Immunotherapy最新文献

Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized hematological cancer treatment but faces challenges in solid tumors, including poor infiltration, cytokine release syndrome (CRS), and toxicity. CAR-T cell-derived exosomes (CAR-T exosomes) offer a promising alternative by inheriting CAR-mediated targeting and cytotoxic molecules (e.g., perforin, granzyme B), while avoiding issues such as CRS. Their nanoscale size enhances tumor penetration, and the lack of MHC reduces immunogenicity, which supports "off-the-shelf" applications. However, scalability remains limited by low yields from traditional isolation methods [e.g., ultracentrifugation (UC)], costly equipment, and inconsistent purification. This review summarizes recent advances in CAR-T exosome biology, scalable production strategies, and combinatorial approaches to overcome immunosuppressive tumor microenvironments (e.g., immune checkpoint inhibitors, cytokine modulation). We also discuss clinical prospects and future directions.

Therapeutic resistance and immune evasion are hallmark features associated with tumor progression, wherein tumor cells utilize programmed death-ligand 1 (PD-L1) to inhibit cytotoxic T-cell activity via programmed cell death protein 1 (PD-1) engagement. Anti-PD-1 monoclonal antibodies have shown tremendous success in multiple cancers. Despite their limited efficacy in non-small cell lung cancer (NSCLC), a deeper investigation into the mechanism of PD-L1-mediated immune evasion is needed to combat therapeutic resistance. While some clinical benefits for anti-PD-L1 therapy have been observed in NSCLC, factors, such as durability of response and resistance mechanisms remain barriers to its broader use. Recent findings suggest that exosomal PD-L1 may serve as a critical mediator in these resistance mechanisms while simultaneously promoting cancer progression. Therapeutically targeting the process of exosome biogenesis, which is controlled by neutral sphingomyelinase 2 (nSMase2) and the Rab proteins, could yield a novel treatment strategy. Evidence suggests that knocking down these regulatory proteins may enhance cancer therapy, but that remains to be seen in NSCLC. This review presents a comprehensive overview of exosomal PD-L1 in lung cancer, considering its implications in therapeutic resistance and novel treatment strategies, positioning it as a valuable resource for advancing next-generation immunotherapy approaches.

Immune checkpoint inhibitors have resulted in treatment paradigm changes for the management of patients with solid tumors, including microsatellite instability-high (MSI-H) colorectal cancer (CRC). Although the benefit of these agents appears to be limited for microsatellite stable (MSS) CRC, recent studies suggest that the immune microenvironment of the early-stage MSS CRC and perhaps those with advanced-stage disease without active liver metastasis may be more immune permissive where relatively more promising responses were noted. At this time, biomarkers of immunotherapy for patients with CRC have not been well-defined. Except for the loss of mismatch repair protein (MMR) function and POLE/POLD1 mutations, most of the biomarkers of response are largely investigational. In this review article, we summarize recent research and drug development with immune checkpoint inhibitors for patients with MSS and MSI-H CRC and elaborate on investigational biomarkers, including but not limited to tumor mutation burden and immunoscore. We also discuss the relevance and potential applicability of these biomarkers to clinical practice for the use of immune checkpoint inhibitors and provided further perspective on future biomarker development.

Mesothelioma is a rare neoplasm with a minority of cases originating from the peritoneum. Patients are generally treated with a combination of cytoreductive surgery, hyperthermic intraperitoneal chemotherapy, and various systemic therapies. In recent years, expression of programmed death ligand 1 (PD-L1) has been investigated in mesothelioma with implications for targeted therapy. In this case report, we present a patient with solitary isolated peritoneal mesothelioma of the right flank with abdominal and chest wall involvement and high PD-L1 positivity. The patient demonstrated a remarkable metabolic response to neoadjuvant immunotherapy using nivolumab and ipilimumab, which was followed by a successful surgical resection. Pathological evaluation revealed a complete pathological response, highlighting the effectiveness of the treatment strategy.

The impact of immune checkpoint inhibitors (ICIs) on transplant rejection remains controversial. We report a case of a hepatocellular carcinoma patient who received Atezolizumab plus Bevacizumab regimen prior to liver transplantation and developed steroid-refractory T cell-mediated rejection combined with antibody-mediated rejection post-transplant. Given the short discontinuation and outstanding tumor response, we believe that the use of ICIs prior to transplantation contributed to this complex condition. The rejection was successfully cured with anti-thymocyte globulin (ATG) combined with an anti-CD20 monoclonal antibody (Rituximab). After 9-months follow-up, no tumor recurrence occurs. This case highlights the unique immune activation state affecting both T and B lymphocytes induced by ICIs. It also provides a case reference for the use of intensive immunosuppressive regimens in ICI recipients experiencing adverse reactions.

Currently, immune checkpoint inhibitors are used in the treatment of ovarian cancer. Immunotherapy agents occasionally cause the development of skin reactions characterized by mild erythematous and maculopapular rashes, usually involving the trunk and extremities of the body, which may occasionally present with pruritus. It is especially seen in the use of anti-PD-1 (nivolumab and pembrolizumab) treatment agents. In this case report, we present a patient who developed discoloration of the tongue toxicity after nivolumab treatment in ovarian cancer patients. Discoloration of the tongue, which is one of the rare side effects of immunotherapy, and factors that may be associated with it are discussed in this case.

Objective: Venous thromboembolism (VTE) is associated with significant morbidity. Although this risk is multifactorial, recent studies suggest immune checkpoint inhibitors (ICIs) may also contribute to increased VTE risk. The aim of this study is to evaluate VTE risk in a cohort of patients with head and neck cancer treated with surgery and ICIs.

Methods: De-identified data from the TriNetX Global Collaborative Network database was used to identify adult surgical patients (≥18 years) using International Classification of Diseases 10^th Revision and Common Procedural Terminology codes and were further refined by use of nivolumab, pembrolizumab, or cemiplimab within 1-year before or up to 3-months after surgery. Cohorts were propensity score matched, and the primary study outcome was the 3-month composite rate of VTE.

Results: After propensity score matching, there were 1,471 patients in each cohort and they were well balanced according to demographics, body mass index, comorbidities, medication use, and radiation history up to 1-year before the index event. The composite rate of VTE in the study population was 3.7% and was higher in patients treated with ICIs (4.6% versus 2.9%; OR, 1.6; 95% CI, 1.1, 2.5).

Conclusions: This study highlights the importance of risk stratification and risk reduction in the setting of increasing ICI use for patients with HNC undergoing surgery.

In recent years, CAR-T cell therapy has emerged as a promising immunotherapeutic approach, demonstrating remarkable therapeutic efficacy in hematologic malignancies such as leukemia and lymphoma. However, its effectiveness in treating solid tumors remains limited, with challenges such as low response rates, poor therapeutic persistence, and high recurrence rates. The unique and complex immune microenvironment of solid tumors, characterized by a dense extracellular matrix, an abundance of immunosuppressive cells, and cytokines, is considered a major factor impeding CAR-T cell infiltration, antitumor activity, and persistence, significantly hindering the clinical potential of this therapy. To address these challenges, various strategies have been developed to optimize CAR-T cell functionality and adaptability. As a rare and highly complex solid tumor, chordoma presents with several challenges for CAR-T cell therapy, including the lack of tumor-specific antigens, rich extracellular matrix, and enrichment of immunosuppressive factors such as TGF-β. This review summarizes the key challenges and corresponding strategies to enhance CAR-T cell therapy in solid tumors, with a particular focus on underlying its therapeutic potential for the treatment of chordoma.

Aims: Novel and multimodal immunotherapy approaches are required for pancreatic cancer. A novel subset of NKT cells, called CD8+ NKT-like cells or variant NKT (vNKT) cells, which are CD8⁺ CD56⁺, CD1d-independent with variant TCR, have been reported to provide potent anti-tumor immunity. With positive immune regulations of stereotactic body radiation therapy (SBRT) reported in previous studies, we hypothesize that there might be a synergy of SBRT with immunotherapy. The aim of this study is to evaluate the efficacy and safety of SBRT plus vNKT cells as adoptive cell therapy for advanced pancreatic cancer.

Methods: The prescription dose of SBRT ranges from 35 to 40 Gy/5f. Transfer of allogeneic vNKT cells is initiated 1-2 weeks after SBRT. Patients receive transfusion of vNKT cells twice a month with a 12-24 h interval within 6 months after SBRT and once a month thereafter. A 12-month transfer is defined as a cycle. The primary outcome is overall survival. The secondary outcomes are progression-free survival, adverse events, and quality of life.

Conclusion: Therapeutic potential of SBRT plus vNKT cells may provide a novel insight into the treatment for advanced pancreatic cancer, and further investigations on the clinical benefits compared to standard chemoradiotherapy are warranted.

Clinical trial registration: www.clinicaltrials.gov identifier is NCT05783076.

Background: Albumin and creatinine are considered important for understanding patient response to immune checkpoint inhibitors (ICIs). However, numerous confounding factors complicate the interpretation of albumin and creatinine alone in clinical practice. This study aims to assess the correlation between survival outcomes and serum-albumin creatinine ratio (sACR) in patients treated with ICIs.

Methods: This study was conducted on individuals who received at least three doses of ICI between 2018 and 2023. Patients were divided into two groups, sACR-High and sACR-Low, based on the median level. The relationship between sACR and survival outcomes was analyzed using a cox regression model. The relationship between sACR and early progression, late progression, and long-term benefit was analyzed using a logistic regression model.

Results: Patients with lower sACR had decreased overall survival (OS) (HR: 1.42, 95% CI 1.07-1.89, p = 0.014) and progression-free survival (PFS) (HR: 1.34, 95% CI 1.08-1.66, p = 0.009). sACR was associated with early progression (HR: 1.86, 95% CI, 1.14-3.01, p = 0.012), late progression (HR: 2.06, 95 % CI 1.0-4.24, p = 0.050), and long-term benefit of ICIs  (HR: 1.72, 95% CI 1.002-2.93, p = 0.049).

Conclusions: Our study demonstrated that sACR could serve as an independent predictor of OS, PFS, early progression, late progression, and long-term benefit in patients treated with ICIs.