. The specimens were tested for PD-L1 IHC expression with antibody clone CAL-10 (Biocare) and scored by Combined Positive Score (CPS). The association between PD-L1 expression and clinicopathological variables was evaluated. PD-L1 was positive in 92% of the cases, and a significant association (P= 0.024) was seen between PD-L1 expression and tumor-infiltrating lymphocytes (TILs). PD-L1 did not show any significant association with patient demographics, tumor site, grade, or stage. In the present study, evaluation of the immunohistochemical expression of PD-L1 on the tumor cells and TILs in HNSCC revealed a high prevalence of PD-L1 expression. PD-L1 IHC studies for patient selection for immunotherapy would be a promising technique. Frequent PD-L1 expression in tumors with significant TILs may be useful in identifying patients who may benefit from anti-PD-1/PD-L1 therapy.

MYC activation impairs cell-intrinsic IFNγ signaling and confers resistance to anti-PD1/PD-L1 therapy in lung cancer

Elucidating the adaptive mechanisms that prevent host immune response in cancer will help predict efficacy of anti-programmed death-1 (PD1)/L1 therapies. Here, we study the cell-intrinsic response of lung cancer (LC) to interferon-γ (IFNγ), a cytokine that promotes immunoresponse and modulates programmed death-ligand 1 (PD-L1) levels. We report complete refractoriness to IFNγ in a subset of LCs as a result of JAK2 or IFNGR1 inactivation. A submaximal response affects another subset that shows constitutive low levels of IFNγ-stimulated genes (IγSGs) coupled with decreased H3K27ac (histone 3 acetylation at lysine 27) deposition and promoter hypermethylation and reduced IFN regulatory factor 1 (IRF1) recruitment to the DNA on IFNγ stimulation. Most of these are neuroendocrine small cell LCs (SCLCs) with oncogenic MYC/MYCL1/MYCN. The oncogenic activation of MYC in SCLC cells downregulates JAK2 and impairs IγSGs stimulation by IFNγ. MYC amplification tends to associate with a worse response to anti-PD1/L1 therapies. Hence alterations affecting the JAK/STAT pathway and MYC activation prevent stimulation by IFNγ and may predict anti-PD1/L1 efficacy in LC.

Immunotherapy in combination with chemotherapy vs. immunotherapy alone for advanced non-small cell lung cancer and programmed death ligand 1 score

IntroductionLittle is known about the effectiveness of immunotherapy alone or with chemotherapy for patients with non-small cell lung cancer (NSCLC) and programmed death ligand 1 (PD-L1) expression <50 %. We examined the outcomes of PD-L1 therapy vs. PD-L1 therapy in combination with chemotherapy as first-line treatment among NSCLC patients with PD-L1 score <50 %. MethodsWe used administrative claims and prior authorization data of a national insurer from November 2015 to July 2021. We selected patients with Stage IIIb/IV NSCLC and PD-L1 expression <50 %. Each patient was required to have ≥1 claim of a PD-L1 or PD-1 inhibitor. Treatment groups were propensity-score matched 1:1 on baseline characteristics. We measured PD-L1 therapy duration, incident immune-related adverse events (irAEs), healthcare utilization, costs, and overall survival (OS). ResultsIn the matched sample totaling 176 patients, mean duration of PD-L1 therapy was similar (4.1 [SD 3.3] months combination vs. 4.0 [SD 4.9] months monotherapy, p = 0.800). IrAEs were similar, both for FDA-recognized irAEs (48.9 % combination, 48.9 % monotherapy, p = 0.710) and other types (34.1 % combination, 39.8 % monotherapy, p = 0.473). The combination group had more all-cause inpatient stays, ER visits, and outpatient visits (all p < 0.001). Total adjusted all-cause medical cost was $112,833 (95 % CI $5,548-$251,973) higher for combination therapy. We saw no difference in OS (adjusted hazard ratio 1.09 [95 % CI 0.72–1.65]). ConclusionThis study found no difference in adverse drug effects or survival between PD-L1 monotherapy compared to combination therapy for patients with Stage IIIb/IV NSCLC and PD-L1 expression <50 %, though the combination therapy cohort had higher healthcare utilization and costs. MicroAbstractUse of immunotherapy alone or combined with chemotherapy for patients with non-small cell lung cancer and programmed death ligand 1 expression <50 % is understudied. Our observational study using claims and authorization data from a matched sample of 176 patients found no difference in survival or the rate of adverse drug effects between groups, although the chemo-immunotherapy cohort generated higher overall healthcare costs.

PD-1 and PD-L1 Expression in Indian Women with Breast Cancer.

The interaction between programmed cell death protein 1 (PD-1) on activated T-lymphocytes and programmed death-ligand 1 (PD-L1) on tumor cells or antigen-presenting cells sends immunosuppressive signals leading to the escape of tumor cells from the host anti-tumor immune response. Inhibiting this interaction with antibodies against PD-1 or PD-L1 is emerging as a valuable therapeutic strategy. However, tissue distribution patterns for PD-L1 and PD-1 in breast cancer patients from India are not reported, yet many clinical trials are underway. In this study the expression of PD-1 and PD-L1 in breast cancer patient samples from India was characterized. The study included 392 cases of operated breast cancer (2012-2017) from a tertiary cancer care center in Bangalore, Karnataka, India. Paraffin blocks were retrievable and receptor status was known. Immunohistochemistry (IHC) was performed using anti-PD-L1 and anti-PD-1 antibodies. RNA was isolated from 76 fresh tumors and nine adjacent normal tissues (2019). PD-L1 transcript levels were measured by RT-qPCR using Hypoxanthine-guanine phosphoribosyl transferase (HPRT) as a reference gene. Based on IHC, PD-1 expression within tumor-infiltrating immune cells (TIICs) was observed in 55/385 cases (14%) across all breast cancer types. In triple-negative breast cancer (TNBC), 21/132 cases (16%) showed PD-1 staining in TIICs. The overall expression of PD-L1 in breast tumor cells across all breast cancer subtypes and TIICs was 11% (41/378) and 39% (151/385), respectively. A relatively higher proportion of TNBC cases had PD-L1 expression in tumor cells (17/132 cases, 13%) and immune cells (68/132 cases, 52%). We also detected PD-L1 transcript expression by qRT-PCR in freshly isolated tumor samples. These findings show that around 52% (68/132) of the TNBC cases express PD-L1 in TIICs. Hence, anti-PD-1/PD-L1 therapy alone or combined with chemotherapy may be a promising treatment for TNBC in Indian patients.

HCC treated with immune checkpoint inhibitors: a hyper-enhanced rim on Sonazoid-CEUS Kupffer phase images is a predictor of tumor response.

We aimed to evaluate the efficacy of anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibody therapy by assessing the hyper-enhanced rim phenomenon of hepatocellular carcinoma (HCC) on Sonazoid-contrast-enhanced ultrasound (CEUS) Kupffer phase images. This retrospective study included 61 patients with HCC who received anti-PD-1/PD-L1 antibody therapy from August 1, 2020, to January 31, 2022. We compared the progression-free survival (PFS) of patients with hyper-enhanced rim+ and hyper-enhanced rim-nodules and the time to nodule progression (TTnP) of hyper-enhanced rim+ and hyper-enhanced rim- nodules. Thirty-nine patients received postoperative therapy, and 22 patients had unresectable HCC. The mean PFS was 11.8 months (95% confidence interval [CI]: 8.7-14.9) for patients with hyper-enhanced rim+ HCC nodules and 16.5 months (95% CI: 14.9-18.1) for patients with hyper-enhanced rim- HCC nodules in the surgery group (p = 0.017). The mean PFS was 9.2 months (95% CI: 3.6-14.8) for patients with hyper-enhanced rim+ HCC nodules and 17.8 months (95% CI: 14.9-20.6) for patients with hyper-enhanced rim- HCC nodules in the non-surgery group (p = 0.015). For hyper-enhanced rim+ HCC nodules, TTnP for each nodule exceeding the specified threshold was 10.1 months, whereas that for hyper-enhanced rim- HCC nodules was 17.6 months (p = 0 .018). The disease control rate was 42.9% (3/7) for hyper-enhanced rim+ HCC nodules and 85.7% (21/24) for hyper-enhanced rim- HCC nodules (p = 0.013). The presence of hyper-enhanced rim on the Kupffer phase images obtained via the non-invasive Sonazoid-CEUS is a promising imaging biomarker for predicting unfavorable response with anti-PD-1/PD-L1 therapy in patients with HCC. • The mean progression-free survival was 11.8 months for patients with hyper-enhanced rim+ HCC nodules and 16.5 months for patients with hyper-enhanced rim- HCC nodules in the surgery group. • The mean progression-free survival was 9.2 months for patients with hyper-enhanced rim+ HCC nodules and 17.8 months for patients with hyper-enhanced rim- HCC nodules in the non-surgery group. • The disease control rate was 42.9% for hyper-enhanced rim+ HCC nodules and 85.7% for hyper-enhanced rim- HCC nodules (p = 0.013).

Radiation-induced PD-L1 expression in tumor and its microenvironment facilitates cancer-immune escape: a narrative review.

Radiotherapy (RT) is one of the fundamental anti-cancer regimens by means of inducing in situ tumor vaccination and driving a systemic anti-tumor immune response. It can affect the tumor microenvironment (TME) components consisting of blood vessels, immunocytes, fibroblasts, and extracellular matrix (ECM), and might subsequently suppress anti-tumor immunity through expression of molecules such as programmed death ligand-1 (PD-L1). Immune checkpoint inhibitors (ICIs), especially anti-programmed cell death 1 (PD-1)/PD-L1 therapies, have been regarded as effective in the reinvigoration of the immune system and another major cancer treatment. Experimentally, combination of RT and ICIs therapy shows a greater synergistic effect than either therapy alone. We performed a narrative review of the literature in the PubMed database. The research string comprised various combinations of "radiotherapy", "programmed death-ligand 1", "microenvironment", "exosome", "myeloid cell", "tumor cell", "tumor immunity". The database was searched independently by two authors. A third reviewer mediated any discordance of the results of the two screeners. RT upregulates PD-L1 expression in tumor cells, tumor-derived exosomes (TEXs), myeloid-derived suppressor cells (MDSCs), and macrophages. The signaling pathways correlated to PD-L1 expression in tumor cells include the DNA damage signaling pathway, epidermal growth factor receptor (EGFR) pathway, interferon gamma (IFN-γ) pathway, cGAS-STING pathway, and JAK/STATs pathway. PD-L1 upregulation post-RT is found not only in tumor cells but also in the TME and is one of the mechanisms of tumor evasion. Therefore, further studies are necessary to fully comprehend this biological process. Meanwhile, combination of therapies has been shown to be effective, and novel approaches are to be developed as adjuvant to RT and ICIs therapy.

PD-L1 expression and association with genetic background in pheochromocytoma and paraganglioma.

Metastatic pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors associated with poor prognosis and limited therapeutic options. Recent advances in oncology-related immunotherapy, specifically in targeting of programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathways, have identified a new treatment potential in a variety of tumors, including advanced and rare tumors. Only a fraction of patients being treated by immune checkpoint inhibitors have shown to benefit from it, displaying a need for strategies which identify patients who may most likely show a favorable response. Building on recent, promising outcomes in a clinical study of metastatic PPGL using pembrolizumab, a humanized IgG4κ monoclonal antibody targeting the PD-1/PD-L1 pathway, we examined PD-L1 and PD-L2 expression in relation to oncogenic drivers in our PPGL patient cohort to explore whether expression can predict metastatic potential and/or be considered a predictive marker for targeted therapy. We evaluated RNA expression in the NIH cohort of 48 patients with known genetic predisposition (sporadic; pseudohypoxia: SDHB, VHL, EPAS1, EGLN1; kinase signaling: RET, NF1) and 6 normal medulla samples (NAM). For comparison, 72 PPGL samples from The Cancer Genome Atlas (TCGA) were used for analysis of gene expression based on the variant status (pseudohypoxia: SDHB, VHL, EPAS1, EGLN1; kinase signaling: NF1, RET). Expression of PD-L1 was elevated in the PPGL cohort compared to normal adrenal medulla, aligning with the TCGA analysis, whereas PD-L2 was not elevated. However, expression of PD-L1 was lower in the pseudohypoxia cluster compared to the sporadic and the kinase signaling subtype cluster, suggesting that sporadic and kinase signaling cluster PPGLs could benefit from PD-1/PD-L1 therapy more than the pseudohypoxia cluster. Within the pseudohypoxia cluster, expression of PD-L1 was significantly lower in both SDHB- and non-SDHB-mutated tumors compared to sporadic tumors. PD-L1 and PD-L2 expression was not affected by the metastatic status. We conclude that PD-L1 and PD-L2 expression in our cohort of PPGL tumors was not linked to metastatic behavior, however, the presence of PPGL driver mutation could be a predictive marker for PD-L1-targeted therapy and an important feature for further clinical studies in patients with PPGL.

The Optimal Therapy after Progression on Immune Checkpoint Inhibitors in MSI Metastatic Gastrointestinal Cancer Patients: A Multicenter Retrospective Cohort Study.

Simple SummaryProgrammed death 1 (PD1)/programmed death ligand-1 (PD-L1) inhibitor is the standard therapy for advanced microsatellite instability (MSI)/mismatch repair-deficient (dMMR) gastrointestinal cancers. However, the suitable therapy after the progression of anti-PD1/PD-L1 for MSI/dMMR gastrointestinal cancer patients was unknown, until now. Here, we conducted a retrospective study to evaluate the efficacy of anti-PD1/PD-L1 plus other drug therapy versus chemotherapy with or without targeted therapy for patients who had progressed on prior anti-PD1/PD-L1 monotherapy. Our study found that anti-PD1/PD-L1 plus other drug therapy had significantly improved the disease control rate, progression-free survival, and overall survival, along with a numerically higher objective response rate versus chemotherapy with or without targeted therapy. The promising findings of our retrospective study need to be further confirmed in prospective trials.Background: In microsatellite instability (MSI)/mismatch repair-deficient (dMMR) gastrointestinal cancers, the optimum therapy after the progression of immune checkpoint inhibitors (ICIs) is yet unknown. Here, we compared the efficacy of programmed death 1 (PD1)/programmed death ligand-1 (PD-L1) inhibitors plus other therapy and chemotherapy with or without targeted therapy in MSI/dMMR gastrointestinal cancer patients after progression on anti-PD1/PD-L1 monotherapy. Methods: We retrospectively recruited MSI/dMMR gastrointestinal cancer patients who had progressed on anti-PD1/PD-L1 monotherapy. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and PFS ratio (PFSr) were compared between patients who received anti-PD1/PD-L1 plus other therapy (ICI-plus group) and patients who received chemotherapy with or without targeted therapy (chemo-targeted group). Results: In total, 26 and 25 patients were recruited in the ICI-plus group and chemo-targeted group, respectively. Significantly better DCR (80.8% vs. 44.0%, p = 0.007), PFS (median PFS 6.9 months vs. 3.0 months, p = 0.001), OS (median OS NR vs. 14.1 months, p = 0.043), and PFSr (2.4 vs. 0.9, p = 0.021), along with a numerically higher ORR (23.1% vs. 12.0%, p = 0.503) were observed in the ICI-plus group compared with the chemo-targeted group. Multivariate analyses identified the therapy regimen as an important prognostic factor in gastrointestinal cancers. Conclusions: Compared to conventional chemotherapy with or without targeted therapy, continuing anti-PD1/PD-L1 in combination with other treatments showed better clinical outcomes in MSI/dMMR gastrointestinal cancer patients who progressed on PD1/PD-L1 blockade, which should be validated prospectively in clinical trials.

Phase Ib study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with advanced or metastatic solid tumors

BackgroundWe conducted a phase I, multicenter, open-label, dose-finding, and expansion study to determine the safety and preliminary efficacy of eprenetapopt (APR-246) combined with pembrolizumab in patients with advanced/metastatic solid tumors (ClinicalTrials.gov NCT04383938).Patients and methodsFor dose-finding, requirements were non-central nervous system primary solid tumor, intolerant to/progressed after ≥1 line of treatment, and eligible for pembrolizumab; for expansion: (i) gastric/gastroesophageal junction tumor, intolerant to/progressed after first-line treatment, and no prior anti-programmed cell death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy; (ii) bladder/urothelial tumor, intolerant to/progressed after first-line cisplatin-based chemotherapy, and no prior anti-PD-1/PD-L1 therapy; (iii) non-small-cell lung cancer (NSCLC) with previous anti-PD-1/PD-L1 therapy. Patients received eprenetapopt 4.5 g/day intravenously (IV) on days 1-4 with pembrolizumab 200 mg IV on day 3 in each 21-day cycle. Primary endpoints were dose-limiting toxicity (DLT), adverse events (AEs), and recommended phase II dose (RP2D) of eprenetapopt.ResultsForty patients were enrolled (median age 66 years; range 27-85) and 37 received eprenetapopt plus pembrolizumab. No DLTs were reported and the RP2D for eprenetapopt in combination was 4.5 g/day IV on days 1-4. The most common eprenetapopt-related AEs were dizziness (35.1%), nausea (32.4%), and vomiting (29.7%). AEs leading to eprenetapopt discontinuation occurred in 2/37 patients (5.4%). In efficacy-assessable patients (n = 29), one achieved complete response (urothelial cancer), two achieved partial responses (NSCLC, urothelial cancer), and six patients had stable disease.ConclusionsThe eprenetapopt plus pembrolizumab combination was well tolerated with an acceptable safety profile and showed clinical activity in patients with solid tumors.

Clinical outcomes of PD-1/PD-L1 inhibitors in patients with advanced hepatocellular carcinoma: a systematic review and meta-analysis.

Programmed death ligand 1(PD-L1)/programmed cell death-1(PD-1) inhibitors have shown promising efficacy in unresectable patients with advanced hepatocellular carcinoma (HCC), but the results are not consistent. Our goal was to evaluate the safety and efficacy of PD-L1/PD-1 inhibitors or plus anti-CTLA-4 antibody or anti-VEGF agents for the treatment of unresectable HCC. Cochrane library, Embase, and PubMed were searched till August 2021. Data on progression-free survival (PFS), objective response rate (ORR), overall survival (OS), and disease control rate (DCR) were pooled and analyzed by Stata14 software. Thirteen prospective trials with 2,386 HCC patients were included. Pooled analysis estimated an ORR of about 0.21 (95% CI = 0.18-0.25) and a DCR of 0.59 (95% CI = 0.52-0.65) for anti-PD-1/PD-L1 therapy. Summary PFS was 4.19 (95% CI = 3.31-5.18) months and summary OS was 13.23 (95% CI = 12.06-14.41) months. After using PD-L1/PD-1 inhibitors plus anti-VEGF agents, ORR was 0.26 (95% CI = 0.20-0.33), DCR was 0.75 (95% CI = 0.69-0.81) and PFS was 6.2 (95% CI = 4.61-7.78) months. PD-L1/PD-1 inhibitors plus anti-CTLA-4 antibody therapy achieved an ORR of 0.23 (95% CI = 0.14-0.33), an DCR of 0.44 (95% CI = 0.39-0.50) and a PFS of 1.88 (95% CI = 1.51-2.26). PD-L1/PD-1 inhibitors were effective and tolerable in patients with advanced HCC. Furthermore, compared with anti-PD-1/PD-L1 monotherapy, PD-L1/PD-1 inhibitors plus anti-VEGF agents resulted in more clinical improvements in ORR, DCR, and PFS.

Serplulimab, a novel anti-PD-1 antibody, plus chemotherapy versus chemotherapy alone as first-line treatment for extensive-stage small-cell lung cancer: An international randomized phase 3 study.

8505 Background: Monoclonal antibodies against programmed death-ligand 1 (PD-L1) have been approved for the first-line treatment of extensive-stage small-cell lung cancer (ES-SCLC) in combination with chemotherapy. However, whether a programmed death 1 (PD-1) inhibitor provides similar survival benefit in this patient population remains unclear. In this study, the efficacy and safety of serplulimab, a novel humanized monoclonal anti-PD-1 antibody, were assessed in combination with chemotherapy in previously untreated ES-SCLC patients. Methods: In this international, randomized, double-blind, multicenter, phase 3 trial (NCT04063163), patients with ES-SCLC who had not received prior systemic therapy were randomized (2:1) to receive serplulimab 4.5 mg/kg or placebo intravenously every 3 weeks. All patients received intravenous carboplatin and etoposide every 3 weeks for up to 4 cycles. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and safety. Results: Between September 12, 2019 and April 27, 2021, 585 patients were randomized (serplulimab group, n = 389; placebo group, n = 196). At interim analysis, the median follow-up duration was 12.3 months. Median OS was significantly prolonged in the serplulimab group than the placebo group (15.4 vs.10.9 months; hazard ratio [HR] 0.63, 95% CI 0.49–0.82; P &lt; 0.001). Median PFS assessed by the independent radiology review committee (IRRC) per RECIST v1.1 was significantly longer in the serplulimab group than the placebo group (5.8 vs. 4.3 months; HR 0.47, 95% CI 0.38–0.59; P &lt; 0.001). Efficacy improvements were also observed in ORR (80.2% vs. 70.4%) and DoR (5.6 vs. 3.2 months) as assessed by IRRC per RECIST v1.1. Grade ≥3 treatment-emergent adverse events (TEAEs) related to serplulimab or placebo were reported in 129 (33.2%) and 54 (27.6%) patients in the respective groups. Incidence of immune-related TEAEs was higher in the serplulimab group compared to the placebo group (37% vs. 18.4%), with the largest difference in endocrine disorders (18.3% vs. 4.6%), which are commonly reported with anti-PD-1/PD-L1 therapies. Four deaths (1 acute coronary syndrome, 1 pyrexia, and 1 platelet count decreased in the serplulimab group; 1 thrombocytopenia in the placebo group) that might be related to study drugs were reported. Conclusions: Serplulimab plus chemotherapy as first-line treatment provided significant benefits and a manageable safety profile compared with chemotherapy alone in ES-SCLC patients. For the first time, OS benefits was demonstrated with a PD-1 inhibitor in a global phase 3 study among previously untreated ES-SCLC patients. Clinical trial information: NCT04063163.