Journal of Immunotherapy最新文献

Immunotherapy has revolutionized endometrial cancer (EC) treatment; our objectives were to characterize immune-related adverse events (irAE) among EC patients and to identify factors associated with risk for irAE. Patients who received pembrolizumab alone or as part of combination therapy for advanced/recurrent EC from 2014 to 2025 were identified. Baseline demographics and cancer characteristics were collected. Potential immune-related adverse events were collected and graded for the cohort. Multiple logistic regression was then performed. A total of 180 patients were included. The mean age was 63.9 years. Black patients comprised 30.6% of the cohort. Endometrioid was the commonest histologic subtype (38.7%), and most tumors (67.7%) were MMR proficient. Ninety-five patients (52.8%) had any-grade irAE, and 14 (7.8%) experienced serious (grades 3-4) irAE. Hypothyroidism was the most common irAE overall (n = 37; 20.6%,) followed by fatigue (n = 23; 12.8%) and diarrhea (n = 20; 11.1%). The most common serious irAEs were diarrhea (n = 4; 2.2%,) followed by hepatitis, dermatitis, and pneumonitis (each n = 3; 1.7%). On univariate analysis, older age, uninsured status, and receipt of pembrolizumab with lenvatinib were associated with any-grade irAE (all P <0.05). In our multiple logistic regression model, uninsured status was an independent predictor of both any-grade irAE (aOR: 5.49; 95% CI: 1.03-29.2) and serious irAE (aOR: 7.96; 95% CI: 1.44-43.9). Receiving pembrolizumab with lenvatinib was independently associated with any-grade irAE (aOR: 7.13; 95% CI: 2.92-17.4). Uninsured status and coadministration with lenvatinib may increase the risk for pembrolizumab-associated irAE among patients with EC. Further collection of real-world data, including unexplored social and economic factors and novel biomarkers, may predict irAE and ultimately help guide clinical decision-making.

This single-center, retrospective real-world study investigated the effectiveness and safety of sugemalimab-based rechallenge in patients with advanced non-small cell lung cancer who experienced disease progression after prior programmed cell death protein 1 (PD-1) inhibitor therapy. Eligible patients had previously achieved clinical benefit (progression-free survival [PFS] ≥6 mo), an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and no actionable driver alterations. Nineteen patients received sugemalimab every 3 weeks as monotherapy or in combination with chemotherapy and/or antiangiogenic agents. The objective response rate was 26.3% (5/19; 95% CI: 9.1-51.2), and the disease control rate was 89.5% (17/19; 95% CI: 66.9-98.7), with a median PFS of 4.4 months. Higher programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) correlated with prolonged PFS (TPS ≥50% vs. TPS <1%: 6.1 vs. 2.8 mo; hazard ratio (HR) 0.4, 95% CI: 0.1-0.8). Hypothyroidism was the most common treatment-related adverse event, while grade 3/4 events were uncommon. These findings indicate measurable activity of sugemalimab-based rechallenge in a pre-enriched population and support prospective validation with biomarker-informed stratification.

Metastatic pituitary neuroendocrine tumors (metPitNETs) are rare neoplasms with limited therapeutic options. Temozolomide is the first-line therapy, but primary or secondary resistance frequently occurs. Immune checkpoint inhibitors (ICIs) are emerging as a promising second-line option; however, clinical experience remains limited. We report the long-term follow-up of a 62-year-old male patient who received pembrolizumab (PBZ) treatment for a silent metPitNET derived from the PIT1 lineage after multiple surgical and radiation therapies and temozolomide failure. PBZ was proposed based on extensive PD-L1 expression by tumor cells. A remarkable clinical, radiologic, and metabolic response was soon observed, progressively leading to complete disease remission after 21 months of treatment, with moderate immune-related adverse events. However, an unexpected rapid neurological deterioration occurred, due to the progression of a pseudotumoral temporal radionecrosis surrounded by an impressive vasogenic oedema, requiring emergency neurosurgery 7 weeks after PBZ withdrawal. The temporal mass had progressively developed on a previous small temporal metastasis treated through stereotactic radiosurgery, the corresponding area was hypometabolic at 18FDG PET-CT imaging, and histopathologic examination confirmed extensive radionecrosis and the absence of residual tumor cells. This is the first documented complete response to ICI in a PIT1-derived metPitNET. However, this remarkable response was complicated by the severe evolution of a brain radionecrosis, probably favoured by long-term PBZ. This case underscores the need for multidisciplinary expertise to differentiate treatment effects from neoplastic progression and to carefully follow-up the patients for potentially severe late treatment-related complications. It also questions the optimal duration of treatment in responsive cases.

This study aimed to assess factors associated with overall survival (OS) in patients with microsatellite stable (MSS) stage IV rectal cancer treated with immunotherapy. In this retrospective review of the NCDB (2015-2021), patients with MSS stage IV rectal adenocarcinoma were divided into immunotherapy and control groups, and propensity-score matched and compared. Multivariable Cox regression analysis was performed to assess the effect of immunotherapy and KRAS genotype on OS. Of 6489 included patients (64.6% males), immunotherapy was given to 47.9%. After matching for age, insurance type, liver metastases, surgery, radiation therapy, and chemotherapy, there were 2422 patients in each group. In the matched cohort, immunotherapy was associated with a similar median OS to the control group [31.8 (95% CI: 27.8-32.2) months vs 29.7 (95% CI: 27.8-32.2) months, P = 0.062]. Immunotherapy was not independently associated with improved OS (HR: 0.88, 95% CI: 0.69-1.14, P = 0.341) but was associated with longer median OS in black patients (25.8 vs 19.1 mo, P = 0.019), patients with bone metastases (22.1 vs 10.7, P < 0.001) and with KRAS mutation (27.4 vs 24.3 mo, P = 0.003). There was no survival benefit from immunotherapy when combined with radical resection, radiation therapy, or chemotherapy. In conclusion, immunotherapy was associated with a modest increase in OS of MSS stage IV rectal cancers, but not independently associated with improved survival. Black patients with bone metastases and KRAS mutations may have survival benefit from immunotherapy. Increased OS with immunotherapy was noted only in patients who did not have surgery, radiation, or chemotherapy. These results seem somewhat disappointing given the enthusiasm for immunotherapy.

Abstract: Kaposi Sarcoma (KS) is an angioproliferative tumor induced by human gammaherpesvirus 8 (HHV-8). For years, cytotoxic chemotherapy was the primary treatment for advanced KS, despite high toxicity and limited efficacy. Immunotherapy, particularly PD-1/PD-L1 inhibitors, has emerged as a promising option with antitumor activity and a favorable safety profile. We conducted a meta-analysis to evaluate its efficacy and safety in KS. A systematic search in Medline, Embase, Cochrane Library, and Web of Science identified single-arm trials on PD-1/PD-L1 inhibitors in KS. Outcomes were expressed as proportions with 95% CIs, heterogeneity assessed using I ², and significance set at P <0.05. Analyses were performed in RStudio 4.4.1. Five studies with 91 patients were included. Prior treatments included chemotherapy (35.0%), radiotherapy (22.3%), and interferon (9.2%). The pooled objective response rate (ORR) was 61% (95% CI: 49-72; I ²=16%), with 17% achieving complete response (CR) (95% CI: 8-31; I ²=0%), and the disease control rate (DCR) was 91% (95% CI: 81-96; I ²=0%). The most frequent adverse events (AEs) were pruritus (42%; 95% CI: 16-73; I ²=74%), fatigue (27%; 95% CI: 8-60; I ²=67%), and arthralgia (14%; 95% CI: 5-37; I ²=60%). This meta-analysis supports the antitumor activity of PD-1/PD-L1 inhibitors in KS. Despite high AE rates, most were clinically manageable.

Cold tumors have an immunosuppressive microenvironment (TME) with weak infiltration of functionally active NK and T cells. Such tumors poorly respond to immunotherapies, and different combined approaches are investigated to reprogram cold tumors into hot ones and improve treatment efficacy. The search for novel immunostimulatory factors for the therapy of cold tumors is of particular clinical relevance. Previously, we showed the antitumor effects of recombinant human Cyclophilin A (rhCypA), an analog of proinflammatory secretory CypA, in experimental models in vivo and indicated it as a stimulator of the antitumor immune response and a modulator of the immune TME. In this study, the effect of rhCypA on the functionality of tumor-infiltrating NK and T cells was investigated using the melanoma B16 tumor model in vivo . After rhCypA treatment, T cells in the TME differently expressed the transcription factors Tbet and Eomes and the exhaustion markers PD-1, LAG-3, and TIM3. Tumors of rhCypA-dosed mice contained a higher proportion of activated CD4 + CD25 + T cells and CD8 + T cells with upregulated activation markers CD44 and CD25 and co-stimulatory CD28. Similarly, rhCypA upregulated PD-1, CTLA-4, and CD25 and downregulated exhaustion markers KLRG-1 and LAG-3 in tumor-infiltrating NK cells. After rhCypA treatment, melanoma B16 was actively infiltrated with CD8 + T cells and NK cells with increased perforin and granzyme B production and TNFα-producing CD4 + cells. Thus, rhCypA reprogrammed the immune tumor microenvironment by boosting the accumulation of functionally more active NK and T cells with the enhanced production of cytotoxic factors while modulating their dysfunction and weakening immunosuppression.

To explore the relationship between early dynamic changes in neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) and treatment outcomes of patients with advanced nonsmall cell lung cancer (NSCLC) undergoing immunotherapy, we retrospectively analyzed 217 advanced NSCLC patients who received immunotherapy. NLR and LMR at baseline and 3 weeks after initiation of treatment and changes of NLR and LMR were calculated. Univariate and multivariable COX regression analysis was applied to explore the predictors of overall survival (OS). One hundred six (48.8%) demonstrated an increase in NLR after 3 weeks of initiating treatment, while 111 (51.2%) displayed a decrease in NLR. Low pretreatment and post-treatment NLR levels (<5), high pretreatment and post-treatment LMR levels (≥4), reduction of post-treatment NLR and elevation of post-treatment LMR were associated with improved objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and OS. In multivariate regression analysis, the number of distant metastases, lines of immunotherapy, levels of pretreatment and post-treatment NLR and LMR were significantly associated with OS. We developed the "NLML" prognostic scoring system, which showed an area under the curve (AUC) of 0.775 (95% CI: 0.700-0.838, P <0.001) and reached its peak at 3 years (AUC=0.955, 95% CI: 0.909-0.982, P <0.001). Early dynamic alterations in NLR and LMR values from pre-treatment to post-treatment, along with individual pretreatment or post-treatment NLR or LMR levels, exhibited correlations with treatment outcomes in patients undergoing either mono-immunotherapy or chemoimmunotherapy. The "NLML" prognostic scoring system emerged as a practical and effective model for predicting survival within this patient population.

The present study was designed to evaluate the efficacy and safety of induction chemotherapy combined with a PD-1 inhibitor (sintilimab) followed by concurrent chemoradiotherapy (CCRT) plus sintilimab and subsequent maintenance (IC-ICCRT-IO) in patients with unresectable locally advanced esophageal squamous carcinoma (ESCC) compared with induction chemotherapy followed by CCRT without PD-1 inhibitors (CT-CCRT) using propensity score matching (PSM). Data collected from patients with histologically confirmed, inoperable ESCC treated with IC-ICCRT-IO or CT-CCRT were retrospectively analyzed-a 1:1 PSM with a caliper of 0.05 balanced potential biases. Treatment effects and adverse events (AEs) were assessed using imaging, medical records, and follow-up. Primary endpoints were median progression-free survival (PFS) and PFS rates at 12 and 18 months. Secondary endpoints included overall survival (OS), response rates, and safety. The results showed that t he PSM produced 27 comparable pairs; the median follow-up was 20.5 months. IC-ICCRT-IO significantly improved PFS (median not reached, 12 mo rate: 96.6% vs. 80.5%; 18 mo rate: 85.2% vs. 63.0%, P =0.011) and OS (median not reached, 12 and 18 mo rate: 100% vs. 88.9%, P =0.007). Objective response rates were 88.9% versus 48.1% ( P =0.003). Grade ≥3 AEs occurred in 55.6% versus 44.4% ( P =0.586), primarily nonimmune-related. Severe immune-related rash and radiation pneumonitis were rare and manageable. The results suggested that IC-ICCRT-IO shows promise as an effective, safe treatment for unresectable, locally advanced ESCC. Prospective studies are needed to confirm these findings.

Abstract: Triple-negative breast cancers (TNBCs), especially metastatic recurrent TNBCs, have a poorer prognosis than many other breast cancers. In recent years, immunotherapy using immune checkpoint inhibitors has been conducted for TNBC patients. Although a limited proportion of patients show excellent response, about half of the patients do not significantly respond to the immunotherapy. Monocytes are the progenitors of macrophages that are most abundantly seen in the tumor microenvironment (TME), but the influence of monocytes on breast cancer cells (BCCs) has not been fully clarified. Thus, we examined whether monocytes prompted BCCs to express PD-L1. As results, BCCs expressed higher levels of PD-L1 and its mRNA after co-culture with monocytes. RNA sequencing analysis revealed overexpression of Moesin mRNA in the BCCs co-cultured with monocytes. siRNA-mediated knockdown of Moesin restored the increase in PD-L1 expression. An addition of CD44 antibody canceled the augmentation of PD-L1 expression caused by the co-culture, suggesting that Moesin and CD44 may be essentially involved in the cell-to-cell interaction between monocytes and BCCs to induce PD-L1 expression. These findings may suggest a novel machinery of tumor escape from anti-tumor immunity, potentially providing implications for improving immunotherapy against TNBCs that are resistant to current immune checkpoint blockade therapy.