Anti-programmed Cell Death Ligand Research Articles

FDA analysis of treatment efficacy based on etiology of hepatocellular carcinoma.

4117 Background: Retrospective analyses of trial-level data report that etiology of hepatocellular carcinoma (HCC) (e.g., viral versus [vs.] non-viral) may influence efficacy of systemic therapies used in advanced HCC. FDA conducted an analysis of 9 randomized controlled trials (RCTs; n=5,417) to assess treatment effects based on drug class, treatment line, and HCC etiology. Methods: FDA conducted a retrospective, exploratory analysis of 3 RCTs comparing first line (1L) treatment with anti-programmed cell death (ligand)-1-containing regimens (αPD-[L]1) to single-agent anti-vascular endothelial growth factor therapy (αVEGF), and 6 RCTs comparing second line (2L) treatment consisting of αPD-(L)1 or αVEGF to placebo. For each line of treatment (1L or 2L), meta-analyses of overall survival (OS) were performed for the overall treatment effect and by disease etiology, viral (hepatitis B [HBV], or hepatitis C [HCV]) vs. non-viral. Subgroup analyses were performed to investigate the confounding effect of subsequent therapy (yes vs. no) and region (Asian vs. non-Asian) on etiology. Trial-level hazard ratios (HRs) and 95% confidence intervals (CI) were mostly calculated using patient-level data submitted to FDA. Pooled HRs and CIs were calculated using a random-effects model. Results: While 1L αPD-(L)1 improved OS compared to 1L αVEGF in the overall population (HR [95% CI]: 0.8 [0.73, 0.88]), treatment effects were comparable for viral (HR [95% CI]: 0.75 [0.6, 0.92]; n=1,435) and non-viral (HR [95% CI]: 0.83 [0.72, 0.95]; n=979) subgroup analyses, and not influenced by subsequent therapy or region. Analyses based on specific viral infection (i.e., HBV or HCV), showed that improvement in OS for αPD-(L)1 vs. αVEGF appeared larger for HBV (HR [95% CI]: 0.7 [0.59, 0.82]; n=833) compared to HCV (HR [95% CI]: 0.83 [0.6, 1.16]; n=602). Treatment effects were also comparable in 2L for different etiologies for both αPD-(L)1 (HR [95% CI] for viral: 0.76 [0.62, 0.93]; n=529 and non-viral: 0.85 [0.65, 1.11]; n=337) and αVEGF (HR [95% CI] for viral: 0.79 [0.69, 0.9]; n=1,288 and non-viral: 0.74 [0.63, 0.88]; n=849), and not influenced by subsequent therapy. Nonetheless, compared to placebo, αPD-(L)1 had a larger treatment effect with HBV (HR [95% CI]: 0.69 [0.5, 0.94]; n=459) compared to non-viral etiologies. Conclusions: The results did not demonstrate that etiology of HCC was predictive of OS for both treatment classes based on retrospective, exploratory meta-analyses of 9 RCTs; however, the treatment effects may be more pronounced in patients with HBV who received αPD-(L)1 as 1L or 2L. Uncertainty remains regarding subgroup treatment effects given limited number of trials in the analyses (mostly leading to approvals), overlapping CIs, number of patients in some subgroups, retrospective nature, and exclusion of trials with inadequate data regarding etiology of HCC.

AFT-50 EndoMAP: A phase IB/II multi-cohort study of targeted agents for patients with recurrent or persistent endometrial cancer.

TPS5634 Background: The prognosis for women with recurrent or persistent EC after progressing on first-line chemotherapy is poor, with a median overall survival (OS) of 12 months, highlighting the need for more efficacious therapies for this population. Immune checkpoint inhibitors either as monotherapy or when combined with kinase inhibitors have recently demonstrated encouraging response rates in pts with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and MS-stable (MSS)/MMR-proficient (MMRp) EC, respectively. Atezo is a humanized monoclonal anti-programmed cell death ligand 1 (PD-L1) inhibitor that has demonstrated monotherapy antitumor activity with an acceptable safety profile in relapsed recurrent EC. Atezo has shown compelling clinical efficacy for pts with certain solid tumors (e.g., urothelial, NSCLC, triple negative breast cancer) as monotherapy and as part of combinatorial therapy. The AFT-50 EndoMAP trial is a platform trial designed to evaluate the efficacy and safety of Atezo in combination with biomarker-defined targeted agents in pts with recurrent or persistent EC. Recognizing pts may have either progressed through or received a checkpoint inhibitor in a prior line of therapy, a non atezo cohort will also be open to enrollment. Methods: This is a phase IB/II non-randomized, multicenter, multicohort, biomarker-driven platform study consisting of two cohorts: A (atezo containing) and B (non atezo). Eligible pts have recurrent or persistent EC and have received no more than 2 prior lines of therapy. FoundationOne CDx (F1CDx) NGS assay will be used for genomic tumor profiling. In cohort A, pts may be eligible for one of the following doublets: Atezo+ipatasertib (PIK3CA/PTEN/AKT1-altered cancers), Atezo+talazoparib (tumors with genomic loss of heterozygosity (LOH) ≥16%), Atezo+Trastuzumab emtansine (ERBB2/HER2 mutated and/or amplified tumors), Atezo+Tiragolumab (MSI-H and/or TMB>10 mut/MB), and Atezo+bevacizumab (biomarker unmatched). Pts will receive Atezo in addition to the targeted agent (at the study approved dosing schedule) until progression, unacceptable toxicity, pt or physician decision to withdraw from the study, death, or study termination. Pts in cohort B, will be eligible for inavolisib (PIK3CA/PTEN/AKT1-altered cancers) + letrozole. Each cohort will enroll ~20 pts; however, the exact size of the cohort may be adjusted. The primary endpoint for Cohort A is confirmed overall response rate (ORR) for each cohort, and for Cohort B is progression free survival at 6 months. Secondary endpoints include disease control rate, duration of response, OS, safety and tolerability, 6-month PFS (cohort A). As a platform study, additional arms may be added, as supported by evolving understanding of EC and molecular targets. EndoMAP is actively enrolling at 17 sites in the US with a target of 25 sites nationwide. Clinical trial information: NCT04486352 .

Functions of Key Enzymes of Glycolytic Metabolism in Tumor Microenvironment.

The tumor microenvironment (TME) plays a crucial role in tumor initiation, growth and metastasis. Metabolic enzymes involved in tumor glycolytic reprogramming, including hexokinase, pyruvate kinase, and lactate dehydrogenase, not only play key roles in tumorigenesis and maintaining tumor cell survival, but also take part in the modulation of the TME. Many studies have been devoted to the role of key glycolytic enzymes in the TME over the past decades. We summarize the studies on the role of glycolytic enzymes in the TME of these years and found that glycolytic enzymes remodel the TME primarily through regulating immune escape, angiogenesis, and affecting stromal cells and exosomes. Notably, abnormal tumor vascular system, peritumoral stromal cells, and tumor immunosuppressive microenvironment are important contributors to the failure of antitumor therapy. Therefore, we discuss the mechanisms of regulation by key glycolytic enzymes that may contribute to a promising biomarker for therapeutic intervention. We argue that targeting key glycolytic enzymes in combination with antiprogrammed cell death ligand 1 or antivascular endothelial growth factor could emerge as the more integrated and comprehensive antitumor treatment strategy.

Polymyalgia rheumatica during combination therapy with atezolizumab plus bevacizumab for advanced hepatocellular carcinoma.

The combination therapy of atezolizumab, an anti-programmed cell death ligand-1 antibody, plus bevacizumab (Atz/Bev) is widely used to treat patients with advanced hepatocellular carcinoma (HCC). The development of polymyalgia rheumatica (PMR) during immune checkpoint inhibitor therapy for patients with HCC has not been reported to date. Two patients who developed PMR during Atz/Bev therapy for advanced HCC are reported. Both patients developed fever, bilateral symmetrical shoulder pain, morning stiffness, and an elevated C-reactive protein level. Their symptoms improved rapidly with prednisolone (PSL) 15-20mg/d, and their C-reactive protein levels decreased. In PMR, long-term low-dose PSL should be administered. In the present patients who developed PMR as immune-related adverse events, starting with a small dose of PSL resulted in rapid improvement of symptoms.

Triple-Combination Immunogenic Nanovesicles Reshape the Tumor Microenvironment to Potentiate Chemo-Immunotherapy in Preclinical Cancer Models.

Immune checkpoint blockade (ICB) therapies have had a tremendous impact on cancer therapy. However, most patients harbor a poorly immunogenic tumor microenvironment (TME), presenting overwhelming de novo refractoriness to ICB inhibitors. To address these challenges, combinatorial regimens that employ chemotherapies and immunostimulatory agents are urgently needed. Here, a combination chemoimmunotherapeutic nanosystem consisting of a polymeric monoconjugated gemcitabine (GEM) prodrug nanoparticle decorated with an anti-programmed cell death-ligand 1 (PD-L1) antibody (αPD-L1) on the surface and a stimulator of interferon genes (STING) agonist encapsulated inside is developed. Treatment with GEM nanoparticles upregulates PD-L1 expression in ICB-refractory tumors, resulting in augmented intratumor drug delivery in vivo and synergistic antitumor efficacy via activation of intratumor CD8+ T cell responses. Integration of a STING agonist into the αPD-L1-decorated GEM nanoparticles further improves response rates by transforming low-immunogenic tumors into inflamed tumors. Systemically administered triple-combination nanovesicles induce robust antitumor immunity, resulting in durable regression of established large tumors and a reduction in the metastatic burden, coincident with immunological memory against tumor rechallenge in multiple murine tumor models. These findings provide a design rationale for synchronizing STING agonists, PD-L1 antibodies, and chemotherapeutic prodrugs to generate a chemoimmunotherapeutic effect in treating ICB-nonresponsive tumors.

Targeting PPAR-gamma counteracts tumour adaptation to immune-checkpoint blockade in hepatocellular carcinoma

ObjectiveTherapy-induced tumour microenvironment (TME) remodelling poses a major hurdle for cancer cure. As the majority of patients with hepatocellular carcinoma (HCC) exhibits primary or acquired resistance to antiprogrammed cell death...

Abstract 6353: Combination of poly-γ-glutamic acid with anti PD-L1 blockade leads to improved anti-tumor activity in murine models

Abstract Immune checkpoint inhibitors(ICIs) have been shown to be key role in cancer therapy. Especially, antibodies targeting programmed cell death ligand1(PD-L1) promoted T cells to activate immune response against cancer cells. However, the current ICIs still have insignificant to motivate effective antitumor immunity by blocking PD-1/PD-L1 pathway and the regulatory network of PD-L1 by cytokines in the tumor microenvironment remains to be uncovered. Previously, we have reported the anti-cancer effects of combination treatment with a natural product, poly-γ-glutamic acid(γ-PGA), and PD-1 blockade. Now, we showed that combination therapy with anti PD-L1 and γ-PGA overcome the limits of ICIs and enhance anticancer effect in murine melanoma(B16F10). In vivo efficacy studies were performed by intraperitoneal injection of antibody targeting PD-L1 and oral administration of γ-PGA in C57BL/6 model transplanted with B16F10 melanoma cell. Systemic changes in immunophenotype were measured by tumor volume size and survival rate. The splenocytes were isolated from mice and the populations of myeloid-driven suppressor cells(MDSCs) and CD4/CD8 T cells were analyzed by FACS. Combination therapy with γ-PGA and anti PD-L1 blockade showed dramatically more suppressive tumor growth and enhanced long-term survival rate than other monotherapic treatment. In addition, γ-PGA was shown to play a role in the immune modulation of tumor microenvironment by activation of T cells and inhibition of MDSCs so as to prevent tumors from immune escape. Therefore, we suggest that γ-PGA can promote ICI-mediated antitumor responses by the transformation of "cold tumors" into “hot tumors” Citation Format: Jae-Pyung Jang, Jae Chul Choi, Kyung-Soo Hahm, Do Young Lee, Young-Chul Park. Combination of poly-γ-glutamic acid with anti PD-L1 blockade leads to improved anti-tumor activity in murine models [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 6353.

Single-Cell RNA Sequencing Reveals Cellular Heterogeneity in an Acral Amelanotic Melanoma After Immunotherapy Treatment.

Anti-programmed cell death ligand-1 (anti-PD-L1) immunotherapy is often used for advanced urothelial carcinoma and melanoma, including amelanotic melanoma, a relatively rare subtype with little to no pigment in the tumor cells. However, cellular heterogeneity of amelanotic melanoma during or after anti-PD-L1 immunotherapy treatments has not been described. To investigate cellular heterogeneity in acral amelanotic melanoma after immunotherapy exposure. We evaluated subtle visual changes of the melanoma by dermoscopy and performed a pathological examination to analyze the heterogeneity of microscopic morphological and immunohistochemistry changes. The cellular transcriptional heterogeneity and corresponding biological function profiles of the melanoma were determined by single-cell RNA sequencing (scRNA-seq). The dermoscopic examination revealed black globules and scar-like depigmentation areas against a homogeneous red background. Pigmented and amelanotic melanoma cells were observed microscopically. The pigmented cells were large and contained melanin granules expressing Melan-A and HMB45; the amelanotic cells were small and did not express HMB45. Ki-67 immunohistochemical staining revealed that the pigmented melanoma cells had a higher proliferative ability than the amelanotic cells. scRNA-seq identified three cell clusters: amelanotic cell cluster 1, amelanotic cell cluster 2, and pigmented cell cluster. Furthermore, a pseudo-time trajectory analysis showed that amelanotic cell cluster 2 originated from amelanotic cell cluster 1 and transformed into the pigmented melanoma cell cluster. The expression pattern of melanin synthesis-related and lysosome-endosome-related genes in different cell clusters supported the cell cluster transformation results. Also, upregulated expression of cell cycle genes indicated that the pigmented melanoma cells had a high proliferative ability. Coexisting amelanotic and pigmented melanoma cells indicated cellular heterogeneity in an acral amelanotic melanoma from a patient who underwent immunotherapy treatment. Additionally, the pigmented melanoma cells acquired a higher proliferative ability than the amelanotic melanoma cells.

Engineering of a Bispecific Nanofitin with Immune Checkpoint Inhibitory Activity Conditioned by the Cross-Arm Binding to EGFR and PDL1.

Re-education of the tumor microenvironment with immune checkpoint inhibitors (ICI) has provided the most significant advancement in cancer management, with impressive efficacy and durable response reported. However, low response rates and a high frequency of immune-related adverse events (irAEs) remain associated with ICI therapies. The latter can be linked to their high affinity and avidity for their target that fosters on-target/off-tumor binding and subsequent breaking of immune self-tolerance in normal tissues. Many multispecific protein formats have been proposed to increase the tumor cell's selectivity of ICI therapies. In this study, we explored the engineering of a bispecific Nanofitin by the fusion of an anti-epidermal growth factor receptor (EGFR) and anti-programmed cell death ligand 1 (PDL1) Nanofitin modules. While lowering the affinity of the Nanofitin modules for their respective target, the fusion enables the simultaneous engagement of EGFR and PDL1, which translates into a selective binding to tumor cells co-expressing EGFR and PDL1 only. We demonstrated that affinity-attenuated bispecific Nanofitin could elicit PDL1 blockade exclusively in an EGFR-directed manner. Overall, the data collected highlight the potential of this approach to enhance the selectivity and safety of PDL1 checkpoint inhibition.

Identification of inflamed-phenotype of small cell lung cancer leading to the efficacy of anti-PD-L1 antibody and chemotherapy

BackgroundPlatinum etoposide plus anti-programmed cell death ligand-1 (PD-L1) antibody therapy is the standard of care for extensive-stage small cell lung cancer (ES-SCLC). However, patient characteristics associated with the efficacy of the combination therapy in SCLC are unclear. MethodsWe retrospectively reviewed post-surgical limited-stage (LS)-SCLC and ES-SCLC patients treated with atezolizumab plus carboplatin and etoposide (ACE). The association between SCLC subtypes based on transcriptomic data and pathological findings, including CD8-positive tumor-infiltrating lymphocyte (TIL) status, was investigated in the LS-SCLC cohort. The association between the efficacy of ACE therapy, pathological subtypes, and TIL status was evaluated in the ES-SCLC cohort. ResultsThe LS-SCLC cohort (N = 48) was classified into four SCLC subtypes (ASCL1 + NEUROD1 [SCLC-A + N, N = 17], POU2F3 [SCLC-P, N = 15], YAP1 [SCLC-Y, N = 10], and inflamed [SCLC-I, N = 6]) based on transcriptomic data. SCLC-I showed enriched immune-related pathways, the highest immune score (CD8A expression and T-cell–inflamed gene expression profiles), and epithelial–mesenchymal transition (EMT), in transcriptional subtypes. Immunohistochemical staining (IHC) showed that SCLC-I had the highest density of CD8-positive TILs in transcriptional subtypes. In the ES-SCLC cohort, the efficacy of ACE therapy did not differ according to pathological subtypes. The progression-free survival (PFS) of TILHigh patients was significantly longer than that of TILLow patients (PFS: 7.3 months vs. 4.0 months, p < 0.001). ConclusionTumors with a high density of TILs, which represent the most immunogenic SCLC subtype (SCLC-I), based on transcriptomic data could benefit from ACE therapy.

Identification of cuproptosis-based molecular subtypes, construction of prognostic signature and characterization of immune landscape in colon cancer.

Cuproptosis is a newly discovered form of cell death induced by targeting lipoacylated proteins involved in the tricarboxylic acid cycle. However, the roles of cuproptosis-related genes (CRGs) in the clinical outcomes and immune landscape of colon cancer remain unknown. We performed bioinformatics analysis of the expression data of 13 CRGs identified from a previous study and clinical information of patients with colon cancer obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. Colon cancer cases were divided into two CRG clusters and prognosis-related differentially expressed genes. Patient data were separated into three corresponding distinct gene clusters, and the relationships between the risk score, patient prognosis, and immune landscape were analyzed. The identified molecular subtypes correlated with patient survival, immune cells, and immune functions. A prognostic signature based on five genes was identified, and the patients were divided into high- and low-risk groups based on the calculated risk score. A nomogram model for predicting patient survival was developed based on the risk score and other clinical features. The high-risk group showed a worse prognosis, and the risk score was related to immune cell abundance, microsatellite instability, cancer stem cell index, checkpoint expression, immune escape, and response to chemotherapeutic drugs and immunotherapy. Findings related to the risk score were validated in the imvigor210 cohort of patients with metastatic urothelial cancer treated with anti-programmed cell death ligand 1. We demonstrated the potential of cuproptosis-based molecular subtypes and prognostic signatures for predicting patient survival and the tumor microenvironment in colon cancer. Our findings may improve the understanding of the role of cuproptosis in colon cancer and lead to the development of more effective treatment strategies.

A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy.

Based on preclinical evidence of epigenetic contribution to sensitivity and resistance to immune checkpoint inhibitors (ICI), we hypothesized that guadecitabine (hypomethylating agent) and atezolizumab (anti-PD-L1) together would potentiate a clinical response in patients with metastatic urothelial carcinoma (UC) unresponsive to initial immune checkpoint blockade therapy. We designed a single arm Phase II study (NCT03179943) with a safety run-in to identify the recommended phase II dose of the combination therapy of guadecitabine and atezolizumab. Patients with recurrent/advanced urothelial carcinoma who had previously progressed on ICI therapy with PD-1 or PD-L1 targeting agents were eligible. Pre-planned correlative analysis was performed to characterize peripheral immune dynamics and global DNA methylation, transcriptome, and immune infiltration dynamics of patient tumors. Safety run-in enrolled 6 patients and Phase II enrolled 15 patients before the trial was closed for futility. No dose-limiting toxicity was observed. Four patients, with best response of stable disease, exhibited extended tumor control (8-11 months) and survival (>14 months). Correlative analysis revealed lack of DNA demethylation in tumors after 2 cycles of treatment. Increased peripheral immune activation and immune infiltration in tumors after treatment correlated with progression-free survival and stable disease. Furthermore, high IL-6 and IL-8 levels in the patients' plasma associates with short survival. No RECIST responses were observed after combination therapy in this trial. Although we could not detect the anticipated tumor-intrinsic effects of guadecitabine, the addition of hypomethylating agent to ICI therapy induced immune activation in a few patients, which associated with longer patient survival.

Immature natural killer cells promote progression of triple-negative breast cancer.

Natural killer (NK) cells are cytotoxic lymphocytes that accumulate within the tumor microenvironment and are generally considered to be antitumorigenic. Using single-cell RNA sequencing and functional analysis of multiple triple-negative breast cancer (TNBC) and basal tumor samples, we observed a unique subcluster of Socs3highCD11b-CD27- immature NK cells that were present only in TNBC samples. These tumor-infiltrating NK cells expressed a reduced cytotoxic granzyme signature and, in mice, were responsible for activating cancer stem cells through Wnt signaling. NK cell-mediated activation of these cancer stem cells subsequently enhanced tumor progression in mice, whereas depletion of NK cells or Wnt ligand secretion from NK cells by LGK-974 decreased tumor progression. In addition, NK cell depletion or inhibition of their function improved anti-programmed cell death ligand 1 (PD-L1) antibody or chemotherapy response in mice with TNBC. Furthermore, tumor samples from patients with TNBC and non-TNBC revealed that increased numbers of CD56bright NK cells were present in TNBC tumors and were correlated to poor overall survival in patients with TNBC. Together, our findings identify a population of protumorigenic NK cells that may be exploited for both diagnostic and therapeutic strategies to improve outcomes for patients with TNBC.

Radiation recall pneumonitis: PET/CT findings.

A 63-year-old woman with locally advanced lung cancer (Fig. 1A) who was treated with curative-intent chemoradiation therapy (cisplatin, etoposide and 60 Gy in 30 fractions) developed minimal radiation-induced fibrosis in the irradiated area 12 months after the end of the radiation therapy (Fig. 1B). The patient subsequently received consolidation therapy with durvalumab (anti-programmed cell death ligand-1). Twenty-four months after radiation therapy was administered, she was found to have on computed tomography (CT) a new-onset consolidation in the previously irradiated field (Fig. 1C), with normal appearance of the rest of the lung parenchyma. A transbronchial biopsy did not show signs of local recurrence. Fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT confirmed a homogeneous mildly hypermetabolic lung consolidation (Fig. 1D), consistent with inflammatory changes. PET/CT did not show any intense FDG focal activity that would suggest lung cancer recurrence. Since the patient was asymptomatic, treatment with durvalumab was not discontinued and a presumptive diagnosis of radiation recall pneumonitis (RRP) was made. Subsequent CT studies showed spontaneous but slow progressive reduction in size of the lung consolidation (Fig. 1E).

A Fluorinated Supramolecular Self-Assembled Peptide as Nanovaccine Adjuvant for Enhanced Cancer Vaccine Therapy.

Adjuvants play an important role in enhancing vaccine-induced immune protection. Adequate cellular uptake, robust lysosomal escape, and subsequent antigen cross-presentation are critical steps for vaccine adjuvants to effectively elicit cellular immunity. Here, a fluorinated supramolecular strategy to generate a series of peptide adjuvants by using arginine (R) and fluorinated diphenylalanine peptide (DP) is adopted. It is found that the self-assembly ability and antigen-binding affinity of these adjuvants increase with the number of fluorine (F)and can be regulated by R. By comparison, 4RDP(F5) shows the strongest binding affinity with model antigen ovalbumin (OVA) and the best performance in dendritic cells maturation and antigen's lysosomal escape, which contributes to the subsequent antigen cross-presentation. As a consequence, 4RDP(F5)-OVA nanovaccine generates a strong cellular immunity in a prophylactic OVA-expressing EG7-OVA lymphoma model, leading to long-term immune memory for resisting tumor challenge. What's more, 4RDP(F5)-OVA nanovaccine in combination with anti-programmed cell death ligand-1(anti-PD-L1) checkpoint blockade could effectively elicit anti-tumor immune responses and inhibit tumor growth in a therapeutic EG7-OVA lymphoma model. Overall, this study demonstrates the simplicity and effectiveness of fluorinated supramolecular strategies for constructing adjuvants and might provide an attractive vaccine adjuvant candidate for cancer immunotherapy.

Engineered indocyanine green and PD-L1 inhibitors co-loaded perfluorochemical double-layered nanodroplets offer effective photoimmunotherapy against colorectal cancer

Colorectal cancer (CRC) ranks the 3rd most common cancer and is the 2nd leading cause of cancer death worldwide, indicating that an effective therapeutic strategy is still urgently desired nowadays. In this study, an emerging indocyanine green (ICG) and anti-programmed cell death ligand 1 monoclonal antibodies (αPD-L1) co-loaded perfluorocarbon double-layer nanodroplets named IPLPNDs were developed for photoimmunotherapy of CRC. The IPLPNDs are able to stabilize the αPD-L1 in the nanocarriers and generate hyperthermia as well as significantly enhanced production of singlet oxygen compared to equal dose of free ICG upon NIR irradiation. Furthermore, the IPLPNDs + NIR can dose-dependently eradicate CT26 cells and subsequently inhibit PD-L1 bioactivity of the survived cells in vitro. Meanwhile, expression levels of HMGB1 and CRT, the two immunogenic cell death (ICD) markers, from the survived cells were elevated 24 h after NIR exposure. Through the animal study, we further demonstrated that the IPLPNDs containing 20-μM ICG and 3-μg/mL αPD-L1 in combination with 1-min NIR irradiation can effectively arrest the growth of CT26 tumor in the mice without generating organ damage, by which the tumor size was merely increased by 56 % while that without drug treatment can be tremendously expanded by 15 folds after 10 days. Moreover, the remained tumors treated by IPLPNDs + NIR indeed showed the least PD-L1 and highest CD8 expressions compared to all the other settings, illustrating the significance of immunogenicity of tumor microenvironment on anticancer efficacy. We reason that such tumor inhibition was carried out by phototherapy followed by ICD-enhanced immunotherapy, a two-stages anticancer process in vivo. Taken together, we anticipate that the developed IPLPND is highly applicable for use in the clinical CRC treatment.

Tri-Site Academic Center Experience with Immunotherapy for Metastatic Skin Cancer in Solid Organ Transplant Patients.

Organ transplant recipients have an increased risk of skin cancer, but treatment options for metastatic skin cancer are limited because of their immunosuppressed state. We sought to qualify the clinical experience and patient safety of immune checkpoint inhibitors (ICIs) for skin cancer treatment in transplant recipients at one large academic institution. We conducted a retrospective chart review including patients who had at least one organ transplant, a diagnosis of skin cancer, and received an ICI to treat their skin cancer. Four patients met our criteria. Three received an ICI for metastatic melanoma and died secondary to their cancer. One patient, treated for squamous cell carcinoma, had remission of his cancer with ICI treatment. Only one patient had transplant rejection. ICIs can be used in organ transplant patients, but the risk of transplant rejection must be carefully discussed because it may be associated with an increased risk of death. A higher risk of rejection exists with anti-programmed cell death 1 and anti-programmed cell death ligand 1 inhibitors.

Resistance to immune checkpoint inhibitors in advanced lung cancer: Clinical characteristics, potential prognostic factors and next strategy.

Immune checkpoint inhibitors (ICIs) have shown unprecedented clinical benefit in cancer immunotherapy and are rapidly transforming the practice of advanced lung cancer. However, resistance routinely develops in patients treated with ICIs. We conducted this retrospective study to provide an overview on clinical characteristics of ICI resistance, optimal treatment beyond disease progression after prior exposure to immunotherapy, as well as potential prognostic factors of such resistance. 190 patients diagnosed with unresectable lung cancer who received at least one administration of an anti-programmed cell death 1 (PD-1)/anti-programmed cell death-ligand 1(PD-L1) at any treatment line at Zhongshan Hospital Fudan University between Sep 2017 and December 2019 were enrolled in our study. Overall survival (OS) and progression-free survival (PFS) were analyzed. Levels of plasma cytokines were evaluated for the prognostic value of ICI resistance. We found that EGFR/ALK/ROS1 mutation and receiving ICI treatment as second-line therapy were risk factors associated with ICI resistance. Patients with bone metastasis at baseline had a significantly shorter PFS1 time when receiving initial ICI treatment. Whether or not patients with oligo-progression received local treatment seemed to have no significant effect on PFS2 time. Systemic therapies including chemotherapy and anti-angiogenic therapy rather than continued immunotherapy beyond ICI resistance had significant effect on PFS2 time. TNF, IL-6 and IL-8 were significantly elevated when ICI resistance. Lower plasma TNF level and higher plasma IL-8 level seemed to be significantly associated with ICI resistance. A nomogram was established to prognosis the clinical outcome of patients treated with ICIs. Patients with EGFR/ALK/ROS1 mutation, or those receiving ICI treatment as second-line therapy had higher risk of ICI resistance. Patients with bone metastasis had poor prognosis during immunotherapy. For those patients with oligo-progression after ICI resistance, combination with local treatment did not lead to a significantly longer PFS2 time. Chemotherapy and anti-angiogenic therapy rather than continued immunotherapy beyond ICI resistance had significant effect on PFS2 time. Levels of plasma cytokines including TNF, IL-6 and IL-8 were associated with ICI resistance.

Treatment of HPV-Related Uterine Cervical Cancer with a Third-Generation Oncolytic Herpes Simplex Virus in Combination with an Immune Checkpoint Inhibitor.

Cervical cancer is one of the most common cancers in women. The development of new therapies with immune checkpoint inhibitors (ICIs) is being investigated for cervical cancer; however, their efficacy is not currently sufficient. Oncolytic virus therapy can increase tumor immunogenicity and enhance the antitumor effect of ICIs. In this report, the therapeutic potential of a triple-mutated oncolytic herpes virus (T-01) with an ICI for human papillomavirus (HPV)-related cervical cancer was evaluated using a bilateral syngeneic murine model. The efficacy of intratumoral (i.t.) administration with T-01 and subcutaneous (s.c.) administration of anti-programmed cell death ligand 1 (PD-L1) antibody (Ab) was equivalent to that of anti-PD-L1 Ab alone on the T-01-injected side. Moreover, combination therapy had no significant antitumor effect compared to monotherapy on the T-01-non-injected side. Combination therapy significantly increased the number of tumor specific T cells in the tumor. While T-01 could not be isolated from tumors receiving combination therapy, it could be isolated following T-01 monotherapy. Furthermore, T-01 had a cytotoxic effect on stimulated T cells. These results suggest that T-01 and anti-PD-L1 Ab partially counteract and therefore concomitant administration should be considered with caution.

Serum-derived exosomal miR-125a-3p predicts the response to anti-programmed cell death-1/programmed cell death-ligand 1 monotherapy in patients with non-small cell lung cancer

BackgroundVersatile biomarkers for immune checkpoint inhibitors (ICI) efficacy in patients with cancer remain to be identified. Liquid biopsy using serum-derived exosomal microRNAs (miRNAs) are widely investigated as diagnostic and therapeutic outcome predictors in patients with cancer. However, exosomal miRNAs linked to the response to ICI in patients with non-small cell lung cancer (NSCLC) remain elusive thus far. Methods: The value of serum-derived exosomal miRNAs in predicting the effect of anti-programmed cell death-1 (PD-1)/anti-programmed cell death-ligand 1 (PD-L1) monotherapy in 41 patients with advanced NSCLC was assessed. We performed functional analysis of candidate miRNAs using NSCLC cell lines. Results: Exosomal miR-125a-3p was associated with response to treatment with ICI. Exosomal miR-125a-3p was more useful in predicting response to ICI versus tumoral PD-L1 in patients with low PD-L1 expression <50 %). Moreover, high expression of miR-125a-3p was associated with worse progression-free and overall survival. In H1975 and H441 cells, induction of miR-125a-3p regulated PD-L1 expression via suppression of neuregulin 1 (NRG1). Conclusions: Exosomal miR-125a-3p is a potential predictor of response to anti-PD-1/PD-L1 therapy in advanced NSCLC patients with low PD-L1 expression.