Liposome-based in situ antigen-modification strategy for "universal" T-cell-receptor engineered T cell in cancer immunotherapy.

T-cell receptor (TCR) engineered T-cell therapy, unlike chimeric antigen receptor T-cell therapy, relies on the inherent ability of TCRs to detect a wider variety of antigenic epitopes, such as protein fragments found internally or externally on cells. Hence, TCR-T-cell therapy offers broader possibilities for treating solid tumors. However, because of the complicated process of identifying specific antigenic peptides, their clinical application still encounters significant challenges. Thus, we aimed to establish a novel "universal" TCR-T "artificial antigen expression" technique that involves the delivery of the antigen to tumor cells using DSPE-PEG-NY-ESO-1157-165 liposomes (NY-ESO-1 Lips) to express TCR-T-cell-specific recognition targets. In vitro as well as in vivo studies revealed that they could accumulate efficiently in the tumor area and deliver target antigens to activate the tumor-specific cytotoxic T-cell immune response. NY-ESO-1 TCR-T therapy, when used in combination, dramatically curbed tumor progression and extended the longevity of mice. Additionally, PD-1 blockage enhanced the therapeutic effect of the aforementioned therapy. In conclusion, NY-ESO-1 Lips "cursed" tumor cells by enabling antigenic target expression on their surface. This innovative technique presents a groundbreaking approach for the widespread utilization of TCR-T in solid tumor treatment.

ß-Mangostin targets and suppresses glioma via STING activation and tumor-associated microglia polarization.

Glioma, a common and highly malignant central nervous system tumor, markedly influences patient prognosis via interactions with glioma-associated macrophages. Previous research has revealed the anticancer potential of ß-mangostin, a xanthone derivative obtained from the mangosteen fruit. This research investigated the role of ß-mangostin on microglia in the glioma microenvironment and evaluated the efficacy of ß-mangostin combined with anti-PD-1 antibody (αPD-1) in glioma-bearing mice. The results showed that, ß-mangostin attenuated M2 polarization in BV2 cells and promoted M1-related interleukin (IL)-1ß and IL-6 secretion, thereby inhibiting glioma invasion. In addition, ß-mangostin improved the anti-glioma effects of αPD-1 and increased CD8+T cell and M1-type microglia infiltration. Mechanistically, ß-mangostin bound to the stimulator of interferon genes (STING) protein, which is crucial for the anti-tumor innate immune response, and promoted STING phosphorylation in microglia, both in vivo and in vitro. These results provide insights into its mode of action and supporting further investigation into ß-mangostin as a therapeutic agent.

PD-L1 expression in keratinocyte and infiltration of CD4 + T lymphocyte can predict a severe type of erythema multiforme major induced by the anti-PD-1 antibody, pembrolizumab.

Skin toxicity is the most common adverse event of treatment with immune check point inhibitors. Among them, erythema multiforme is a rare occurrence with a frequency of 4%, with most of the cases developing grade 1/2 disease. We experienced high grade erythema multiforme major developing with pembrolizumab treatment for anal canal cancer with extensive skin metastases. Steroid ointment was ineffective, and the skin lesions with blisters expanded to > 45% of the body surface area. The patient was at risk for symptom aggravation, and a pulse therapy with methylprednisolone and increasing the dose of oral prednisolone (1 mg/kg) were started. The skin lesions improved in 1.8 months. Unless urgent and appropriate treatments such as high dose steroid administration were conducted, the skin toxicities could not be controlled. The presence of CD4+ T cells and PD-L1+ keratinocytes in the skin biopsy might be a predictive marker of erythema multiforme major resistant to standard steroid treatment. Supplementary Information: The online version contains supplementary material available at 10.1007/s13691-024-00676-4.

Neogambogic acid enhances anti-PD-1 immunotherapy efficacy by attenuating suppressive function of MDSCs in pancreatic cancer.

BACKGROUND: Anti-PD-1-based immunotherapy has limited benefits in patients with pancreatic cancer. Accumulating data indicate that natural products exert antitumor activity by remodeling the tumor immune microenvironment. It has been reported that neogambogic acid (NGA), an active natural monomer extracted from Garcinia, has anti-inflammatory and antitumor effects. Nevertheless, there are few systematic studies on the antitumor efficacy and immunomodulatory effects of NGA in pancreatic cancer. METHODS: An orthotopic mouse model of pancreatic cancer was established and were treated with different doses of NGA. Tumor growth and ascites were observed. Flow cytometry and immunohistochemistry (IHC) were used to investigate the tumor immune microenvironment. CD11b+ MDSCs were infused back into mice with pancreatic cancer to observe tumor progression after NGA treatment. Bone marrow cells were induced to differentiate into MDSCs, and the effects of NGA on MDSCs were analyzed and the underlying mechanism was explored. The effects of NGA combined with an anti-PD-1 antibody on pancreatic cancer were further tested. RESULTS: NGA significantly inhibited the tumor growth and improve ascites character in pancreatic cancer model mice. Flow cytometry and IHC analysis revealed that NGA decreased the MDSCs proportion and infiltration in the tumor microenvironment. Moreover, adoptive MDSCs largely attenuated the inhibitory effect of NGA on the progression of pancreatic cancer. In addition, we showed that NGA significantly promoted apoptosis and inhibited the differentiation, migration and immunosuppressive function of MDSCs and decreased level of STAT3 and p-STAT3. Furthermore, we demonstrated that NGA synergistically enhanced the efficacy of anti-PD-1 antibodies against pancreatic cancer. CONCLUSION: NGA inhibited the progression of pancreatic cancer by inhibiting MDSCs in the tumor microenvironment, and enhanced the efficacy of anti-PD-1 therapy in the treatment of pancreatic cancer.

Rocaglamide promotes infiltration and differentiation of T cells and coordinates with PD-1 inhibitor to overcome checkpoint resistance in multiple tumor models.

Tumor-infiltrating lymphocyte (TIL) deficiency is the most conspicuous obstacle to limit the cancer immunotherapy. Immune checkpoint inhibitors (ICIs), such as anti-PD-1 antibody, have achieved great success in clinical practice. However, due to the limitation of response rates of ICIs, some patients fail to benefit from monotherapy. Thus, novel combination therapy that could improve the response rates emerges as new strategies for cancer treatment. Here, we reported that the natural product rocaglamide (RocA) increased tumor-infiltrating T cells and promoted Th17 differentiation of CD4+ TILs. Despite RocA monotherapy upregulated PD-1 expression of TILs, which was considered as the consequence of T cell activation, combining RocA with anti-PD-1 antibody significantly downregulated the expression of PD-1 and promoted proliferation of TILs. Taken together, these findings demonstrated that RocA could fuel the T cell anti-tumor immunity and revealed the remarkable potential of RocA as a therapeutic candidate when combining with the ICIs.

Successful treatment with tislelizumab plus chemotherapy for SMARCA4-deficient undifferentiated tumor: a case report.

SMARCA4-deficient undifferentiated tumor (SMARCA4-dUT) is a devastating subtype of thoracic tumor with SMARCA4 inactivation and is characterized by rapid progression, poor prognosis, and high risk of postoperative recurrence. However, effective treatments for SMARCA4-dUT are lacking. Herein, we describe a patient with SMARCA4-dUT who exhibited an impressive response to the anti-programmed cell death protein-1 (PD-1) antibody (tislelizumab) in combination with conventional chemotherapy (etoposide and cisplatin). To the best of our knowledge, this is the first case of SMARCA4-dUT treated with chemotherapy, comprising etoposide and cisplatin, combined with anti-PD-1 inhibitors. Immunotherapy combined with etoposide and cisplatin may be a promising strategy to treat SMARCA4-dUT.

The efficacy of subsequent therapy after failure of anti-PD-1 antibody in metastatic renal cell carcinoma.

Background: The optional regimens of subsequent therapy after failure of anti-programmed cell death protein-1 (PD-1) antibody in metastatic renal cell carcinoma (mRCC) remain to be explored. There are reports of the efficacy of single-agent vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) in patients with mRCC after failure of anti-PD-1 antibody therapy. However, it is not clear whether it is beneficial for patients to receive anti-PD-1 antibody as post-progression treatment. It has great significance to explore whether continuous application of anti-PD-1 antibody is beneficial for patients with mRCC whose diseases progressed to the state of pre-anti-PD-1 therapy. The purposes of this study are to explore the efficacy and safety of subsequent treatment on whether to continue using anti-PD-1 antibody therapy for patients who have progressive mRCC after prior treatment with anti-PD-1 antibody. Methods: The clinical data of patients with mRCC from the Department of Immunotherapy in the Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital from February 1, 2019 to December 31, 2021 were analyzed retrospectively. The primary endpoints were the objective response rate (ORR) and progression-free survival (PFS). The ORR and disease control rate (DCR) were estimated with Fisher's exact test. PFS and overall survival (OS) were assessed using the Kaplan-Meier method and log-rank tests. The associations between potential prognostic variables and PFS were evaluated with univariate and multivariate Cox regression analyses. A P value of less than or equal to 0.05 was deemed as statistically significant. Results: A total of 35 patients were included in this study, during which 19 received VEGFR-TKI monotherapy and 16 received the VEGFR-TKI plus anti-PD-1 antibody therapy. Until the last follow-up on June 30, 2022, 19 patients experienced progressive disease (PD), five were in remission, and 11 kept stable disease (SD). After a median follow-up of 28.7 [95% confidence interval (CI): 17.0-35.6] months, the median PFS (mPFS) was 11.6 months for the VEGFR-TKI group and 9.1 months for the VEGFR-TKI plus anti-PD-1 antibody group [hazard ratio (HR) =0.81, 95% CI: 0.32-1.03, P=0.44]. Median OS (mOS) were 16.9 and 11.2 months respectively (HR =0.99, 95% CI: 0.44-2.27, P=0.90). The ORRs were 26.3% and 0% (P=0.049), and the DCRs were 47.4% and 43.8% (P=0.55) respectively. Treatment-related adverse events (TRAEs) occurred in 14 patients (73.7%) in the VEGFR-TKI group and 14 patients (87.5%) in the VEGFR-TKI plus anti-PD-1 antibody group (P=0.42); grade 3/4 TRAEs occurred in two patients (10.5%) and six patients (37.5%) respectively (P=0.11). Conclusions: VEGFR-TKI monotherapy is an efficacious regimen for patients with mRCC whose diseases progressed on previous anti-PD-1 antibody therapy, and continuous anti-PD-1 therapy after failure of anti-PD-1 antibody could not provide additional clinical benefit but increased the incidence of TRAEs.

Glycoengineering-based anti-PD-1-iRGD peptide conjugate boosts antitumor efficacy through T cell engagement.

Despite the important breakthroughs of immune checkpoint inhibitors in recent years, the objective response rates remain limited. Here, we synthesize programmed cell death protein-1 (PD-1) antibody-iRGD cyclic peptide conjugate (αPD-1-(iRGD)2) through glycoengineering methods. In addition to enhancing tissue penetration, αPD-1-(iRGD)2 simultaneously engages tumor cells and PD-1+ T cells via dual targeting, thus mediating tumor-specific T cell activation and proliferation with mild effects on non-specific T cells. In multiple syngeneic mouse models, αPD-1-(iRGD)2 effectively reduces tumor growth with satisfactory biosafety. Moreover, results of flow cytometry and single-cell RNA-seq reveal that αPD-1-(iRGD)2 remodels the tumor microenvironment and expands a population of "better effector" CD8+ tumor infiltrating T cells expressing stem- and memory-associated genes, including Tcf7, Il7r, Lef1, and Bach2. Conclusively, αPD-1-(iRGD)2 is a promising antibody conjugate therapeutic beyond antibody-drug conjugate for cancer immunotherapy.

The effect of liver metastases on clinical efficacy of first-line programmed death-1 inhibitor plus chemotherapy in esophageal squamous cell carcinoma: A post hoc analysis of ASTRUM-007 and meta-analysis.

OBJECTIVE: To explore the efficacy of serplulimab plus chemotherapy in esophageal squamous cell carcinoma (ESCC) patients with liver metastases. METHODS: A post hoc exploratory analysis of ASTRUM-007 study was performed, focusing on the association between the liver metastases status and the clinical outcomes. A systematic literature search of electronic databases was conducted to identify eligible randomized controlled trials for the meta-analysis. Study-level pooled analyses of hazard ratios (HRs) for PFS according to liver metastases were performed. RESULTS: The post hoc analysis of ASTRUM-007 showed that although patients with liver metastases had a worse prognosis comparing with the non-liver metastases patients in both treatment arms (serplulimab plus chemotherapy arm: median PFS, 5.7 vs. 6.6 months, HR 1.57 [95% CI, 1.15-2.13]; median OS, 13.7 vs. 15.3 months, HR 1.48 [95% CI, 1.09-1.98]; placebo plus chemotherapy arm: median PFS, 4.3 vs. 5.5 months, HR 1.58 [95% CI, 1.01-2.39]; median OS, 10.3 vs. 11.2 months, HR 1.32 [95% CI, 0.84-2.00]), OS and PFS benefits derived from serplulimab plus chemotherapy versus placebo plus chemotherapy in this study were observed in both patients with liver metastases (HR of PFS: 0.60; 95% CI, 0.37-0.97; HR of OS: 0.68; 95% CI, 0.43-1.11) and the non-liver metastases patients (HR of PFS: 0.62; 95% CI, 0.49-0.80; HR of OS: 0.69; 95% CI, 0.55-0.87) with similar magnitude. Three randomized controlled trials were included in the meta-analysis. Pooled HRs demonstrated that the addition of anti-PD-1 antibodies significantly improved PFS compared to chemotherapy alone regardless of liver metastases status. CONCLUSIONS: This study reveals that the presence of liver metastases is a poor prognostic factor but does not affect the improvements in both PFS and OS brought by adding PD-1 blockade to chemotherapy in ESCC patients. Predictive biomarkers for survival in these patients warrant further investigation.

Anti-programmed-death-receptor-1 (PD-1) antibody (Pembrolizumab) induced pancreatitis diagnosed on 18F-FDG PET/CT.

Immunotherapy related adverse events are commonly seen with immune check point inhibitors therapy. We report the case of a 40-year-old female diagnosed with stage IVB endometroid grade III endometrial cancer, on pembrolizumab immunotherapy, an anti-programmed-death-receptor-1 (PD-1) antibody. Patient was referred for 18F-FDG PET/CT for restaging. 18F-FDG PET/CT demonstrated diffuse increased FDG uptake throughout the body of the pancreas associated with fat stranding in the peripancreatic region, suggestive of pembrolizumab-induced pancreatitis. The diagnosis was confirmed by elevated amylase and lipase levels. immune-related adverse events (irAE) are frequently identified on 18F-FDG PET-CT, which may lead to early diagnosis, close clinical follow-up, and appropriate clinical management of immune-related adverse events.

CXCL9 Overexpression Predicts Better HCC Response to Anti-PD-1 Therapy and Promotes N1 Polarization of Neutrophils.

Background: Anti-programmed death-1 (PD1) antibodies have changed the treatment landscape for hepatocellular carcinoma (HCC) and exhibit promising treatment efficacy. However, the majority of HCCs still do not respond to anti-PD-1 therapy. Methods: We analyzed the expression of CXCL9 in blood samples from patients who received anti-PD-1 therapy and evaluated its correlation with clinicopathological characteristics and treatment outcomes. Based on the results of Cox regression analysis, a nomogram was established for predicting HCC response to anti-PD-1 therapy. qRT‒PCR and multiple immunofluorescence assays were utilized to analyze the proportions of N1-type neutrophils in vitro and in tumor samples, respectively. Results: The nomogram showed good predictive efficacy in the training and validation cohorts and may be useful for guiding clinical treatment of HCC patients. We also found that HCC cell-derived CXCL9 promoted N1 polarization of neutrophils in vitro and that AMG487, a specific CXCR3 inhibitor, significantly blocked this process. Moreover, multiple immunofluorescence (mIF) showed that patients with higher serum CXCL9 levels had greater infiltration of the N1 phenotype of tumor-associated neutrophils (TANs). Conclusion: Our study highlights the critical role of CXCL9 as an effective biomarker of immunotherapy efficacy and in promoting the polarization of N1-type neutrophils; thus, targeting the CXCL9-CXCR3 axis could represent a novel pharmaceutical strategy to enhance immunotherapy for HCC.

GNUV201, a novel human/mouse cross-reactive and low pH-selective anti-PD-1 monoclonal antibody for cancer immunotherapy.

BACKGROUND: Several PD-1 antibodies approved as anti-cancer therapies work by blocking the interaction of PD-1 with its ligand PD-L1, thus restoring anti-cancer T cell activities. These PD-1 antibodies lack inter-species cross-reactivity, necessitating surrogate antibodies for preclinical studies, which may limit the predictability and translatability of the studies. RESULTS: To overcome this limitation, we have developed an inter-species cross-reactive PD-1 antibody, GNUV201, by utilizing an enhanced diversity mouse platform (SHINE MOUSE™). GNUV201 equally binds to human PD-1 and mouse PD-1, equally inhibits the binding of human PD-1/PD-L1 and mouse PD-1/PD-L1, and effectively suppresses tumor growth in syngeneic mouse models. The epitope of GNUV201 mapped to the "FG loop" of hPD-1, distinct from those of Keytruda® ("C'D loop") and Opdivo® (N-term). Notably, the structural feature where the protruding epitope loop fits into GNUV201's binding pocket supports the enhanced binding affinity due to slower dissociation (8.7 times slower than Keytruda®). Furthermore, GNUV201 shows a stronger binding affinity at pH 6.0 (5.6 times strong than at pH 7.4), which mimics the hypoxic and acidic tumor microenvironment (TME). This phenomenon is not observed with marketed antibodies (Keytruda®, Opdivo®), implying that GNUV201 achieves more selective binding to and better occupancy on PD-1 in the TME. CONCLUSIONS: In summary, GNUV201 exhibited enhanced affinity for PD-1 with slow dissociation and preferential binding in TME-mimicking low pH. Human/monkey/mouse inter-species cross-reactivity of GNUV201 could enable more predictable and translatable efficacy and toxicity preclinical studies. These results suggest that GNUV201 could be an ideal antibody candidate for anti-cancer drug development.

An oncolytic HSV-1 armed with Visfatin enhances antitumor effects by remodeling tumor microenvironment against murine pancreatic cancer.

Oncolytic viruses (OVs) have shown potential in converting a "cold" tumor into a "hot" one and exhibit effectiveness in various cancer types. However, only a subset of patients respond to oncolytic virotherapy. It is important to understand the resistance mechanisms to OV treatment in pancreatic ductal adenocarcinoma (PDAC) to engineer oncolytic viruses. In this study, we used transcriptome RNA sequencing (RNA-seq) to identify Visfatin, which was highly expressed in the responsive tumors following OV treatment. To explore the antitumor efficacy, we modified OV-mVisfatin, which effectively inhibited tumor growth. For the first time, we revealed that Visfatin promoted the antitumor efficacy of OV by remodeling the tumor microenvironment, which involved enhancing CD8+ T cell and DC cell infiltration and activation, repolarizing macrophages towards the M1-like phenotype, and decreasing Treg cells using single-cell RNA sequencing (scRNA-seq) and flow cytometry. Furthermore, PD-1 blockade significantly enhanced OV-mVisfatin antitumor efficacy, offering a promising new therapeutic strategy for PDAC.

Efficacy and safety of tislelizumab plus lenvatinib as first-line treatment in patients with unresectable hepatocellular carcinoma: a multicenter, single-arm, phase 2 trial.

BACKGROUND: Lenvatinib is widely used in treatment of unresectable hepatocellular carcinoma (uHCC), but the benefit of its combination with immunotherapy needs to be verified. This study evaluated the efficacy and safety of tislelizumab plus lenvatinib in systemic treatment-naïve patients with uHCC. METHODS: In this multicenter, single-arm, phase 2 study, systemic treatment-naïve patients with uHCC received tislelizumab 200 mg every three weeks plus lenvatinib (bodyweight ≥ 60 kg: 12 mg; < 60 kg: 8 mg; once daily). Dose-limiting toxicities (DLTs) were evaluated in safety run-in phase to determine whether to enter the expansion phase. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Based on Simon's two-stage design, > 6 responders were needed in stage 1 (n = 30) to continue the study, and ≥ 18 responders were needed by the end of stage 2 (n = 60) to demonstrate statistical superiority to a historical control of lenvatinib monotherapy. RESULTS: Sixty-four patients were enrolled. No DLTs were reported. The study achieved statistical superiority (p = 0.0003) with 23 responders assessed by IRC per RECIST v1.1 in the first 60 patients of the efficacy evaluable analysis set (n = 62). After a median follow-up of 15.7 months, confirmed ORR and disease control rate were 38.7% (24/62, 95% confidence interval [CI], 26.6-51.9) and 90.3% (56/62, 95% CI, 80.1-96.4), respectively. Median progression-free survival was 8.2 months (95% CI, 6.8-not evaluable). Overall survival rate at 12 months was 88.6% (95% CI, 77.7-94.4). Grade ≥ 3 treatment-related adverse events occurred in 18 (28.1%) patients. CONCLUSIONS: Tislelizumab plus lenvatinib demonstrated promising antitumor activity with favourable tolerability as first-line therapy for patients with uHCC. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04401800).

Long-Term Follow-Up of Combination Therapy with Sintilimab and Anlotinib in Gallbladder Follicular Dendritic Cell Sarcoma: A Rare Case Report.

Follicular dendritic cell sarcoma (FDCS) is a rare malignant neoplasm for which a standardized treatment approach has yet to be established. The prevailing therapeutic strategy typically involves resection followed by adjuvant chemotherapy or radiation. This case report details the long-term follow-up of a 59-year-old Chinese male diagnosed with gallbladder FDCS and liver metastases. The patient received a combination therapy of sintilimab and anlotinib, resulting in a substantial partial response (PR) lasting for a noteworthy duration of 30 months. Notably, this is the first documented instance of gallbladder FDCS with liver metastases being treated with PD-1 antibody and antiangiogenic agents as first-line therapy. These findings suggest that this treatment regimen may offer a potential therapeutic option for patients with gallbladder FDCS and liver metastases, with a duration of PR lasting up to 30 months.

Characterization of a novel T cell-engaging bispecific antibody for elimination of L1CAM-positive tumors.

Neural cell adhesion molecule L1 (L1CAM) is a cell-surface glycoprotein involved in cancer occurrence and migration. Up to today, L1CAM-targeted therapy appeared limited efficacy in clinical trials although quite a few attempts by monoclonal antibody (mAb) or chimeric antigen receptor T-cell therapy (CAR-T) have been reported. Therefore, the development of new effective therapies targeting L1CAM is highly desirable. It has been demonstrated that T cell-engaging bispecific antibody (TCE) plays an effective role in cancer immunotherapy by redirecting the cytotoxic activity of CD3+ T cells to tumor cells, resulting in tumor cell death. In this study, we designed and characterized a novel bispecific antibody (CE7-TCE) based on the IgG-(L)-ScFv format, which targets L1CAM and CD3 simultaneously. In vitro, CE7-TCE induced specific killing of L1CAM-positive tumor cells through T cells. In vivo, CE7-TCE inhibited tumor growth in human peripheral blood mononuclear cell/tumor cell co-grafting models. To overcome the adaptive immune resistance (AIR) that impairs the efficacy of TCEs, we conducted a combination therapy of CE7-TCE with Pembrolizumab (anti-PD1 mAb), which enhanced the anti-tumor activity of CE7-TCE. Our results confirmed the feasibility of using L1CAM as a TCE target for the treatment of solid tumors and revealed the therapeutic potential of CE7-TCE combined with immune checkpoint inhibitors.

Anlotinib enhanced CD8+ T cell infiltration via induction of CCL5 improves the efficacy of PD-1/PD-L1 blockade therapy in lung cancer.

Non-small cell lung cancer (NSCLC) is a leading cause of mortality worldwide and requires effective treatment strategies. Recently, the development of a novel multiple-target tyrosine kinase inhibitor, anlotinib, has drawn increasing attention, especially it shows advantages when combined with PD-1/PD-L1 blockade. However, the mechanism by which anlotinib improves immunotherapy and remodeling of the tumor microenvironment remains unclear. In this study, we found that anlotinib combined with PD-1 blockade significantly inhibited tumor growth and reduced tumor weight in a lung cancer xenograft model compared to any single treatment. Both immunofluorescence and flow cytometry analyses revealed that anlotinib induced a CD8+ T cell dominated tumor microenvironment, which might account for its improved role in immunotherapy. Further investigations showed that CCL5-mediated CD8+ T cell recruitment plays a critical role in anlotinib and PD-1 blockade strategies. The depletion of CD8+ T cells abrogated this process. In conclusion, our findings showed that the combination of anlotinib and PD-1 blockade produced promising effects in the treatment of lung cancer, and that the induction of CCL5-mediced CD8+ T cell recruitment by anlotinib provided a novel mechanism of action.

Severe autoimmune hemolytic anemia following immunotherapy with checkpoint inhibitors in two patients with metastatic melanoma: a case report.

Introduction: Over the past decade, immune checkpoint inhibitors such as antibodies against cytotoxicity T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have become an important armamentarium against a broad spectrum of malignancies. However, these specific inhibitors can cause adverse autoimmune reactions by impairing self-tolerance. Hematologic side effects of immune checkpoint inhibitors, including autoimmune hemolytic anemia (AIHA), are rare but can be life-threatening. Case report: Herein, we report two patients on immune checkpoint inhibitors for metastatic melanoma who developed AIHA with symptoms of dyspnea and fatigue. In the first patient, symptoms alleviated after discontinuation of combined anti CTLA-4 and anti-PD-1 therapy, initiation of corticosteroids and application of a single red blood cell transfusion. Due to subsequent progress of melanoma, combinational anti-PD-1 and tyrosine kinase inhibitor therapy was initiated based on multidisciplinary tumor board decision. After two months, she again developed the described hematological and clinical signs of AIHA leading to cessation of anti-PD-1 therapy and initiation of corticosteroids, which again resulted in an alleviation of her symptoms. Due to further progression, the patient received dacarbazine for several months before she decided to stop any therapy other than palliative supportive care. In the second patient, discontinuation of anti-PD-1 therapy and initiation of corticosteroids entailed a complete alleviation of his symptoms. After refusing chemotherapy due to subsequent melanoma progression, he received radiotherapy of bone metastases and is currently enrolled in a clinical trial. The patient did not develop AIHA ever since. Conclusion: Hematologic immune-related adverse events due to treatment with immune checkpoint inhibitors are rare but can have life-threatening consequences. If dyspnea and other clinical symptoms are present, AIHA should be considered as a potential cause and treated promptly in a multidisciplinary setting. An expanded comprehension of risk factors and pathogenesis of AIHA is needed to identify high-risk patients beforehand, leading to more effective predictive and reactive treatment approaches.

Brain Delivery of Biomimetic Phosphorus Dendrimer/Antibody Nanocomplexes for Enhanced Glioma Immunotherapy via Immune Modulation of T Cells and Natural Killer Cells.

Fully mobilizing the activities of multiple immune cells is crucial to achieve the desired tumor immunotherapeutic efficacy yet still remains challenging. Herein, we report a nanomedicine formulation based on phosphorus dendrimer (termed AK128)/programmed cell death protein 1 antibody (aPD1) nanocomplexes (NCs) that are camouflaged with M1-type macrophage cell membranes (M1m) for enhanced immunotherapy of orthotopic glioma. The constructed AK128-aPD1@M1m NCs with a mean particle size of 160.3 nm possess good stability and cytocompatibility. By virtue of the decorated M1m having α4 and ß1 integrins, the NCs are able to penetrate the blood-brain barrier to codeliver both AK128 with intrinsic immunomodulatory activity and aPD1 to the orthotopic glioma with prolonged blood circulation time. We show that the phosphorus dendrimer AK128 can boost natural killer (NK) cell proliferation in peripheral blood mononuclear cells, while the delivered aPD1 enables immune checkpoint blockade (ICB) to restore the cytotoxic T cells and NK cells, thus promoting tumor cell apoptosis and simultaneously decreasing the tumor distribution of regulatory T cells vastly for improved glioma immunotherapy. The developed nanomedicine formulation with a simple composition achieves multiple modulations of immune cells by utilizing the immunomodulatory activity of nanocarrier and antibody-mediated ICB therapy, providing an effective strategy for cancer immunotherapy.

Mechanism exploration of Zoledronic acid combined with PD-1 in the treatment of hepatocellular carcinoma.

How to increase the response of immune checkpoint inhibitors (ICIs) is a challenge. In clinical, we found that Zoledronic acid (ZA) may increase the anti-tumor effect of immunotherapy for hepatocellular carcinoma (HCC). To explore the underlying mechanism, we established a mouse model of HCC by subcutaneously injecting Hepa1-6 cell line. The result showed that the tumor volume in the ZA plus anti-PD-1 monocloning antibody (anti-PD-1 mAb) treatment groups was significantly smaller than that of control group, and the onset time of tumor inhibition was even shorter than that of the anti-PD-1 mAb group. Using flow cytometry (FC) to detect the proportion of major immune cell subsets in tumor tissues of each group of mice, we found that the synergistic anti-tumor effect of ZA and anti-PD-1 mAb may be related to ZA-induced polarization of macrophages toward the M1 phenotype. Next, we performed bulk RNA sequencing on tumor samples from different groups to obtain differentially expressed genes (DEGs), which were then input DEGs into pathway enrichment analysis. Data indicated that ZA participated in the M1-type polarization via ferroptosis-related pathways. Our results revealed how ZA involves in the anti-tumor effect of PD-1 monoclonal antibody and provided a potential therapeutic candidate for patients with HCC.