Anti-programmed Cell Death Protein Research Articles

Pt-Te-Nanorod-Based Photothermal Chemokine Immunotherapy for All Stages of Cancer via Adaptive and Innate Immunity.

The chemokine (C-X-C) motif ligand 9 (CXCL9) is one of the lymphocyte-traffic-involved chemokines. Despite the immunotherapeutic potential of CXCL9 for recruiting effector T cells (cluster of differentiation 4+ (CD4+) and CD8+ T cells) and natural killer cells (NK cells) around the tumors, practical applications of CXCL9 have been limited because of its immune toxicity and lack of stability in vivo. To overcome these limitations, we designed and synthesized Pt-Te nanorods (PtTeNRs), which exhibited excellent photothermal conversion efficiency with stable CXCL9 payload characteristics under the physiological conditions of in vivo environments. We developed a CXCL9-based immunotherapy strategy by utilizing the unique physicochemical properties of developed PtTeNRs. The investigation revealed that the PtTeNR-loaded CXCL9 was effectively accumulated in the tumor, subsequently released in a sustained manner, and successfully recruited effector T cells for immunotherapy of the designated tumor tissue. In addition, a synergistic effect was observed between the photothermal (PT) therapy and antiprogrammed cell death protein 1 (aPD-1) antibody. In this study, we demonstrated that PtTeNR-based CXCL9, PT, and aPD-1 antibody trimodal therapy delivers an outstanding tumor suppression effect in all stages of cancer, including phases 1-4 and tumor recurrence.

Target-Driven Tissue-Agnostic Drug Approvals—A New Path of Drug Development

The regulatory approvals of tumor-agnostic therapies have led to the re-evaluation of the drug development process. The conventional models of drug development are histology-based. On the other hand, the tumor-agnostic drug development of a new drug (or combination) focuses on targeting a common genomic biomarker in multiple cancers, regardless of histology. The basket-like clinical trials with multiple cohorts allow clinicians to evaluate pan-cancer efficacy and toxicity. There are currently eight tumor agnostic approvals granted by the Food and Drug Administration (FDA). This includes two immune checkpoint inhibitors, and five targeted therapy agents. Pembrolizumab is an anti-programmed cell death protein-1 (PD-1) antibody that was the first FDA-approved tumor-agnostic treatment for unresectable or metastatic microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) solid tumors in 2017. It was later approved for tumor mutational burden-high (TMB-H) solid tumors, although the TMB cut-off used is still debated. Subsequently, in 2021, another anti-PD-1 antibody, dostarlimab, was also approved for dMMR solid tumors in the refractory setting. Patients with fusion-positive cancers are typically difficult to treat due to their rare prevalence and distribution. Gene rearrangements or fusions are present in a variety of tumors. Neurotrophic tyrosine kinase (NTRK) fusions are present in a range of pediatric and adult solid tumors in varying frequency. Larotrectinib and entrectinib were approved for neurotrophic tyrosine kinase (NTRK) fusion-positive cancers. Similarly, selpercatinib was approved for rearranged during transfection (RET) fusion-positive solid tumors. The FDA approved the first combination therapy of dabrafenib, a B-Raf proto-oncogene serine/threonine kinase (BRAF) inhibitor, plus trametinib, a mitogen-activated protein kinase (MEK) inhibitor for patients 6 months or older with unresectable or metastatic tumors (except colorectal cancer) carrying a BRAFV600E mutation. The most recent FDA tumor-agnostic approval is of fam-trastuzumab deruxtecan-nxki (T-Dxd) for HER2-positive solid tumors. It is important to identify and expeditiously develop drugs that have the potential to provide clinical benefit across tumor types.

Tumor Microenvironment Reprogramming Improves Nanomedicine-Based Chemo-Immunotherapy in Sarcomas

Abstract Sarcomas are a heterogeneous group of rare cancers that originate in soft tissues or bones. Their complexity and tendency for metastases make treatment challenging, highlighting the need for new therapeutic approaches to improve patient survival. The difficulties in treating these cancers primarily stem from abnormalities within the tumor microenvironment (TME), which leads to reduced blood flow and oxygen levels in tumors. Consequently, this hampers the effective delivery of drugs to tumors and diminishes treatment efficacy despite higher toxic doses of chemotherapy. In this study, we tested the mechanotherapeutic ketotifen combined with either pegylated liposomal doxorubicin (PLD) or pegylated liposomal coencapsulated alendronate–doxorubicin (PLAD) plus anti–programmed cell death protein 1 antibody in mouse models of fibrosarcoma and osteosarcoma. We found that ketotifen successfully reprogrammed the TME by reducing tumor stiffness and increasing perfusion, proven by changes measured by shear-wave elastography and contrast-enhanced ultrasound, respectively, and enhanced the therapeutic efficacy of our nanomedicine-based chemo-immunotherapy protocols. Furthermore, we observed a trend toward improved antitumor responses when nano-chemotherapy is given alongside anti–programmed cell death protein 1 and when the immunomodulator alendronate was present in the treatment. We next investigated the mechanisms of action of this combination. Ketotifen combined with nanomedicine-based chemo-immunotherapy increased T-cell infiltration, specifically cytotoxic CD8+ T cells and CD4+ T helper cells, and decreased the number of regulatory T cells. In addition, the combination also altered the polarization of tumor-associated macrophages, favoring the M1 immune-supportive phenotype over the M2 immunosuppressive phenotype. Collectively, our findings provide evidence that ketotifen-induced TME reprogramming can improve the efficacy of nanomedicine-based chemo-immunotherapy in sarcomas.

Neutrophil extracellular traps promote immune escape in hepatocellular carcinoma by up-regulating CD73 through Notch2

Immune escape is the main reason that immunotherapy is ineffective in hepatocellular carcinoma (HCC). Here, this study illustrates a pathway mediated by neutrophil extracellular traps (NETs) that can promote immune escape of HCC. Mechanistically, we demonstrated that NETs up-regulated CD73 expression through activating Notch2 mediated nuclear factor kappa B (NF-κB) pathway, promoting regulatory T cells (Tregs) infiltration to mediate immune escape of HCC. In addition, we found the similar results in mouse HCC models by hydrodynamic plasmid transfection. The treatment of deoxyribonuclease I (DNase I) could inhibit the action of NETs and improve the therapeutic effect of anti-programmed cell death protein 1 (PD-1). In summary, our results revealed that targeting of NETs was a promising treatment to improve the therapeutic effect of anti-PD-1.

Neutrophil extracellular traps promote immune escape in hepatocellular carcinoma by up-regulating CD73 through Notch2

Immune escape is the main reason that immunotherapy is ineffective in hepatocellular carcinoma (HCC). Here, this study illustrates a pathway mediated by neutrophil extracellular traps (NETs) that can promote immune escape of HCC. Mechanistically, we demonstrated that NETs up-regulated CD73 expression through activating Notch2 mediated nuclear factor kappa B (NF-κB) pathway, promoting regulatory T cells (Tregs) infiltration to mediate immune escape of HCC. In addition, we found the similar results in mouse HCC models by hydrodynamic plasmid transfection. The treatment of deoxyribonuclease I (DNase I) could inhibit the action of NETs and improve the therapeutic effect of anti-programmed cell death protein 1 (PD-1). In summary, our results revealed that targeting of NETs was a promising treatment to improve the therapeutic effect of anti-PD-1.

Harnessing lipid metabolism modulation for improved immunotherapy outcomes in lung adenocarcinoma

BackgroundWhile anti-programmed cell death protein-1 (PD-1) monotherapy has shown effectiveness in treating lung cancer, its response rate is limited to approximately 20%. Recent research suggests that abnormal lipid metabolism in...

Tislelizumab in previously treated, locally advanced unresectable/metastatic microsatellite instability-high/mismatch repair-deficient solid tumors.

The open-label, phase II RATIONALE-209 study evaluated tislelizumab (anti-programmed cell death protein 1 antibody) as a tissue-agnostic monotherapy for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) tumors. Adults with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled. Patients received tislelizumab 200 mg intravenously every 3 weeks. Objective response rate (ORR; primary endpoint), duration of response (DoR), and progression-free survival (PFS) were assessed by independent review committee (Response Evaluation Criteria in Solid Tumors v1.1). Eighty patients were enrolled and treated; 75 (93.8%) patients had measurable disease at baseline. Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease (n=79; 98.8%). At primary analysis (data cutoff July 8, 2021; median follow-up 15.2 months), overall ORR [46.7%; 95% confidence interval (95% CI), 35.1-58.6; one-sided P<0.0001] and ORR across tumor-specific subgroups [colorectal (n=46): 39.1% (95% CI, 25.1-54.6); gastric/gastroesophageal junction (n=9): 55.6% (95% CI, 21.2-86.3); others (n=20): 60.0% (95% CI, 36.1-80.9)] were significantly greater with tislelizumab vs. a prespecified historical control ORR of 10%; five (6.7%) patients had complete responses. Median DoR, PFS, and overall survival were not reached with long-term follow-up (data cutoff December 5, 2022; median follow-up 28.9 months). Tislelizumab was well tolerated with no unexpected safety signals. Treatment-related adverse events (TRAEs) of grade ≥3 occurred in 53.8% of patients; 7.5% of patients discontinued treatment due to TRAEs. Tislelizumab demonstrated a significant ORR improvement in patients with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.

Efficacy of axitinib in a US cohort of patients with programmed cell death protein 1-resistant mucosal melanoma.

Mucosal melanoma is a rare melanoma subtype, accounting for about 1% of all diagnosed melanomas. It is characterized by an aggressive phenotype with a poor prognosis and a low response rate to approved treatments. We retrospectively analyzed the clinical features, treatments, and outcomes of patients diagnosed with mucosal melanoma treated with axitinib ± anti-programmed cell death protein 1 (PD-1) therapy at a single US referral center between 2018 and 2021. Radiologic response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), v1.1. Twenty-three patients were included in this study. In all, 78% were females with a median age of 62 years. The originating site of mucosal melanoma was the sinonasal (35%), genitourinary (35%), and gastrointestinal (30%) tracts. Sixty-five percent of patients had M1c or M1d disease and 0% had BRAF V600 mutations detected. The majority (96%) had prior treatment inclusive of anti-PD-1, with a median of 2 prior lines, and 78% of patients received a combination of axitinib and PD-1 and the median duration of treatment was 3.2 months. The overall response rate was 13% and the disease control rate was 26%. The median progression-free survival was 3.2 months, and the median overall survival was 8.2 months. Overall, the regimen was well tolerated with 39% of patients requiring dose reduction and 9% requiring treatment cessation. Axitinib with anti-PD-1 therapy has modest clinical activity in heavily pretreated patients with mucosal melanoma outside of Asia, including some with long-term benefits. This data supports the worldwide clinical trials evaluating this combination and the role of incorporating vascular endothelial growth factor-based therapy in the therapeutic paradigm for patients with mucosal melanoma.

How to treat advanced Hodgkin lymphoma?

In this review, we analyzed the different therapy options in patients with advanced Hodgkin lymphoma (HL). The treatment of advanced HL has greatly evolved during the last decade even still based on polychemotherapy. Mature data established that the better strategies require Positron emission tomography (PET)-driven treatments which allow to optimize the balance between disease control and both immediate and late treatment adverse effects, leading to cure most patients while minimizing the risk of toxicity. Indeed, PET-driven deescalated strategies offer the better treatment option. The recent incorporation of targeted therapies, anti-CD30 or anti-programmed cell death protein 1 (PD1) in combination with chemotherapy should quickly change the game and be a step forward to still decrease the risk of treatment toxicity and improve the cure rate. The standard of care for advanced HL remains currently PET-driven chemotherapy and should rapidly evolve with the addition of targeted therapy combined with chemotherapy.

Targeted protein degradation combined with PET imaging reveals the role of host PD-L1 in determining anti-PD-1 therapy efficacy.

Immunohistochemical staining of programmed death-ligand 1 (PD-L1) in tumor biopsies acquired through invasive procedures is routinely employed in clinical practice to identify patients who are most likely to benefit from anti-programmed cell death protein 1 (PD-1) therapy. Nevertheless, PD-L1 expression is observed in various cellular subsets within tumors and their microenvironments, including tumor cells, dendritic cells, and macrophages. The impact of PD-L1 expression across these different cell types on the responsiveness to anti-PD-1 treatment is yet to be fully understood. We synthesized polymer-based lysosome-targeting chimeras (LYTACs) that incorporate both PD-L1-targeting motifs and liver cell-specific asialoglycoprotein receptor (ASGPR) recognition elements. Small-animal positron emission tomography (PET) imaging of PD-L1 expression was also conducted using a PD-L1-specific radiotracer 89Zr-αPD-L1/Fab. The PD-L1 LYTAC platform was capable of specifically degrading PD-L1 expressed on liver cancer cells through the lysosomal degradation pathway via ASGPR without impacting the PD-L1 expression on host cells. When coupled with whole-body PD-L1 PET imaging, our studies revealed that host cell PD-L1, rather than tumor cell PD-L1, is pivotal in the antitumor response to anti-PD-1 therapy in a mouse model of liver cancer. The LYTAC strategy, enhanced by PET imaging, has the potential to surmount the limitations of knockout mouse models and to provide a versatile approach for the selective degradation of target proteins in vivo. This could significantly aid in the investigation of the roles and mechanisms of protein functions associated with specific cell subsets in living subjects.

Breast Cancer Immunotherapy: A Clinical Review for the Plastic Surgeon.

Immunotherapy has transformed breast cancer management. However, it can be challenging to remain familiar with the adverse events, contraindications, and perioperative recommendations for each agent. We used FDALabel to identify all Food and Drug Administration-approved immunotherapies indicated for the treatment of breast cancer. We extracted details regarding warnings and precautions, indications, and adverse events from each package insert. We identified nine immunotherapies belonging to three classes: anti-human epidermal growth factor receptor 2 (HER2) agents, anti-programmed cell death protein 1 (PD-1) agents, and anti-trophoblast cell-surface antigen 2 (TROP-2) agents. Cardiotoxicity, including heart failure and cardiomyopathy, was common among those receiving anti-HER2 agents, and hypothyroidism was common among patients receiving the anti-PD-1 agent. The anti-TROP-2 agent was associated with diarrhea and neutropenia. Given the adverse event profile for each drug, we recommend preoperative evaluation components, including transthoracic echocardiography, liver function tests, and thyroid panels. We also indicate here which immunotherapies raise concern for venous thromboembolism, hematoma, and infection. Using data from clinical trials, we recommend a preoperative evaluation tailored to the immunotherapeutic regimen of individual patients.

A phase II clinical evaluation of radiofrequency ablation (RFA) combined with regorafenib and toripalimab in patients with colorectal cancer with liver metastases.

3566 Background: In several clinical studies, the combination of anti-programmed cell death protein 1 (anti-PD-1) antibodies with targeted antiangiogenic agents has demonstrated clinical benefits for patients with metastatic colorectal cancer (mCRC). However, individuals with liver metastases have shown suboptimal responses. Prior preclinical study indicates a synergistic efficacy of radiofrequency ablation (RFA) when employed in conjunction with immunotherapy. The study aimed to explore whether RFA combined with regorafenib and toripalimab (an anti-PD-1 antibody) could provide better outcomes in patients with colorectal cancer liver metastases. Methods: Using Simon's two-stage design, a total of 32 subjects were required for enrollment, with10 subjects included in stage 1. If there were no or less patients having response, the study would be terminated; otherwise, it would proceed to stage 2, enrolling an additional 22 subjects. The cohort consisted of 10 microsatellite stable (MSS) mCRC patients with multiple liver metastases who had previously failed fluorouracil, oxaliplatin, irinotecan, with or without targeted therapy. RFA was performed on a single hepatic lesion, with others designated as target lesions. Treatment with regorafenib and toripalimab commenced one week post-RFA, following a 4-week cycle. Toripalimab was administered intravenously biweekly, and regorafenib was given orally at daily dose of 80 mg (three weeks on, one week off, in a 4-week period). The primary endpoint was response rate. Results: Ten patients (3 women) were enrolled in this study, with ages ranging from 26 to 76 years (median: 52 years), and 60% being 52 years or older.Seventy percent had ECOG performance status (PS) of 0; 60% had primary colon tumors; 90% presented with synchronous liver metastases, and 80% had both intrahepatic and extrahepatic metastases. Half of the participants achieved stable disease; however, none exhibited confirmed partial or complete responses. The median progression-free survival was 3.3 months, and the median overall survival reached 11.3 months. The median number of cycles was two (range: 0.5 to 3), with 60% undergoing at least two cycles. Adverse events (AEs) included hand-foot syndrome, liver dysfunction, fatigue, abdominal distension, and thrombocytopenia. The most frequently reported AE was hand-foot syndrome, occurring in 50% of patients. Serious AEs (grade≥3) potentially related to treatment included hand-foot syndrome and hyperbilirubinemia, each with an incidence of 10%. Notably, one patient experienced hyperprogression during immunotherapy. Conclusions: The combination of RFA, regorafenib, and toripalimab has not shown encouraging efficacy in patients with CRC liver metastases. However, the observed safety profile is acceptable. Clinical trial information: NCT05485909 .

Global, randomized, phase III study of tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced/metastatic esophageal squamous cell carcinoma (RATIONALE-306 update): Minimum 3-year survival follow-up.

4032 Background: RATIONALE-306 (NCT03783442) is the first global study to investigate anti-programmed cell death protein 1 therapy in combination with different chemotherapy (chemo) options in the first-line (1L) treatment of advanced/metastatic esophageal squamous cell carcinoma (ESCC). At interim analysis (IA), tislelizumab (TIS) plus chemo demonstrated a statistically significant, clinically meaningful improvement in overall survival (OS) versus placebo (PBO) plus chemo, with a manageable safety profile. Here, we report updated efficacy and safety data with minimum 3 years’ follow-up after study unblinding at IA. Methods: Adults with unresectable locally advanced recurrent/metastatic ESCC and no prior systemic treatment for advanced disease were enrolled and randomized (1:1; stratified by region, prior definitive therapy, and investigator [INV]-chosen chemo) to receive TIS 200 mg (Arm A) or PBO (Arm B) IV every 3 weeks plus chemo (platinum plus fluoropyrimidine or platinum plus paclitaxel), until disease progression or intolerable toxicity. The primary endpoint was OS in the intent-to-treat population. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR), all per INV, and safety. Results: In total, 649 patients (pts) were randomized (Arm A, n=326; Arm B, n=323). At a minimum study follow-up of 36.0 months, improvements in OS, PFS, and DoR in Arm A versus B (Table) were maintained relative to the IA. The hazard ratio (HR) for OS with TIS plus chemo versus PBO plus chemo was 0.70 (95% confidence interval: 0.59, 0.83). Similar to the IA, incidences of any-grade (96.6% vs 96.3%) or grade ≥3 (67.0% vs 64.5%) treatment-related adverse events (TRAEs) were comparable between Arms A and B, respectively; treatment-emergent adverse events leading to treatment discontinuation were higher in Arm A (32.1%) versus B (22.1%). In Arm A versus B, respectively, serious TRAEs occurred in 29.9% vs 19.6% of pts; TRAEs leading to death occurred in 1.9% and 1.2%. Conclusions: After minimum 3 years’ follow-up, 1L TIS plus chemo continued to demonstrate clinically meaningful improvements in OS and PFS and durable antitumor response benefit versus PBO plus chemo in pts with advanced/metastatic ESCC, with no new safety signals. Clinical trial information: NCT03783442 . [Table: see text]

CD112 is an epithelial-to-mesenchymal transition-related and immunological biomarker in pan-cancer.

The nectin adhesion molecule CD112, an important component of tumor progression, belongs to the nectin family. However, a comprehensive evaluation of its clinical relevance and mechanism in various cancers is yet to be conducted. This investigation fully examined the relationship between prognosis and CD112 expression. We clarified the function of CD112 in tumor immunity by employing The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. This involved examining its connections to tumor mutation burden (TMB), DNA methylation, tumor immune invasion, mismatch repair (MMR), microsatellite instability (MSI), and common immune checkpoint inhibitors (ICIs). Additionally, the impact of CD112 knockdown on cell function was examined in colorectal cancer (CRC) cell lines. In the current study, we found malignant tissues express high levels of CD112, which was related to TMB, MMR, MSI, and DNA methylation. Survival analysis indicated that patients with high CD112 expression had an unfavorable prognosis more frequently. In addition, CD112 expression was negatively associated with infiltration levels of CD4 positive (CD4+) T cells, CD8 positive (CD8+) T cells, and T cells. Western blotting and pathway enrichment analysis showed that CD112 is significantly linked to epithelial-to-mesenchymal transition (EMT). Additionally, CRC cells migrate and proliferate less when CD112 was knocked down. CD112 expression was found to be negatively associated with anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) treatment outcomes in patients. CD112 may act as a possible prognostic marker in immune therapy and may stimulate tumor growth by upregulating the EMT pathway.

Cadonilimab with chemotherapy in HER2-negative gastric or gastroesophageal junction adenocarcinoma: the phase 1b/2 COMPASSION-04 trial.

Treatment with anti-programmed cell death protein 1 (PD-1) therapy and chemotherapy prolongs the survival of patients with unresectable advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The benefit from anti-PD-1 therapy is enriched in patients with programmed cell death 1 ligand 1 (PD-L1) combined positive score (CPS)-positive or CPS-high tumors compared with patients with PD-L1 CPS-negative or CPS-low tumors. In this phase 1b/2 study, we evaluated the efficacy and safety of cadonilimab, a bispecific antibody targeting PD-1 and cytotoxic T-lymphocyte antigen-4, plus chemotherapy as first-line treatment in patients with human epidermal growth factor receptor 2-negative unresectable advanced or metastatic gastric or GEJ adenocarcinoma. The primary endpoint was the recommended phase 2 dose (RP2D) for phase 1b and the objective response rate for phase 2. Secondary endpoints included disease control rate, duration of response, time to response, progression-free survival, overall survival (OS) and safety. The primary endpoint was met. No dose-limiting toxicities were observed during dose escalation in phase 1b; the recommended phase 2 dose was determined as 6 mg kg-1 every 2 weeks. The objective response rate was 52.1% (95% confidence interval (CI) = 41.6-62.5), consisting of complete and partial responses in 4.3% and 47.9% of patients, respectively. The median duration of response, progression-free survival and OS were 13.73 months (95% CI = 7.79-19.12), 8.18 months (95% CI = 6.67-10.48) and 17.48 months (95% CI = 12.35-26.55), respectively. The median OS in patients with a PD-L1 CPS ≥ 5 was 20.32 months (95% CI = 4.67-not estimable); in patients with a PD-L1 CPS < 1, the median OS reached 17.64 months (95% CI = 11.63-31.70). The most common treatment-related grade 3 or higher adverse events were decreased neutrophil count (19.1%), decreased platelet count (16.0%), anemia (12.8%) and decreased leukocyte count (8.5%). No new safety signal was identified. The current regimen showed promising clinical activity and manageable safety in patients with gastric or GEJ adenocarcinoma regardless of PD-L1 expression. Chinadrugtrials.org.cn registration: CTR20182027.

TREM2 deficiency reprograms intestinal macrophages and microbiota to enhance anti-PD-1 tumor immunotherapy.

The gut microbiota and tumor-associated macrophages (TAMs) affect tumor responses to anti-programmed cell death protein 1 (PD-1) immune checkpoint blockade. Reprogramming TAM by either blocking or deleting the macrophage receptor triggering receptor on myeloid cells 2 (TREM2) attenuates tumor growth, and lack of functional TREM2 enhances tumor elimination by anti-PD-1. Here, we found that anti-PD-1 treatment combined with TREM2 deficiency in mice induces proinflammatory programs in intestinal macrophages and a concomitant expansion of Ruminococcus gnavus in the gut microbiota. Gavage of wild-type mice with R. gnavus enhanced anti-PD-1-mediated tumor elimination, recapitulating the effect occurring in the absence of TREM2. A proinflammatory intestinal environment coincided with expansion, increased circulation, and migration of TNF-producing CD4+ T cells to the tumor bed. Thus, TREM2 remotely controls anti-PD-1 immune checkpoint blockade through modulation of the intestinal immune environment and microbiota, with R. gnavus emerging as a potential probiotic agent for increasing responsiveness to anti-PD-1.

Long-term survival after anti-PD-1 discontinuation in advanced cutaneous squamous cell carcinoma (cSCC): a proof of concept of benefit of concomitant cemiplimab and radiotherapy

BackgroundIn a princeps study we conducted in patients with advanced cutaneous squamous cell carcinoma treated with concomitant anti-Programmed cell death protein 1 (PD-1) and radiotherapy, we demonstrated a clinico radiological response to cemiplimab that appeared to persist over time, 1 year after treatment discontinuation.MethodWe conducted a single-center descriptive study at Caen Hospital from September 1, 2021 to September 2023, in 14 patients with advanced carcinoma treated with cemiplimab until September 1, 2021. The aim of this update is to examine clinical and radiological follow-up 2 years after discontinuation of cemiplimab.ResultsOf the 12 patients with a partial or complete response, we report 8 (66.7%) persistent responses 2 years after stopping cemiplimab, with only 2 patients progressing to distant disease, one lost to follow-up, and one death a priori unrelated to the disease.ConclusionOur study confirms a long-term and persistent effect despite discontinuation of cemiplimab at least up to 2 years later.

Abstract PO2-18-11: Short-term Pre-OPerative Durvalumab (MEDI 4736) in early small triple negative breast cancer patients (POP-Durva)

Abstract Background: Immune checkpoint inhibitors (ICIs) are one of the major therapeutic advancements in cancer treatment. Anti-programmed cell death protein 1 (Anti-PD1)/PD-L1 ICIs have improved progression-free survival in patients with metastatic triple negative breast cancer (TNBC) and pathologic complete response (pCR) and event-free survival in patients with early TNBC. Nevertheless, some patients treated with anti-PD(L)1 ICIs experience recurrence or do not achieve sustained clinical benefit. In addition, very interesting data show the existence of a subgroup of patients with exceptional tumour responses to monotherapy with anti-PD(L)1 ICIs. These exceptional responses are observed in various tumour types, such as colorectal or breast cancer. Although in colorectal cancer, the determinants for this extreme sensitivity to immunotherapy treatment are identified (existence of MSI) in breast cancer, this is not the case. There is still a lack of knowledge about predictive biomarkers and mechanisms of action for ICIs. Trial Design: POP-Durva (NCT05215106) is a prospective, one-arm-only study aiming at determining the pCR rate after two administrations of Durvalumab monotherapy in patients with stage I TNBC. This window-of-opportunity study will recruit 195 consecutive cases of stage I TNBC (ER &amp;lt; 1%, PR &amp;lt; 1%, HER2 negative) and TILs≥5%, eligible for short-term treatment with durvalumab. Study treatment consists of two administrations of intravenous Durvalumab monotherapy, 10mg/kg, at two weeks intervals. After study treatment, patients will receive a standard treatment strategy (surgery or neoadjuvant systemic treatment) as per physician choice. The primary endpoint is the pCR rate after treatment with Durvalumab, defined as the absence of invasive disease in the breast and negative axillary nodes (ypT0/yTis ypN0). Assessment of the primary endpoint will be performed at the surgery or at the biopsy at the end of treatment) for patients undergoing neoadjuvant treatment. For patients in whom neo-adjuvant therapy is the first standard treatment strategy (i.e. after study treatment) a breast ultrasound-guided biopsy is mandatory at the end of the treatment visit. If the biopsy-proven residual disease is demonstrated, patients can receive standard neoadjuvant therapy at the discretion of the treating investigator. Patients with biopsy-proven residual disease will be considered as having no pCR. Those with a complete response may proceed directly to surgery. The expected pCR rate with Durvalumab monotherapy is 20%. The sample size of 195 patients will allow us to estimate this expected pCR rate with a 95% confidence interval of a precision of 6.2%. Secondary objectives are objective response rate and safety. Exploratory objectives are to: a. describe immune cell dynamics associated with exceptional responses to ICI (using spectral cytometry analysis), b. describe somatic genetic contributions to the determination of immune responsiveness (using whole exome sequencing (WES) and in a subset of patient's single-cell RNA-seq), c. characterize tumour cells – immune cells' interaction/spatial distribution(using imaging mass cytometry), d. explore the association between gut microbiome composition/signatures predictive of response to ICI (using 16s rRNA sequencing) and e. identify predictive tissue/blood-based biomarkers of response and to anti-PD(L)1 ICIs therapy. A total of two dedicated FFPE samples and two fresh biopsies will be collected at the time of inclusion and at the end of treatment biopsy or on the surgical specimen. In addition, we will collect stool samples pre and at the completion of all Durvalumab treatments and blood samples at the time of inclusion, during treatment (before each Durvalumab administration) and at the end of treatment for serum and plasma extraction and whole blood to serve as a control for WES. Citation Format: Joana Mourato Ribeiro, Isabelle Pic, Quentin Blampey, Elie Rassy, Nusaibah Ibrahimi, Laura Salabert, Olivier Trédan, Monica Arnedos, Semih Dogan, Kamar Serhal Serhal, Clementine Mahaut, Alessandro Viansone, Salim Laghouati, Barbara Pistilli, Charles-Antoine Dutertre, Magali Lacroix-Triki, Jean-Yves Scoazec, Lisa Derosa, Laurence Zitvogel, Corinne Balleyguier, Nadege Bercovici, Paul-Henry Cournede, Stefan Michiels, Fabrice André. Short-term Pre-OPerative Durvalumab (MEDI 4736) in early small triple negative breast cancer patients (POP-Durva) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-18-11.

Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer with PD-L1 ≥ 1 %: A subgroup analysis from the EMPOWER-Lung 3 part 2 trial

ObjectivesEMPOWER-Lung 3 part 2 (NCT03409614), a double-blind, placebo-controlled phase 3 study, assessed cemiplimab (anti-programmed cell death protein 1) plus chemotherapy versus chemotherapy alone in patients with advanced non-small cell lung cancer (NSCLC) without EGFR, ALK, or ROS1 aberrations, regardless of histology or PD-L1 expression levels. We report results from subgroup analysis of patients with PD-L1 expression ≥ 1 %. Materials and MethodsPatients were randomized to receive cemiplimab 350 mg or placebo with chemotherapy every 3 weeks for up to 108 weeks. Overall survival (OS), progression-free survival (PFS), overall response rates (ORRs), patient-reported outcomes (PROs), and safety were assessed. ResultsOf the 327 patients with PD-L1 ≥ 1 % (466 in the overall study), 217 received cemiplimab plus chemotherapy and 110 received chemotherapy alone. After median follow-up of 28.0 months, median OS for cemiplimab plus chemotherapy was 23.5 months (95 % confidence interval [CI]: 20.9–27.2) vs. 12.1 months (95 % CI: 10.1–15.7) for chemotherapy alone (hazard ratio [HR] = 0.51, 95 % CI: 0.38–0.69, P < 0.0001); median PFS was 8.3 months (95 % CI: 6.7–10.8) versus 5.5 months (95 % CI: 4.3–6.2; HR = 0.48; 95 % CI: 0.37–0.62, P < 0.0001), and ORR was 47.9 % versus 22.7 %, respectively. PRO results favored cemiplimab plus chemotherapy over chemotherapy alone. Improved efficacy over chemotherapy alone was observed in both squamous and non-squamous histology. Safety was consistent with previous reports. ConclusionIn this subgroup analysis from EMPOWER-Lung 3 part 2, cemiplimab plus chemotherapy demonstrated clinical benefit over chemotherapy alone in patients with advanced squamous or non-squamous NSCLC with PD-L1 ≥ 1 %.

Inhalable nanoparticles with enhanced cuproptosis and cGAS–STING activation for synergistic lung metastasis immunotherapy

Due to the insufficient Cu+ accumulation, Cu+ efflux mechanism, and highly immunosuppressive tumor microenvironment (TME) in lung metastasis, the cuproptosis efficacy is limited. Herein, an inhalable nanodevice (CLDCu) is constructed to successfully overcome the drawbacks of cuproptosis. CLDCu consists of a Cu2+-chitosan shell and low molecular weight heparin-tocopherol succinate (LMWH-TOS, LT) core with disulfiram (DSF) loading. The prepared CLDCu can be inhaled and accumulate in large amounts in lung lesions (63.6%) with 56.5 times higher than intravenous injection. Within tumor cells, the mild acidity triggers the co-release of DSF and Cu2+, thus generating bis(diethyldithiocarbamate)-copper (CuET) to block Cu+ efflux protein ATP7B and forming toxic Cu+, leading to enhanced cuproptosis. Meanwhile, the released chitosan cooperates with CLDCu-induced cuproptosis to activate stimulator of interferon genes (STING) pathway, which significantly potentiates dendritic cells (DCs) maturation, as wells as evokes innate and adaptive immunity. In lung metastatic mice model, CLDCu is found to induce cuproptosis and reverse the immunosuppressive TME by inhalation administration. Moreover, CLDCu combined with anti-programmed cell death protein ligand-1 antibody (aPD-L1) provokes stronger antitumor immunity. Therefore, nanomedicine that combines cuproptosis with STING activation is a novel strategy for tumor immunotherapy.