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Drug resistance presents a significant challenge in cancer treatment. By far, there is no effective method to solve this issue. Therapeutic cancer vaccine, which uses tumor antigens, e.g. neoantigens, to activate the hosts' immune system to eliminate tumor cells, may be effective for overcoming tumor resistance. So, it is hypothesized that resistant tumors may have much more abundant tumor mutations in comparison to naive tumors, and the corresponding vaccine may overcome drug resistance. The proteomics data confirmes that cell lysates from resistant tumors to gemcitabine (GEM), a model drug, contain abundant tumor‐associated antigens, tumor‐specific antigens, damage‐associated molecular patterns, and neoantigens, which can activate immune responses. Herein, to enhance antigen presentation, a mesoporous silicon nanovaccine is developed, which is loaded with antigens from GEM treated GEM‐resistant triple‐negative breast cancer 4T1 cells. When mice bearing GEM‐resistant tumors are vaccinated, the nanovaccine displays efficacy against GEM‐resistant tumors. Moreover, when combined with immunotherapy, the efficacy of the developed nanovaccine on GEM‐resistant tumors are further improved by increasing intratumoral T‐cell infiltrations. The work presents a new strategy for overcoming drug resistance using cancer nanovaccine, which broadens clinical application prospects. [ABSTRACT FROM AUTHOR]

Background: Programmed cell death 1 receptor (PD-1) inhibition as monotherapy followed by Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibition in case of progression or as upfront double co-inhibition has drastically improved the survival outcomes of metastatic melanoma. Still, many patients develop primary or acquired resistance to both agents, relapse soon, and survive less. For these patients, the therapeutic options are very limited, and for many years, conventional chemotherapy (CC) was the standard of care. Recently, the phase II LEAP-004 trial supported that pembrolizumab/lenvatinib could potentially overcome anti-PD-1/anti-CTLA-4 immunotherapy refractoriness. Materials and methods: In the absence of any prospective comparative study and to evaluate in a real-world context the clinical benefit of re-administering a PD-1 inhibitor (pembrolizumab 200 mg i.v. every 3 weeks, Q3W) with a multi-kinase inhibitor (lenvatinib, but at a reduced dose 10 mg p.o. daily due to its known toxicity) in this frail population of unmet need, we conducted here a retrospective comparison of LEAP-004-proposed combination with CC (carboplatin 4 AUC and dacarbazine 850 mg/m2 i.v. Q3W) in melanoma patients who relapsed to both checkpoint inhibitors, either in combinatorial or in sequential setting, between July 2022 and January 2024. Baseline demographics, disease characteristics, and treatment outcomes (objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)) were recorded. Survival analyses were performed using the Kaplan-Meier method. All patients were also considered for safety analysis. Results: A total of 84 patients were included in the effectiveness and safety analysis (pembrolizumab/lenvatinib, n=39 and CC, n=45). The median age was 67 (45-87) years and 64 (34-87) years, and men were 33.3% and 46.7%, respectively. The distribution of their metastatic sites was comparable, including 12.8% and 20% with brain involvement. Most patients had a good PS<2 (69.9% and 56.5%), increased lactate dehydrogenase (LDH) (71.8% and 84.4%), BRAF-wild status (82.1% and 84.8%), and received ≥2 previous systemic therapies (61.5% and 53.3%). The median follow-up was 18 months. The ORR was 23.1% and 11.1% (p<0.0001), the median PFS was 4.8 months and 3.8 months [HR (95%CI), 0.57 (0.36-0.92); p=0.017], and the median OS was 14.2 months and 7.8 months [HR (95%CI), 0.39 (0.22-0.69), p=0.0009] in pembrolizumab/lenvatinib and CC arms, respectively. Grade 3-5 treatment-related adverse events were documented in 48.7% (pembrolizumab/lenvatinib) and 75.6% (CC) of patients (p=0.034), which led to treatment discontinuation in 10.3% and 17.8% of cases, respectively. Conclusions: This is the first comparative study in patients with metastatic melanoma refractory to PD-1/CTLA-4 inhibition and showed significantly longer outcomes in cases treated with pembrolizumab/lenvatinib versus CC. [ABSTRACT FROM AUTHOR]

Vaccine‐based therapeutics for cancers face several challenges including lack of immunogenicity and tumor escape pathways for single antigen targets. It has been reported that radiotherapy has an in situ vaccine effect that provides tumor antigens following irradiation, helping to activate antigen‐presenting cells (APCs). Herein, a new vaccine approach is developed by combining genetically engineered irradiated tumor cell debris (RTD) and hyaluronic acid (HA), termed HA@RTD. A cancer cell line is developed that overexpresses granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). A hydrogel was developed by covalent conjugation of HA with RTD proteins that acted as a potent vaccine system, the effects which were probed with T cell receptor sequencing. The engineered vaccine activated antitumor immunity responses and prevented tumor growth in mice even with a single immunization. HA@RTD vaccine efficacy was also assessed in therapeutic settings with established tumors and in combination with immune checkpoint blockade. [ABSTRACT FROM AUTHOR]

Background Currently, treatment options for patients with advanced melanoma who experience failed immunotherapy or targeted therapy are lacking. Recent studies suggest the antitumor activity of combined pembrolizumab and lenvatinib in patients with advanced melanoma progressing on immunotherapy. Herein, we report the clinical outcomes of combined lenvatinib and a programmed cell death protein-1 inhibitor (PD-1) in this population. Materials and Methods This French multicenter real-world study was conducted between September 2020 and July 2023. The primary endpoint was the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumours (version 1.1). Secondary variables were treatment-related adverse events (TRAEs), progression-free survival (PFS), overall survival (OS), and duration of response (DOR). Results Of the 67 patients included (median age, 69 years; median follow-up, 5.0 months), 85% had stage IV-M1c or M1d disease. The overall ORR was 28.4% (95% CI, 18%-41%), including 3 complete (4.5%) and 16 partial (23.9%) responses. Median DOR was 3.1 (interquartile range, 1.3-4.3) months. Median PFS and OS were 3.1 (95% CI, 2.5-3.7) and 9.8 (95% CI, 5.6-13.9) months, respectively. Grades 3-5 TRAEs occurred in 16 (24%) patients; common TRAEs were fatigue (43.3%), nausea/vomiting (26.8%), diarrhea (20.9%), and hypertension (20.9%). No treatment-related deaths occurred. Conclusion Our real-world study demonstrates an interesting response rate and acceptable safety profile in a population with poor prognostic factors. Our data support this treatment option for refractory melanoma, as it is not approved by the Food and Drug Administration or European Medicines Agency, and highlight the need for new strategies. [ABSTRACT FROM AUTHOR]

Melanoma is the most aggressive and deadly form of skin cancer, and its incidence has been steadily increasing over the past few decades, particularly in the Caucasian population. Immune checkpoint inhibitors (ICI), anti-PD-1 monotherapy or in combination with anti-CTLA-4, and more recently, anti-PD-1 plus anti-LAG-3 have changed the clinical evolution of this disease. However, a significant percentage of patients do not benefit from these therapies. Therefore, to improve patient selection, it is imperative to look for novel biomarkers. Immune subsets, particularly the quantification of lymphocyte T populations, could contribute to the identification of ICI responders. The main purpose of this review is to thoroughly examine significant published data on the potential role of lymphocyte T subset distribution in peripheral blood (PB) or intratumorally as prognostic and predictive of response biomarkers in advanced melanoma patients treated with ICI regardless of BRAFV600 mutational status. [ABSTRACT FROM AUTHOR]

Abstract Human epidermal growth factor receptor 2 (HER2) expression is one of the most important pathological characteristics of gastric cancer. The positive rate of HER2 expression in patients with gastric cancer is approximately 20%. The phase III Keynote-811 study revealed that anti-HER2 and anti-PD-1 therapy combined with chemotherapy could significantly improve the objective response rate as first-line treatment in patients with HER2-positive advanced gastric cancer. In the present study, we aimed to evaluate the efficacy of combination therapy with trastuzumab and PD-1 inhibitors in patients with advanced HER2-positive gastric cancer in a real-world setting. Seventy-two HER2-positive gastric cancer patients from three hospitals in China were retrospectively reviewed. These patients were treated with trastuzumab plus one anti-PD-1 agent with or without chemotherapy. The overall response rate, progression-free survival and overall survival were assessed according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). From January 2018 to October 2021, 72 patients with HER2-positive gastric cancer received trastuzumab and a PD-1 inhibitor with or without chemotherapy as neoadjuvant chemotherapy, first-line therapy, second-line therapy or salvage therapy. The ORR was 54.2% for all patients and 79.4% for previously untreated patients. The median PFS and median OS were 10 months (95% CI: 8–13 months) and 26.1 months (95% CI: 18.5-NA months), respectively, for all patients. Grade 3 adverse effects occurred in approximately 25% of patients. Immune-related adverse effects occurred in approximately 12.5% of patients. Trastuzumab and PD-1 inhibitor combination therapy with or without chemotherapy achieved satisfactory survival outcomes in patients with HER2-positive gastric cancer with acceptable safety.

Abstract Objective This study aimed to investigate the critical role of MDSCs in CRC immune suppression, focusing on the CSF1R and JAK/STAT3 signaling axis. Additionally, it assessed the therapeutic efficacy of LNCs@CSF1R siRNA and anti-PD-1 in combination. Methods Single-cell transcriptome sequencing data from CRC and adjacent normal tissues identified MDSC-related differentially expressed genes. RNA-seq analysis comprehensively profiled MDSC gene expression in murine CRC tumors. LNCs@CSF1R siRNA nanocarriers effectively targeted and inhibited CSF1R. Flow cytometry quantified changes in MDSC surface markers post-CSF1R inhibition. RNA-seq and pathway enrichment analyses revealed the impact of CSF1R on MDSC metabolism and signaling. The effect of CSF1R inhibition on the JAK/STAT3 signaling axis was validated using Colivelin and metabolic assessments. Glucose and fatty acid uptake were measured via fluorescence-based flow cytometry. The efficacy of LNCs@CSF1R siRNA and anti-PD-1, alone and in combination, was evaluated in a murine CRC model with extensive tumor section analyses. Results CSF1R played a significant role in MDSC-mediated immune suppression. LNCs@CSF1R siRNA nanocarriers effectively targeted MDSCs and inhibited CSF1R. CSF1R regulated MDSC fatty acid metabolism and immune suppression through the JAK/STAT3 signaling axis. Inhibition of CSF1R reduced STAT3 activation and target gene expression, which was rescued by Colivelin. Combined treatment with LNCs@CSF1R siRNA and anti-PD-1 significantly slowed tumor growth and reduced MDSC abundance within CRC tumors. Conclusion CSF1R via the JAK/STAT3 axis critically regulates MDSCs, particularly in fatty acid metabolism and immune suppression. Combined therapy with LNCs@CSF1R siRNA and anti-PD-1 enhances therapeutic efficacy in a murine CRC model, providing a strong foundation for future clinical applications.

Abstract Background Photodynamic therapy (PDT) is an antitumor therapy and has traditionally been regarded as a localized therapy in itself. However, recent reports have shown that it not only exerts a direct cytotoxic effect on cancer cells but also enhances body's tumor immunity. We hypothesized that the immunological response induced by PDT could potentially enhance the efficacy of programmed death‐1 (PD‐1) / programmed death‐ligand 1 (PD‐L1) blockade. Methods The cytotoxic effects of PDT on colon 26 cells were investigated in vitro using the WST assay. We investigated whether the antitumor effect of anti‐PD‐1 antibodies could be amplified by the addition of PDT. We performed combination therapy by randomly allocating tumor‐bearing mice to four treatment groups: control, anti‐PD‐1 antibodies, PDT, and a combination of anti‐PD‐1 antibodies and PDT. To analyze the tumor microenvironment after treatment, the tumors were resected and pathologically evaluated. Results The viability rate of colon 26 cells decreased proportionally with the laser dose. In vivo experiments for combined PDT and anti‐PD‐1 antibody treatment, combination therapy showed an enhanced antitumor effect compared with the control. Immunohistochemical findings of the tumor microenvironment 10 days after PDT indicated that the number of CD8+ cells, the area of Iba‐1+ cells and the area expressing PD‐L1 were significantly higher in tumors treated with combination therapy than in tumors treated with anti‐PD‐1 antibody alone, PDT alone, or the control. Conclusions PDT increased immune cell infiltration into the tumor microenvironment. The immunological response induced by PDT may enhance the efficacy of PD‐1/PD‐L1 blockade.

Introduction: The prognosis of relapsed/refractory acute myeloid leukemia (r/ rAML) is dismal, and allogeneic hematopoietic stem cell transplant (allo-HSCT) is a potential cure. Combining anti-PD-1, hypomethylating agent (HMA), and CAG (cytarabine, aclarubicin/idarubicin, granulocyte colony-stimulating factor) regimen has showed primary efficacy in r/rAML. However, pre-transplant exposure to anti-PD-1 may lead to severe graft-versus-host disease (GVHD). This preliminary study aimed to evaluate the safety and efficacy of allo-HSCT in r/ rAML patients receiving the anti-PD-1+HMA+CAG regimen. Methods: Fifteen r/rAML patients (12 related haploidentical donors [HIDs], 2 matched siblings, 1 unrelated donor) received this regimen and subsequent peripheral blood HSCT. Results: Four patients with HIDs received a GVHD prophylaxis regimen consisted of Anti-thymocyte globulin and a reduced-dose of post-transplant cyclophosphamide. The median follow-up was 20.9 months (range, 1.2-34.2). The cumulative incidences of acute GVHD grade 2-4 and grade 3-4 were 40% and 13.3%, respectively. The 2-year incidence of moderate-to-severe chronic GVHD, nonrelapse mortality, and relapse were 10%, 22.3%, and 22.5%, respectively. The 2-year overall survival and GVHD-free/relapse-free survival rates were 54% and 48.6%, respectively. No death or relapse was observed in the PTCy group. Conclusion: The anti-PD-1+HMA+CAG regimen bridging to allo-HSCT for r/r AML was tolerable with promising efficacy. GVHD prophylaxis with PTCy for HIDHSCT showed preliminary survival advantage. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of death worldwide. surgery, transarterial chemoembolization (TACE), systemic therapy, local ablation therapy, radiotherapy, and targeted drug therapy with agents such as sorafenib. However, the tumor microenvironment of liver cancer has a strong immunosuppressive effect. Therefore, new treatments for liver cancer are still necessary. Immune checkpoint molecules, such as programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4), along with high levels of immunosuppressive cytokines, induce T cell inhibition and are key mechanisms of immune escape in HCC. Recently, immunotherapy based on immune checkpoint inhibitors (ICIs) as monotherapy or in combination with tyrosine kinase inhibitors, anti-angiogenesis drugs, chemotherapy agents, and topical therapies has offered great promise in the treatment of liver cancer. In this review, we discuss the latest advances in ICIs combined with targeted drugs (targeted-immune combination) and other targeted-immune combination regimens for the treatment of patients with advanced HCC (aHCC) or unresectable HCC (uHCC), and provide an outlook on future prospects. The literature reviewed spans the last five years and includes studies identified using keywords such as "hepatocellular carcinoma," "immune checkpoint inhibitors," "targeted therapy," "combination therapy," and "immunotherapy". [ABSTRACT FROM AUTHOR]

Background: Stage III surgically resected melanoma is a disease at high risk of recurrence. Immune checkpoint inhibitors (ICIs) and the target therapy with BRAF and MEK inhibitors significantly changed the outcome of patients with metastatic melanoma and several studies have also shown their benefit in the adjuvant setting for the delay of recurrence in stage III melanoma patients. Hyperprogression disease was observed as a possible adverse response to immunotherapy in the metastatic setting, suggesting that some patients could face additional risk of progression with ICIs, although no consensus was found for the correct definition of this event. Case presentation: We describe here two cases of rapid multiorgan metastatization during adjuvant immunotherapy in patients with stage III resected melanoma. Even though it would be not accurate to define this syndrome as hyperprogression because of apparent absence of the initial disease in the adjuvant setting, we observed in these two cases the same very rapid progression after first administration of adjuvant ICIs that resulted in death of patients within two months from the starting of treatment. Both patients had NRAS mutated melanoma. Conclusion: There is an urgent need for a better understanding of the causes of these fatal outcomes and for the identification of biomarkers that would allow to select the patients before offering theman adjuvant treatment, reducing the risk of hyperprogression. Fromthese cases, we suggest that it could be useful a particular attention in proposing ICI adjuvant treatment based on the molecular profile. [ABSTRACT FROM AUTHOR]

Thymic carcinoma (TC) is an uncommon type of thymic epithelial tumors. Patients with relapsed or refractory TCs have a poor prognosis. Immune checkpoint inhibitor monotherapy can be applied as a second-line treatment for such cases. This study reported a TC patient who did not respond to conventional chemotherapy and radiotherapy but achieved prolonged partial remission lasting 17 months following the third-line treatment with antiprogrammed cell death-1 inhibitor sintilimab. This patient did not experience any serious side effects associated with sintilimab treatment. The above results demonstrated that sintilimab could be a feasible therapeutic option for refractory TC patients. [ABSTRACT FROM AUTHOR]

Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin–paclitaxel compared with placebo plus carboplatin–paclitaxel in patients with primary advanced or recurrent endometrial cancer (EC). At the first interim analysis, the trial met one of its dual primary endpoints with statistically significant progression-free survival benefits in the mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis. RUBY is a phase III, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent EC who were randomly assigned (1 : 1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin–paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual primary endpoint. A total of 494 patients were randomized (245 in the dostarlimab arm; 249 in the placebo arm). In the overall population, with 51% maturity, RUBY met the dual primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death [hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.54 - 0.89, P = 0.0020] in patients treated with dostarlimab plus carboplatin–paclitaxel versus carboplatin–paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32, 95% CI 0.17 - 0.63, nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair-proficient/microsatellite stable population (HR = 0.79, 95% CI 0.60 - 1.04, nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin–paclitaxel was consistent with the first interim analysis. Dostarlimab in combination with carboplatin–paclitaxel demonstrated a statistically significant and clinically meaningful OS benefit in the overall population of patients with primary advanced or recurrent EC while demonstrating an acceptable safety profile. • RUBY compared dostarlimab + chemotherapy to chemotherapy alone in patients with primary advanced/recurrent EC. • RUBY showed statistically significant and clinically relevant improvements in OS with dostarlimab + chemotherapy. • These are clinically important results for patients with primary advanced/recurrent EC. • This represents a new standard of care for primary advanced/recurrent EC. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the critical role of MDSCs in CRC immune suppression, focusing on the CSF1R and JAK/STAT3 signaling axis. Additionally, it assessed the therapeutic efficacy of LNCs@CSF1R siRNA and anti-PD-1 in combination. Methods: Single-cell transcriptome sequencing data from CRC and adjacent normal tissues identified MDSC-related differentially expressed genes. RNA-seq analysis comprehensively profiled MDSC gene expression in murine CRC tumors. LNCs@CSF1R siRNA nanocarriers effectively targeted and inhibited CSF1R. Flow cytometry quantified changes in MDSC surface markers post-CSF1R inhibition. RNA-seq and pathway enrichment analyses revealed the impact of CSF1R on MDSC metabolism and signaling. The effect of CSF1R inhibition on the JAK/STAT3 signaling axis was validated using Colivelin and metabolic assessments. Glucose and fatty acid uptake were measured via fluorescence-based flow cytometry. The efficacy of LNCs@CSF1R siRNA and anti-PD-1, alone and in combination, was evaluated in a murine CRC model with extensive tumor section analyses. Results: CSF1R played a significant role in MDSC-mediated immune suppression. LNCs@CSF1R siRNA nanocarriers effectively targeted MDSCs and inhibited CSF1R. CSF1R regulated MDSC fatty acid metabolism and immune suppression through the JAK/STAT3 signaling axis. Inhibition of CSF1R reduced STAT3 activation and target gene expression, which was rescued by Colivelin. Combined treatment with LNCs@CSF1R siRNA and anti-PD-1 significantly slowed tumor growth and reduced MDSC abundance within CRC tumors. Conclusion: CSF1R via the JAK/STAT3 axis critically regulates MDSCs, particularly in fatty acid metabolism and immune suppression. Combined therapy with LNCs@CSF1R siRNA and anti-PD-1 enhances therapeutic efficacy in a murine CRC model, providing a strong foundation for future clinical applications. [ABSTRACT FROM AUTHOR]

Immune checkpoint therapies (ICT) improve overall survival of patients with cancer but may cause immune-related adverse events (irAEs) such as myocarditis. Cytotoxic T lymphocyte-associated antigen 4 immunoglobulin fusion protein (CTLA-4 Ig), an inhibitor of T cell costimulation through CD28, reverses irAEs in animal models. However, concerns exist about potentially compromising antitumor response of ICT. In mouse tumor models, we administered CTLA-4 Ig 1) concomitantly with ICT or 2) after ICT completion. Concomitant treatment reduced antitumor efficacy, while post-ICT administration improved efficacy without affecting frequency and function of CD8 T cells. The improved response was independent of the ICT used, whether CTLA-4 or PD-1 blockade. The frequency of Tregs was significantly decreased with CTLA-4 Ig. The resulting increased CD8/Treg ratio potentially underlies the enhanced efficacy of ICT followed by CTLA-4 Ig. This paradoxical mechanism shows that a CTLA-4 Ig regimen shown to reduce irAE severity does not compromise antitumor efficacy. [ABSTRACT FROM AUTHOR]

In this paper, a mathematical ordinary differential tumor-immune model is proposed based on an immune checkpoint inhibitor, which is an innovative method for tumor immunotherapies. Two important factors in tumor-immune response are the programmed cell death protein 1 (PD-1) and its ligand PD-L1. The model consists of three populations: tumor cells, activated T cells and anti-PD-1. By analyzing the dynamics of the model, it is found that there is always a unique tumor-free equilibrium and at most two tumor interior equilibria. The nonexistence of nontrivial positive periodic orbits is established by using the new Dulac function, and then a global dynamics of the model is obtained. The conclusions of our analysis show that increasing the possibility of T cells killing tumor cells (p), early detection of tumor cells, or the use of PD-1 inhibitors to activate T cells are effective in eliminating tumor cells. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) presents significant mortality risks, underscoring the urgency of timely diagnosis and intervention. Advanced stages of CRC are managed through chemotherapy, targeted therapy, immunotherapy, radiotherapy, and surgery. Immunotherapy, while effective in bolstering the immune system against cancer cells, often carries toxic side effects, including colitis. This study aimed to evaluate the incidence of colitis in patients with metastatic CRC (mCRC) undergoing various immunotherapy treatments. Through a systematic search of Google Scholar and PubMed databases from inception until November 2023, nine relevant studies were identified. Subgroup analyses revealed a higher incidence of colitis, particularly in patients treated with anti-cytotoxic T-lymphocyte-associated molecule-4 (anti-CTLA-4) and combination therapies compared to monotherapy with programmed cell death receptor-1 (PD-1) or programmed cell death ligand receptor-1 (PDL-1) inhibitors. Notably, naive-treated metastatic CRC patients exhibited elevated colitis incidences compared to those previously treated. In conclusion, anti-CTLA-4 and combination therapies, such as nivolumab plus ipilimumab, were associated with increased colitis occurrences in metastatic CRC patients, highlighting the need for vigilant monitoring and management strategies, especially in immunotherapy-naive individuals. [ABSTRACT FROM AUTHOR]

Background: Photodynamic therapy (PDT) is an antitumor therapy and has traditionally been regarded as a localized therapy in itself. However, recent reports have shown that it not only exerts a direct cytotoxic effect on cancer cells but also enhances body's tumor immunity. We hypothesized that the immunological response induced by PDT could potentially enhance the efficacy of programmed death‐1 (PD‐1) / programmed death‐ligand 1 (PD‐L1) blockade. Methods: The cytotoxic effects of PDT on colon 26 cells were investigated in vitro using the WST assay. We investigated whether the antitumor effect of anti‐PD‐1 antibodies could be amplified by the addition of PDT. We performed combination therapy by randomly allocating tumor‐bearing mice to four treatment groups: control, anti‐PD‐1 antibodies, PDT, and a combination of anti‐PD‐1 antibodies and PDT. To analyze the tumor microenvironment after treatment, the tumors were resected and pathologically evaluated. Results: The viability rate of colon 26 cells decreased proportionally with the laser dose. In vivo experiments for combined PDT and anti‐PD‐1 antibody treatment, combination therapy showed an enhanced antitumor effect compared with the control. Immunohistochemical findings of the tumor microenvironment 10 days after PDT indicated that the number of CD8+ cells, the area of Iba‐1+ cells and the area expressing PD‐L1 were significantly higher in tumors treated with combination therapy than in tumors treated with anti‐PD‐1 antibody alone, PDT alone, or the control. Conclusions: PDT increased immune cell infiltration into the tumor microenvironment. The immunological response induced by PDT may enhance the efficacy of PD‐1/PD‐L1 blockade. [ABSTRACT FROM AUTHOR]

Aim: To investigate the efficacy and safety of combining Recombinant Human Endostatin Injection (marketed as Endo) with anti-PD-1 in elderly patients aged 80 and above with non-small cell lung cancer (NSCLC). Methods: Retrospective analysis of 181 patients with NSCLC aged 80 and above treated in the Department of Respiratory and Critical Care Medicine at Chaohu Hospital, affiliated with Anhui Medical University, from June 2019 to January 2024. Patients who received at least one cycle of combined Endo with anti-PD-1 were included based on inclusion criteria. Clinical and pathological data were collected, including complete blood count, liver and kidney function, electrocardiogram, coagulation function, thyroid function, cardiac enzymes, and whole-body imaging. Adverse events were recorded with a final follow-up on January 25, 2024. The primary endpoints were progression-free survival (PFS) and overall survival (OS), with safety as a secondary endpoint. Results: This study involved 14 elderly patients with NSCLC aged over 80. Median progression-free survival (mPFS) was 102 days, and median overall survival (mOS) was 311 days. Subgroup analyses based on treatment cycles showed a nonsignificant 441-day mPFS increase in the long-term group (≥6 cycles, 5 patients) compared to the short-term group (<6 cycles, 9 patients). However, the mOS in the long-term group significantly exceeded the short-term group by 141 days, with statistical significance (P=0.048). Further categorization revealed a 204-day shorter mPFS in the monotherapy maintenance group (Endo or Immunol) compared to the combination maintenance group (Endo combined with Immunol, 441 days). The mOS of the monotherapy maintenance group was longer (686 days) than the combination maintenance group (311 days), but no statistical significance (P= 0.710, 0.920). Throughout the treatment, 77 adverse events were recorded, mainly grade 1–2, with no new treatment-related reactions occurred. Overall, the safety of Endo combined with anti-PD-1 was considered good and manageable Conclusion: The combination of Endo and anti-PD-1 could be an effective treatment choice for patients with NSCLC aged 80 and above. [ABSTRACT FROM AUTHOR]

The current research investigated the use of gelatin nanoparticles (GNPs) for enhancing the cytotoxic effects of nivolumab, an immune checkpoint inhibitor. The unique feature of GNPs is their biocompatibility and functionalization potential, improving the delivery and the efficacy of immunotherapeutic drugs with fewer side effects compared to traditional treatments. This exploration of GNPs represents an innovative direction in the advancement of nanomedicine in oncology. Nivolumab-loaded GNPs were prepared and characterized. The optimum formulation had a particle size of 191.9 ± 0.67 nm, a polydispersity index of 0.027 ± 0.02, and drug entrapment of 54.67 ± 3.51%. A co-culture experiment involving A549 target cells and effector Jurkat cells treated with free nivolumab solution, and nivolumab-loaded GNPs, demonstrated that the latter had significant improvements in inhibition rate by scoring 87.88 ± 2.47% for drug-loaded GNPs against 60.53 ± 3.96% for the free nivolumab solution. The nivolumab-loaded GNPs had a lower IC50 value, of 0.41 ± 0.01 µM, compared to free nivolumab solution (1.22 ± 0.37 µM) at 72 h. The results indicate that administering nivolumab-loaded GNPs augmented the cytotoxicity against A549 cells by enhancing effector Jurkat cell activity compared to nivolumab solution treatment. [ABSTRACT FROM AUTHOR]

Abstract Vaccine‐based therapeutics for cancers face several challenges including lack of immunogenicity and tumor escape pathways for single antigen targets. It has been reported that radiotherapy has an in situ vaccine effect that provides tumor antigens following irradiation, helping to activate antigen‐presenting cells (APCs). Herein, a new vaccine approach is developed by combining genetically engineered irradiated tumor cell debris (RTD) and hyaluronic acid (HA), termed HA@RTD. A cancer cell line is developed that overexpresses granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). A hydrogel was developed by covalent conjugation of HA with RTD proteins that acted as a potent vaccine system, the effects which were probed with T cell receptor sequencing. The engineered vaccine activated antitumor immunity responses and prevented tumor growth in mice even with a single immunization. HA@RTD vaccine efficacy was also assessed in therapeutic settings with established tumors and in combination with immune checkpoint blockade.

BackgroundProgrammed cell death 1 receptor (PD-1) inhibition as monotherapy followed by Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibition in case of progression or as upfront double co-inhibition has drastically improved the survival outcomes of metastatic melanoma. Still, many patients develop primary or acquired resistance to both agents, relapse soon, and survive less. For these patients, the therapeutic options are very limited, and for many years, conventional chemotherapy (CC) was the standard of care. Recently, the phase II LEAP-004 trial supported that pembrolizumab/lenvatinib could potentially overcome anti-PD-1/anti-CTLA-4 immunotherapy refractoriness.Materials and methodsIn the absence of any prospective comparative study and to evaluate in a real-world context the clinical benefit of re-administering a PD-1 inhibitor (pembrolizumab 200 mg i.v. every 3 weeks, Q3W) with a multi-kinase inhibitor (lenvatinib, but at a reduced dose 10 mg p.o. daily due to its known toxicity) in this frail population of unmet need, we conducted here a retrospective comparison of LEAP-004-proposed combination with CC (carboplatin 4 AUC and dacarbazine 850 mg/m2 i.v. Q3W) in melanoma patients who relapsed to both checkpoint inhibitors, either in combinatorial or in sequential setting, between July 2022 and January 2024. Baseline demographics, disease characteristics, and treatment outcomes (objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)) were recorded. Survival analyses were performed using the Kaplan–Meier method. All patients were also considered for safety analysis.ResultsA total of 84 patients were included in the effectiveness and safety analysis (pembrolizumab/lenvatinib, n=39 and CC, n=45). The median age was 67 (45–87) years and 64 (34–87) years, and men were 33.3% and 46.7%, respectively. The distribution of their metastatic sites was comparable, including 12.8% and 20% with brain involvement. Most patients had a good PS

Introduction: Anti-PD-1 immunotherapies enhance T-cell responses against tumor cells by blocking the interaction between PD-1 and its ligand, PD-L1. While these therapies offer significant benefits in treating various malignancies, they can also lead to several immune-related adverse events (irAEs), most notably manifesting in the skin. Lichenoid reactions, eczema, and vitiligo are the three most prevalent forms of cutaneous irAE. Case Presentation: Here, we report a rare case of a pityriasis lichenoides et varioliformis acuta (PLEVA) that developed during pembrolizumab treatment for invasive bladder cancer. A 53-year-old man, receiving pembrolizumab for invasive bladder cancer, developed erythematous papules on his legs after his 11th infusion. The skin lesions gradually spread to his entire trunk and extremities. A punch biopsy revealed several apoptotic keratinocytes and spongiosis, along with perivascular and lichenoid lymphocytic infiltration with vacuolar alteration. Immunohistochemistry showed infiltration of CD4+ and CD8+ T cells in both the epidermis and dermis. Granzyme B-positive inflammatory cells were also slightly present. From these results, he was diagnosed with PLEVA, which might be classified as a lichenoid eruption, especially based on the histological findings. Conclusion: We hypothesize that the anti-PD-1 antibody might lead to epidermal necrosis by amplifying the expression of cytolytic molecules such as granzyme B in CD8+ T cells.

Cancer immunotherapy is an attractive strategy because it stimulates immune cells to target malignant cells by regulating the intrinsic activity of the immune system. However, due to lacking many immunologic markers, it remains difficult to treat glioma, a representative "cold" tumor. Herein, to wake the "hot" tumor immunity of glioma, Porphyromonas gingivalis (Pg) is customized with a coating to create an immunogenic tumor microenvironment and further prove the effect in combination with the immune checkpoint agent anti‐PD‐1, exhibiting elevated therapeutic efficacy. This is accomplished not by enhancing the delivery of PD‐1 blockade to enhance the effect of immunotherapy, but by introducing bacterial photothermal therapy to promote greater involvement of M1 cells in the immune response. After reaching glioma, the bacteria further target glioma cells and M2 phenotype macrophages selectively, enabling precise photothermal conversion for lysing tumor cells and M2 phenotype macrophages, which thereby enhances the positive feedback loop of cancer cells‐M1 macrophages‐T cells. Collectively, the bacteria synergized with PD‐1 blockade strategy may be the key to overcoming the immunosuppressive glioma microenvironment and improving the outcome of immunotherapy toward glioma. [ABSTRACT FROM AUTHOR]

Pregnancy-related gastric cancer is characterized by a refractory nature and poor prognosis; few gastric cancer cases during pregnancy achieved acceptable outcomes by using anti-PD-1 as a monotherapy. A 32-year-old pregnant female patient was admitted to the emergency department of the obstetrics and gynecology department and eventually diagnosed with gastric cancer. Radical surgery for gastric cancer was conducted after the termination of pregnancy. At 1-year postoperative follow-up, tumor recurrence was revealed. This patient has achieved a decrease in tumor burden after receiving anti-PD-1 as a monotherapy. This case documents tumor response to PD-1 monotherapy in pregnancy-related gastric cancer and highlights the potential for future use in specific clinical scenarios. [ABSTRACT FROM AUTHOR]

Serving as a pivotal immunotherapeutic approach against tumors, anti-PD-1/PDL1 therapy amplifies the immune cells' capability to eliminate tumors by obstructing the interaction between PD-1 and PD-L1. Research indicates that immune checkpoint inhibitors are effective when a patient's gut harbors unique beneficial bacteria. As such, it has further been revealed that the gut microbiome influences tumor development and the efficacy of cancer treatments, with metabolites produced by the microbiome playing a regulatory role in the antitumor efficacy of Immune checkpoint inhibitors(ICBs). This article discusses the mechanism of anti-PD-1 immunotherapy and the role of intestinal flora in immune regulation. This review focuses on the modulation of intestinal flora in the context of PD-1 immunotherapy, which may offer a new avenue for combination therapy in tumor immunotherapy. [ABSTRACT FROM AUTHOR]

The remarkable efficacy of cancer immunotherapy has been established in several tumor types. Of the various immunotherapies, PD-1/PD-L1 inhibitors are most extensively used in the treatment of many cancers in clinics. These inhibitors restore the suppressed antitumor immune response and inhibit tumor progression by blocking the PD-1/PD-L1 signaling. However, the low response rate is a major limitation in the clinical application of PD-1/PD-L1 inhibitors. Therefore, combination strategies that enhance the response rate are the need of the hour. In this investigation, PT-100 (also referred to as Talabostat, Val-boroPro, and BXCL701), an orally administered and nonselective dipeptidyl peptidase inhibitor, not only augmented the effectiveness of anti-PD-1 therapy but also significantly improved T immune cell infiltration and reversed the immunosuppressive tumor microenvironment. The combination of PT-100 and anti-PD-1 antibody increased the number of CD4+ and CD8+ T cells. Moreover, the mRNA expression of T cell-associated molecules was elevated in the tumor microenvironment. The results further suggested that PT-100 dramatically reduced the ratio of tumor-associated macrophages. These findings provide a promising combination strategy for immunotherapy in lung cancer. [ABSTRACT FROM AUTHOR]

As most patients with metastatic urothelial carcinoma will be treated with immune checkpoint inhibitors (ICI), familiarity with their toxicities is fundamental to clinical management. Our single-institution experience demonstrated a high rate of immune-related adverse events (irAEs) in patients undergoing ICI rechallenge following an initial irAE, while a durable clinical benefit off treatment was seen in those requiring permanent ICI discontinuation. Introduction: As most patients with metastatic urothelial carcinoma (mUC) will be treated with immune checkpoint inhibitors (ICI), familiarity with their associated immune-related adverse events (irAEs) is cr itical. We descr ibe the characteristics and outcomes of ICI-treated mUC patients who experienced irAEs requiring treatment interruption (TI) or permanent discontinuation. Materials and Methods: ICI-treated mUC patients who developed grade ≥2 irAEs were reviewed. Clinical-, treatment-, and toxicity-related data were evaluated. Toxicity was graded per common terminology for categorization of adverse events v5.0. Cohorts were divided into patients who underwent ICI rechallenge and those who required permanent ICI discontinuation. Time to treatment interruption (TTI), time to next treatment, and duration of clinical benefit were assessed descriptively. Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier methodology. Results: Of 200 ICI-treated mUC patients at Cleveland Clinic between October 2015 and October 2020, 16 (8%) experienced ≥ grade 2 irAEs necessitating TI. Median TTI among all patients was 6.5 months (range, 1-19). Eleven patients (69%) required corticosteroids. ICI were held and rechallenged in 10 patients (62%) and permanently discontinued in 6 patients (38%). Of the 10 ICI-rechallenged patients, 7 (70%) experienced another irAE upon rechallenge with median time to irAE recurrence of 2.9 months (range, 0.1-10.9); 3 (30%) eventually discontinued ICI due to recrudescent irAEs. Four (40%) of the 10 ICI-rechallenged patients received subsequent therapy. Five (83%) of the 6 patients who permanently discontinued ICI demonstrated durable clinical benefit off therapy with median duration of clinical benefit 17.7 months (range, 14.2-55.2). Two-year OS was 40% (95% CI: 19%-86%) in the ICI rechallenge cohort and 67% (95% CI: 38%-100%) in the permanent discontinuation cohort. Conclusion: ICI-treated mUC patients who developed irAEs requiring TI had a high rate of subsequent irAEs upon ICI rechallenge. Importantly, patients who permanently discontinued ICI due to irAE demonstrated durable clinical benefit off treatment. [ABSTRACT FROM AUTHOR]

Introduction: Expression of PD-L1 on cancer cells is the only validated predictive factor for immunotherapy in NSCLC (Non-Small Cell Lung Cancer) patients. However, on this basis, it is difficult to predict the occurrence of resistance to immune checkpoint inhibitors (ICIs). MicroRNAs are widely studied as biomarkers of cancers. Our study was designed to determine whether microRNAs can be sensitive predictive factors in the qualification of NSCLC patients to first-line immunotherapy or chemoimmunotherapy. Material and methods: The two-stage research on validation group (n=20) and study group (n=35) of patients with advanced NSCLC was conducted. Analysis of microRNAs expression by qPCR in plasma collected prior to the start of immunotherapy (pembrolizumab) or chemoimmunotherapy (combination of pembrolizumab with chemotherapy) was made. Broad-spectrum analysis of microRNAs expression was used in the studied group. Three microRNAs selected in that group as important for the effectiveness of ICIs were then examined in the validation group. Results: In the studied group, significantly higher expression of miRNA-126-3p, miR-144-3p and miR-146-5p was observed in patients with long PFS compared to those with short PFS. In the validation group, low miRNA-126 expression indicated lower median progression-free survival and overall survival (2.3 vs. 5.0 months and 5.2 vs 11.2, respectively). These patients had a significantly higher risk of progression (HR= 2.92, 95% CI: 1.01 to 8.40, p=0.04) and death (HR=3.64, 95% CI: 1.22 to 10.84, p=0.02). Conclusion: Our study showed that the expression of miR-126 in blood plasma may be a predictive factor for the effectiveness of first-line immunotherapy or chemoimmunotherapy in advanced NSCLC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of this study was to analyze the safety and effectiveness of ICIs used in 42 pediatric patients with various types of highly advanced malignancies. Good outcomes were achieved in patients with malignant cutaneous melanoma or Hodgkin lymphoma. Age > 14 years and good performance status were favorable prognostic factors. Background/aim: The role of immune checkpoint inhibitors (ICIs; anti-PD1) in the treatment of childhood cancers is still evolving. The aim of this nationwide retrospective study was to assess the safety and effectiveness of ICIs used in a group of 42 patients, with a median age of 13.6 years, with various types of advanced malignancies treated in pediatric oncology centers in Poland between 2015 and 2023. Results: The indications for treatment with anti-PD1 were as follows: Hodgkin lymphoma (11); malignant skin melanoma (9); neuroblastoma (8); and other malignancies (14). At the end of follow-up, complete remission (CR) was observed in 37.7% (15/42) of children and disease stabilization in 9.5% (4/42), with a mean survival 3.6 (95% CI = 2.6–4.6) years. The best survival (OS = 1.0) was observed in the group of patients with Hodgkin lymphoma. For malignant melanoma of the skin, neuroblastoma, and other rare malignancies, the estimated 3-year OS values were, respectively, 0.78, 0.33, and 0.25 (p = 0.002). The best progression-free survival value (0.78) was observed in the group with malignant melanoma. Significantly better effects of immunotherapy were confirmed in patients ≥ 14 years of age and good overall performance ECOG status. Severe adverse events were observed in 30.9% (13/42) patients. [ABSTRACT FROM AUTHOR]

BackgroundStage III surgically resected melanoma is a disease at high risk of recurrence. Immune checkpoint inhibitors (ICIs) and the target therapy with BRAF and MEK inhibitors significantly changed the outcome of patients with metastatic melanoma and several studies have also shown their benefit in the adjuvant setting for the delay of recurrence in stage III melanoma patients. Hyperprogression disease was observed as a possible adverse response to immunotherapy in the metastatic setting, suggesting that some patients could face additional risk of progression with ICIs, although no consensus was found for the correct definition of this event.Case presentationWe describe here two cases of rapid multiorgan metastatization during adjuvant immunotherapy in patients with stage III resected melanoma. Even though it would be not accurate to define this syndrome as hyperprogression because of apparent absence of the initial disease in the adjuvant setting, we observed in these two cases the same very rapid progression after first administration of adjuvant ICIs that resulted in death of patients within two months from the starting of treatment. Both patients had NRAS mutated melanoma.ConclusionThere is an urgent need for a better understanding of the causes of these fatal outcomes and for the identification of biomarkers that would allow to select the patients before offering them an adjuvant treatment, reducing the risk of hyperprogression. From these cases, we suggest that it could be useful a particular attention in proposing ICI adjuvant treatment based on the molecular profile.

BackgroundImmune checkpoint inhibitors (ICI) have improved overall survival in patients with different cancer types. However, treatment efficacy varies between patients depending on several factors. Recent research suggested that antibiotic-induced dysbiosis can impair ICI efficacy. Here we review the impact of antibiotic use in clinical outcome of patients with gastrointestinal cancer treated with ICI.MethodsThis is a systematic review and utilized a thorough search of MEDLINE, Cochrane, Scopus, EB-SCO, Web of Science of studies published till September 2023. The aim of the study is to determine the association between antibiotic use and ICI treatment efficacy in patients with gastrointestinal cancers (GI). We utilized a meta-analysis of the association between the use of antibiotics and overall survival and progression-free survival.ResultsNine studies met the inclusion criteria with a total of 2,214 patients. The most common type of cancers was hepatocellular carcinoma (HCC). The majority of the studies were retrospective, and one was collective of clinical trials. The use of antibiotics was associated with decreased both overall survival [haz-ard ratio (HR) 1.92, 95% confidence interval (CI) 1.41, 2.63] and progression-free survival [HR 1.81, 95% CI 1.29, 2.54].ConclusionThe use of antibiotics may affect clinical outcomes in patients with GI cancers treated with ICI. Further prospective studies are needed to improve the understanding of this phenomenon.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023462172.

Abstract Background Immune checkpoint inhibitors (ICIs) can improve survivals of metastatic triple negative breast cancer (mTNBC); however, we still seek circulating blood biomarkers to predict the efficacy of ICIs. Materials and methods In this study, we analyzed the data of ICIs treated mTNBC collected in Anhui Medical University affiliated hospitals from 2018 to 2023. The counts of lymphocytes, monocytes, platelets, and ratio indexes (NLR, MLR, PLR) in peripheral blood were investigated via the Kaplan-Meier curves and the Cox proportional-hazards model. Results The total of 50 mTNBC patients were treated with ICIs. High level of peripheral lymphocytes and low level of NLR and MLR at baseline and post the first cycle of ICIs play the predictable role of immunotherapies. Lymphocytes counts (HR = 0.280; 95% CI: 0.095–0.823; p = 0.021) and NLR (HR = 1.150; 95% CI: 1.052–1.257; p = 0.002) are significantly correlated with overall survival. High NLR also increases the risk of disease progression (HR = 2.189; 95% CI:1.085–4.414; p = 0.029). When NLR at baseline ≥ 2.75, the hazard of death (HR = 2.575; 95% CI:1.217–5.447; p = 0.013) and disease progression (HR = 2.189; 95% CI: 1.085–4.414; p = 0.029) significantly rise. HER-2 expression and anti-tumor therapy lines are statistically correlated with survivals. Conclusions Before the initiation of ICIs, enriched peripheral lymphocytes and poor neutrophils and NLR contribute to the prediction of survivals.

Simple Summary: Immune-mediated hepatotoxicity (IMH) is a not-so-rare complication of immune checkpoint inhibitors (ICIs) and it is extremely heterogeneous in its clinical presentation and severity. This narrative review aims to report the current knowledge on hepatic immune-related adverse events (irAEs) during immunotherapy from pathogenesis to multidisciplinary management. Immune-mediated hepatotoxicity (IMH) is not-so-rare complication during treatment with immune checkpoint inhibitors (ICIs). This narrative review aims to report the current knowledge on hepatic immune-related adverse events (irAEs) during immunotherapy from pathogenesis to multidisciplinary management. The majority of cases of IMH are asymptomatic and only a few patients may have clinical conditions. The severity of IMH is usually stratified according to Common Terminology for Clinical Adverse Events (CTCAE) criteria, but these scores may overestimate the clinical severity of IMH compared to the Drug-Induced Liver Injury Network (DILIN) scale. The differential diagnosis of IMH is challenging because the elevated liver enzymes can be due to a number of etiologies such as viral infection, autoimmune and metabolic diseases, liver metastases, biliary diseases, and other drugs. The cornerstones of IMH management are represented by withholding or delaying ICI administration and starting immunosuppressive therapy. A multidisciplinary team, including oncologists, hepatologists, internists, and emergency medicine physicians, is essential for the management of IMH. [ABSTRACT FROM AUTHOR]

Simple Summary: While melanoma treatment has advanced and generally offers good results, treatment resistance remains a major source of morbidity and mortality in the patients it afflicts. While advances have been made in its treatment, there continues to be several patients that still have disease progression. The use of fecal microbiota transplantation has been used to augment the gut microbiome, decreasing overall inflammation, offering support in the treatment of other diseases such as C. difficile infection, with good utility. Thus, investigation of its use in other conditions and its ability to help augment medication effects is underway. This manuscript aims to review the use of FMT in advanced melanoma that has demonstrated treatment resistance. While immune checkpoint inhibitors have evolved into the standard of care for advanced melanoma, 40–50% of melanoma cases progress while on therapies. The relationship between bacterium and carcinogenesis is well founded, such as in H. pylori in gastric cancers, and Fusobacterium in colorectal cancers. This interplay between dysbiosis and carcinogenesis questions whether changes in the microbiome could affect treatment. Thus, FMT may find utility in modifying the efficacy of anti-PD-1. This review aims to examine the use of FMT in treatment-resistant melanoma. A literature search was performed using the keywords "fecal microbiota transplant" and "skin cancer". Studies were reviewed for inclusion criteria and quality and in the final stage, and three studies were included. Overall objective responses were reported in 65% of patients who were able to achieve CR, and 45% who achieved PR. Clinical benefit rate of combined CR/PR with stable disease greater or equal to 6 months was 75%. Reported objective responses found durable stable disease lasting 12 months. Overall survival was 7 months, and overall PRS was 3 months. As for the evaluation of safety, many patients reported grade 1–2 FMT related AE. Only following the administration of anti-PD-1 therapy were there a grade 3 or higher AE. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) can improve survivals of metastatic triple negative breast cancer (mTNBC); however, we still seek circulating blood biomarkers to predict the efficacy of ICIs. Materials and methods: In this study, we analyzed the data of ICIs treated mTNBC collected in Anhui Medical University affiliated hospitals from 2018 to 2023. The counts of lymphocytes, monocytes, platelets, and ratio indexes (NLR, MLR, PLR) in peripheral blood were investigated via the Kaplan-Meier curves and the Cox proportional-hazards model. Results: The total of 50 mTNBC patients were treated with ICIs. High level of peripheral lymphocytes and low level of NLR and MLR at baseline and post the first cycle of ICIs play the predictable role of immunotherapies. Lymphocytes counts (HR = 0.280; 95% CI: 0.095–0.823; p = 0.021) and NLR (HR = 1.150; 95% CI: 1.052–1.257; p = 0.002) are significantly correlated with overall survival. High NLR also increases the risk of disease progression (HR = 2.189; 95% CI:1.085–4.414; p = 0.029). When NLR at baseline ≥ 2.75, the hazard of death (HR = 2.575; 95% CI:1.217–5.447; p = 0.013) and disease progression (HR = 2.189; 95% CI: 1.085–4.414; p = 0.029) significantly rise. HER-2 expression and anti-tumor therapy lines are statistically correlated with survivals. Conclusions: Before the initiation of ICIs, enriched peripheral lymphocytes and poor neutrophils and NLR contribute to the prediction of survivals. [ABSTRACT FROM AUTHOR]

Introduction: Anti-PD-1 immunotherapies enhance T-cell responses against tumor cells by blocking the interaction between PD-1 and its ligand, PD-L1. While these therapies offer significant benefits in treating various malignancies, they can also lead to several immune-related adverse events (irAEs), most notably manifesting in the skin. Lichenoid reactions, eczema, and vitiligo are the three most prevalent forms of cutaneous irAE. Case Presentation: Here, we report a rare case of a pityriasis lichenoides et varioliformis acuta (PLEVA) that developed during pembrolizumab treatment for invasive bladder cancer. A 53-year-old man, receiving pembrolizumab for invasive bladder cancer, developed erythematous papules on his legs after his 11th infusion. The skin lesions gradually spread to his entire trunk and extremities. A punch biopsy revealed several apoptotic keratinocytes and spongiosis, along with perivascular and lichenoid lymphocytic infiltration with vacuolar alteration. Immunohistochemistry showed infiltration of CD4+ and CD8+ T cells in both the epidermis and dermis. Granzyme B-positive inflammatory cells were also slightly present. From these results, he was diagnosed with PLEVA, which might be classified as a lichenoid eruption, especially based on the histological findings. Conclusion: We hypothesize that the anti-PD-1 antibody might lead to epidermal necrosis by amplifying the expression of cytolytic molecules such as granzyme B in CD8+ T cells. [ABSTRACT FROM AUTHOR]

Simple Summary: This study examines the role of antibiotic use on the immunotherapeutic response in patients with hepatocellular carcinoma (HCC) treated with an immune checkpoint inhibitor (ICI). HCC is the leading cause of cancer death worldwide. In this work, we examine 59 patients with HCC treated with ICI, 39 patients did not use antibiotics, and 20 patients did use antibiotics concurrent with ICI. We found that patients with Child–Pugh class A advanced HCC who did not take antibiotics during the treatment course had significantly longer overall survival compared to those who did. This work adds to the growing evidence that antibiotic use during the treatment course with ICI might negatively affect survival outcomes. This work along with others suggests the need for a careful prescription of antibiotics to patients with HCC undergoing ICI. Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide with a poor prognosis. Treatment with immune checkpoint inhibitors (ICIs) has improved overall survival in patients with HCC. However, not all patients benefit from the treatment. In this study, 59 patients with HCC were enrolled from two medical centers in Saudi Arabia, with 34% using antibiotics concurrently with their Nivolumab (anti-PD1 blockade). The impact of antibiotic use on the clinical outcomes of patients with HCC undergoing treatment with anti-PD1 blockade was examined. The patients' overall survival (OS) was 5 months (95% CI: 3.2, 6.7) compared to 10 months (95% CI: 0, 22.2) (p = 0.08). Notably, patients with Child–Pugh A cirrhosis receiving anti-PD1 blockade treatment without concurrent antibiotic use showed a significantly longer median OS reaching 22 months (95% CI: 6.5, 37.4) compared to those who were given antibiotics with a median OS of 6 months (95% CI: 2.7, 9.2) (p = 0.02). This difference in overall survival was particularly found in Child–Pugh class A patients receiving anti-PD1 blockade. These findings suggest that antibiotic use may negatively affect survival outcomes in HCC patients undergoing anti-PD1 blockade, potentially due to antibiotic-induced alterations to the gut microbiome impacting the anti-PD1 blockade response. This study suggests the need for careful consideration when prescribing antibiotics to patients with HCC receiving anti-PD1 blockade. [ABSTRACT FROM AUTHOR]

Introduction: Immunotherapy has resulted in pathologic responses in hepatocellular carcinoma (HCC), but the benefits and molecular mechanisms of neoadjuvant immune checkpoint blockade are largely unknown. Methods: In this study, we evaluated the efficacy and safety of preoperative nivolumab (anti-PD-1) in patients with intermediate and locally advanced HCC and determined the molecular markers for predicting treatment response. Results: Between July 2020 and November 2021, 20 treatment-naive HCC patients with intermediate and locally advanced tumors received preoperative nivolumab at 3 mg/kg for 3 cycles prior to surgical resection. Nineteen patients underwent surgical resection on trial. Seven (36.8%) of the 19 patients had major pathologic tumor necrosis (≥60%) in the post-nivolumab resection specimens, with 3 having almost complete (>90%) tumor necrosis. The tumor necrosis was hemorrhagic and often accompanied by increased or dense immune cell infiltrate at the border of the tumors. None of the patients developed major adverse reactions contradicting hepatectomy. RNA-sequencing analysis on both pre-nivolumab tumor biopsies and post-nivolumab resected specimens showed that, in cases with major pathologic necrosis, the proportion of CD8 T cells in the HCC tissues predominantly increased after treatment. Moreover, to investigate noninvasive biomarker for nivolumab response, we evaluated the copy number variation (CNV) using target-panel sequencing on plasma cell-free DNA of the patients and derived a CNV-based anti-PD-1 score. The score correlated with the extent of tumor necrosis and was validated in a Korean patient cohort with anti-PD-1 treatment. Conclusion: Neoadjuvant nivolumab demonstrated promising clinical activity in intermediate and locally advanced HCC patients. We also identified useful noninvasive biomarker predicting responsiveness. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer remains one of the leading killers world-wide. In recent years new drugs to treat cancer that exploit the immune system to attack cancer have been developed called immune checkpoint inhibitors (ICIs). As use of these potent anti-cancer therapeutics have grown, researchers have noticed an unsettling association with use of ICIs and cardiovascular complications known as immune-related adverse events (irAEs). This review discusses how ICIs work as a cancer treatment, how to clinically recognize and manage patients with cardiovascular irAEs, what risk factors may contribute to irAEs, and discusses some of the current theories of mechanisms driving cardiovascular irAEs. Cancer remains a prominent global cause of mortality, second only to cardiovascular disease. The past decades have witnessed substantial advancements in anti-cancer therapies, resulting in improved outcomes. Among these advancements, immunotherapy has emerged as a promising breakthrough, leveraging the immune system to target and eliminate cancer cells. Despite the remarkable potential of immunotherapy, concerns have arisen regarding associations with adverse cardiovascular events. This review examines the complex interplay between immunotherapy and cardiovascular toxicity and provides an overview of immunotherapy mechanisms, clinical perspectives, and potential biomarkers for adverse events, while delving into the intricate immune responses and evasion mechanisms displayed by cancer cells. The focus extends to the role of immune checkpoint inhibitors in cancer therapy, including CTLA-4, PD-1, and PD-L1 targeting antibodies. This review underscores the multifaceted challenges of managing immunotherapy-related cardiovascular toxicity. Risk factors for immune-related adverse events and major adverse cardiac events are explored, encompassing pharmacological, treatment-related, autoimmune, cardiovascular, tumor-related, social, genetic, and immune-related factors. The review also advocates for enhanced medical education and risk assessment tools to identify high-risk patients for preventive measures. Baseline cardiovascular evaluations, potential prophylactic strategies, and monitoring of emerging toxicity symptoms are discussed, along with the potential of adjunct anti-inflammatory therapies. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) antibodies, have initiated a new era in the treatment of malignant melanoma. ICIs can be used in various settings, including first-line, adjuvant, and neo-adjuvant therapy. In the scope of this review, we examined clinical studies utilizing ICIs in the context of treating oral mucosal melanoma, a rare disease, albeit with an extremely poor prognosis, with a specific focus on unraveling the intricate web of resistance mechanisms. The absence of a comprehensive review focusing on ICIs in oral mucosal melanoma is notable. Therefore, this review seeks to address this deficiency by offering a novel and thorough analysis of the current status, potential resistance mechanisms, and future prospects of applying ICIs specifically to oral malignant melanoma. Clarifying and thoroughly understanding these mechanisms will facilitate the advancement of effective therapeutic approaches and enhance the prospects for patients suffering from oral mucosal melanoma. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) are one of the most promising approaches toward advanced melanoma. Here, we aimed to perform a meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy of all studied ICIs. We conducted a comprehensive search to identify the relevant publications (PROSPERO registration ID: CRD42023470649). Then we performed a meta-analysis to evaluate the efficacy of different ICIs for metastatic melanoma. We used Cochrane's tool to assess the quality of studies. The outcome measures were overall survival (OS), progression-free survival (PFS), and recurrence-free survival (RFS). Twenty reports of RCTs entered our systematic review, 18 of which were included in our data analysis. ICIs showed improved survival compared with control group (hazard ratio (HR) = 0.57; 95% CI: 0.43–0.71; P<0.001). Using a meta-regression, we found a significant relation between patients' mean age and their OS (P<0.001, ${{\rm{R}}^2}$ R 2 = 100.00%). Also, our analysis revealed greater HR for CTLA-4 inhibitors than PD-1/PD-L1 inhibitors (HR = 0.71, 95%CI: 0.63–0.79, P<0.001 vs. HR = 0.63, 95%CI: 0.46–0.79, P<0.001). The effect sizes of different types of PD-1/PD-L1 inhibitors were comparable Our results suggest that ICI-based immunotherapy is associated with enhanced OS, PFS, and RFS (P < 0.001) and will assist clinicians in choosing the optimal approach toward treating metastatic melanoma. [ABSTRACT FROM AUTHOR]

Abstract Cancer immunotherapy is an attractive strategy because it stimulates immune cells to target malignant cells by regulating the intrinsic activity of the immune system. However, due to lacking many immunologic markers, it remains difficult to treat glioma, a representative “cold” tumor. Herein, to wake the “hot” tumor immunity of glioma, Porphyromonas gingivalis (Pg) is customized with a coating to create an immunogenic tumor microenvironment and further prove the effect in combination with the immune checkpoint agent anti‐PD‐1, exhibiting elevated therapeutic efficacy. This is accomplished not by enhancing the delivery of PD‐1 blockade to enhance the effect of immunotherapy, but by introducing bacterial photothermal therapy to promote greater involvement of M1 cells in the immune response. After reaching glioma, the bacteria further target glioma cells and M2 phenotype macrophages selectively, enabling precise photothermal conversion for lysing tumor cells and M2 phenotype macrophages, which thereby enhances the positive feedback loop of cancer cells‐M1 macrophages‐T cells. Collectively, the bacteria synergized with PD‐1 blockade strategy may be the key to overcoming the immunosuppressive glioma microenvironment and improving the outcome of immunotherapy toward glioma.

Abstract Objective The effectiveness and security of radiofrequency ablation (RFA) in combination with toripalimab (anti‐PD‐1) for the treatment of recurrent hepatocellular carcinoma (HCC) was studied in this article. Methods Total of 40 patients were enrolled in the study between September 2019 and November 2021. Data follow‐up ends in April 2022. The study’s main focus is on recurrence free survival (RFS), while the secondary objectives was safety. Chi‐square tests, Kaplan‐Meier, and Cox proportional hazards models were utilized to analyze the data. Results The median follow‐up period was 21.40 months, and the median RFS was 15.40 months in the group that received combination therapy, which was statistically significantly different (HR: 0.44, p = 0.04) compared with the RFA group (8.2 months). RFS rates (RFSr) at 6, 12 and 18 months in the combination therapy groups and RFA groups were 80% vs 65%, 62.7% vs 35% and 48.7% vs 18.8%, respectively. Between the two groups, significant difference of RFSr was found at 18 months (p = 0.04). No statistical differences were observed between the two groups in terms of safeness (p > 0.05). The subgroup analysis indicated that the combination of RFA and anti‐PD‐1 led to better RFS than RFA alone. Moreover, patients benefited more from combination therapy in the groups younger than 60 years (HR: 0.26, p = 0.018), male (HR: 0.32, p = 0.028) and Child‐Pugh grade A (HR: 0.38, p = 0.032). Conclusions Combining RFA with anti‐PD‐1 showed improved RFS and was deemed safe for patients with recurrent HCC who had previously undergone RFA treatment alone.

Abstract Background Prostate cancer (PCa) is the most common malignancy diagnosed in men. Immune checkpoint blockade (ICB) alone showed disappointing results in PCa. It is partly due to the formation of immunosuppressive tumor microenvironment (TME) could not be reversed effectively by ICB alone. Methods We used PCa cell lines to evaluate the combined effects of CN133 and anti-PD-1 in the subcutaneous and osseous PCa mice models, as well as the underlying mechanisms. Results We found that CN133 could reduce the infiltration of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), and CN133 combination with anti-PD-1 could augment antitumor effects in the subcutaneous PCa of allograft models. However, anti-PD-1 combination with CN133 failed to elicit an anti-tumor response to the bone metastatic PCa mice. Mechanistically, CN133 could inhibit the infiltration of PMN-MDSCs in the TME of soft tissues by downregulation gene expression of PMN-MDSC recruitment but not change the gene expression involved in PMN-MDSC activation in the CN133 and anti-PD-1 co-treatment group relative to the anti-PD-1 alone in the bone metastatic mice model. Conclusions Taken together, our work firstly demonstrated that combination of CN133 with anti-PD-1 therapy may increase the therapeutic efficacy to PCa by reactivation of the positive immune microenvironment in the TME of soft tissue PCa.

Abstract Background The efficacy of anti‐programmed cell death protein 1 (PD‐1) immunotherapy in various cancers, including gastric cancer (GC), needs to be potentiated by more effective targeting to enhance therapeutic efficacy or identifying accurate biomarkers to predict clinical responses. Here, we attempted to identify molecules predicting or/and promoting anti‐PD‐1 therapeutic response in advanced GC (AGC). Methods The transcriptome of AGC tissues from patients with different clinical responses to anti‐PD‐1 immunotherapy and GC cells was analyzed by RNA sequencing. The protein and mRNA levels of the major facilitator superfamily domain containing 2A (MFSD2A) in GC cells were assessed via quantitative real‐time polymerase chain reaction, Western blotting, and immunohistochemistry. Additionally, the regulation of anti‐PD‐1 response by MFSD2A was studied in tumor‐bearing mice. Cytometry by Time‐of‐Flight, multiple immunohistochemistry, and flow cytometry assays were used to explore immunological responses. The effects of MFSD2A on lipid metabolism in mice cancer tissue and GC cells was detected by metabolomics. Results Higher expression of MFSD2A in tumor tissues of AGC patients was associated with better response to anti‐PD‐1 immunotherapy. Moreover, MFSD2A expression was lower in GC tissues compared to adjacent normal tissues, and its expression was inversely correlated with GC stage. The overexpression of MFSD2A in GC cells enhanced the efficacy of anti‐PD‐1 immunotherapy in vivo by reprogramming the tumor microenvironment (TME), characterized by increased CD8+ T cell activation and reduced its exhaustion. MFSD2A inhibited transforming growth factor β1 (TGFβ1) release from GC cells by suppressing cyclooxygenase 2 (COX2)‐prostaglandin synthesis, which consequently reprogrammed TME to promote anti‐tumor T cell activation. Conclusions MFSD2A potentially serves as a predictive biomarker for anti‐PD‐1 immunotherapy response in AGC patients. MFSD2A may be a promising therapeutic target to potentiate the efficacy of anti‐PD‐1 immunotherapy by reprogramming the TME to promote T cells activation.

Objective(s): Immunotherapy has changed the landscape of oncology over the last decade and has become a standard of care for various cancers. Researchers previously demonstrated that B16-F10 melanoma in C57Bl6 mice is resistant to immune checkpoint inhibitors. The goal of this study was to investigate how anti-PD1 antibodies functioned in combination with a new antimicrobial peptide (AMP) called moronecidin-like peptide (MLP).Materials and Methods: We studied the cytotoxic effect of AMP on the B10-F16 tumor cell line with the MTT experiment. The necrotic and apoptotic cells were determined by Presidium iodide (PI) /Annexin V staining and flow cytometry-based methods. Mice were inoculated subcutaneously with B10-F16 tumor cells in the mammary gland. Each group was sacrificed two weeks after the last injection to examine tumor-specific CD8+ T cell responses using flow cytometry. Results: Annexin V and PI staining assay revealed that MPL significantly induces apoptosis in B16F10 cells. It should be noted that MLP in combination with anti-PD-1 improved antigen-specific T-cell responses synergistically (P=0.01) when compared with respective monotherapy. Furthermore, when compared with the respective monotherapies, combination therapy significantly controlled tumor growth in B10-F16 tumor cells and increased survival rate.Conclusion: Treatments with anti-PD-1 inhibitors alone had only a minor effect on tumor size, whereas combination therapy resulted in significant tumor growth control and increased animal survival. MLP therapy combined with anti-PD-1 antibody improves anti-tumor immune response in addition to inducing tumor cell apoptosis. As a result, the evidence suggests that intratumoral injection of MPL can improve anti-PD-1 antibody antitumor response.

Melanoma is the most aggressive and deadly form of skin cancer, and its incidence has been steadily increasing over the past few decades, particularly in the Caucasian population. Immune checkpoint inhibitors (ICI), anti-PD-1 monotherapy or in combination with anti-CTLA-4, and more recently, anti-PD-1 plus anti-LAG-3 have changed the clinical evolution of this disease. However, a significant percentage of patients do not benefit from these therapies. Therefore, to improve patient selection, it is imperative to look for novel biomarkers. Immune subsets, particularly the quantification of lymphocyte T populations, could contribute to the identification of ICI responders. The main purpose of this review is to thoroughly examine significant published data on the potential role of lymphocyte T subset distribution in peripheral blood (PB) or intratumorally as prognostic and predictive of response biomarkers in advanced melanoma patients treated with ICI regardless of BRAFV600 mutational status.