The limited efficacy of current therapeutic options highlights a clear unmet need in patients with digestive neuroendocrine carcinoma. Tarlatamab is a bispecific T-cell engager targeting CD3 on T cells and delta-like ligand 3 on tumor cells. Since delta-like ligand 3 is highly expressed in digestive neuroendocrine carcinomas, tarlatamab might be a potential treatment option in this setting. However, the efficacy of tarlatamab in patients with digestive neuroendocrine carcinoma remains unknown. Herein, we report a case of metastatic esophageal neuroendocrine carcinoma that achieved a complete radiologic response following treatment with tarlatamab. A 47-year-old woman presented with progressive dysphagia and was diagnosed with esophageal small-cell neuroendocrine carcinoma with mediastinal lymph node metastases. She received first-line chemoimmunotherapy and radiotherapy to the primary tumor and mediastinal lymph nodes. Following three months of maintenance therapy with atezolizumab, new metastatic lesions in the liver and brain developed. Second-line treatment with tarlatamab was initiated. Tarlatamab induced complete resolution of the metastatic lesions in the liver and brain, without adverse events attributable to tarlatamab. This case underscores the potential value of delta-like ligand 3-targeted therapy with tarlatamab in metastatic digestive neuroendocrine carcinoma, a rare and highly aggressive malignancy with few effective treatment options.

Immunotherapy with immune checkpoint inhibitors (ICI) has become a transformative pillar in cancer treatment, offering significant improvements in survival and reducing treatment-related side effects compared to traditional therapies. In gynecologic cancers, ICIs have transformed the treatment of endometrial (EC) and cervical cancers, whereas they have not demonstrated clinical benefit in ovarian cancer. This review examines the current state of ICI advancements in EC. Given the unique immunological characteristics of EC, a comprehensive understanding of advancements is crucial for optimizing decision-making and patient outcomes. While ICIs have demonstrated robust and durable efficacy in dMMR/MSI-H EC, the magnitude of benefit in pMMR disease remains modest. Additionally, we examine promising future directions, including personalized immunotherapy approaches and novel combination therapies (e.g. antibody-drug conjugates, PARP inhibitors, antiangiogenic drugs).

Immune checkpoint inhibitors (ICIs) have brought a paradigm shift in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC), but their first-line efficacy remains inconsistent. This meta-analysis compared the efficacy of ICIs versus the EXTREME regimen in R/M HNSCC patients. Randomized controlled trials evaluating the efficacy of ICIs versus EXTREME in R/M HNSCC patients and reporting on programmed death-ligand 1 (PD-L1) expression, overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were included. Kaplan-Meier curves of OS and PFS were reconstructed; ORR was presented as odds ratios. From an initial pool of 356 studies, three trials were included. In the total population, median OS was similar among ICI monotherapy (11.5 months), dual ICIs (12.5 months), and EXTREME (12.0 months). In the PD-L1 high expression population, ICI monotherapy and dual ICIs demonstrated a trend toward improved OS relative to EXTREME. EXTREME demonstrated better PFS and ORR than ICI monotherapy and dual ICIs in both the total and PD-L1 high expression populations. First-line ICI monotherapy and dual ICIs did not significantly improve OS, PFS, and ORR compared with EXTREME. However, a discernible trend suggested a potential survival benefit for ICIs in patients with high PD-L1 expression.

Immune checkpoint inhibitors (ICIs) are pivotal in systemic anticancer therapy. The aim of the study was to investigate incidence, severity and consequences of immune-related adverse events (irAEs) in ICI combinations by comparing different adverse events classification systems. A retrospective multicentre cohort study included patients treated with ICI combinations. IrAEs were assessed by CTCAE v.5, NCC MERP index and SITC consensus for chronic irAEs. Among 612 patients, 244 (40%) experienced 354 irAEs, in total 58 irAEs per 100 patients varying between treatments. Higher incidence was observed for autoimmune disease, thoracic radiotherapy, melanoma, dual ICI and ICI/TKI. Severe irAEs occurred in 147 patients, leading to treatment discontinuation and hospitalization in half of the patients. Chronic irAEs were common, with 64% persisting beyond three months after ICI discontinuation, 22% of these resolved (median 135 steroid days, 154 days to resolution). Common chronic toxicities included endocrine, pulmonary or rheumatic irAEs. Fatal irAEs affected 16 patients, primarily from pneumonitis, colitis or hepatitis. NCC MERP better captured clinical consequences compared to CTCAE, while SITC criteria uniquely identified long-term irAEs. Severe and chronic irAEs were frequent, emphasizing the need for improved communication about irAE management and prospective studies with revised toxicity definitions.ClinicalTrials.govIDNCT06476158.

ABSTRACTChimeric antigen receptor (CAR) natural killer (NK) cell therapy represents an emerging frontier in cancer immunotherapy. CAR‐NK cells offer the potential for “off‐the‐shelf” treatments with a favorable safety profile, due in part to their innate capacity for HLA‐unrestricted tumor targeting and an absence of graft‐versus‐host disease. Landmark clinical studies using cord blood – derived CAR-NK cells and another employing iPSC-derived CAR-NK cells have reported impressive response rates, durable remissions, and minimal toxicity. Furthermore, a growing landscape of ongoing clinical trials is exploring innovative strategies to enhance persistence, overcome solid tumor challenges, and prevent antigen escape. These advances collectively underscore the potential of CAR-NK therapies to revolutionize cancer treatment while addressing limitations associated with current CAR-T cell approaches.

This study aimed to evaluate the cost-utility analyses of blinatumomab in children with relapsed/refractory B-cell Acute Lymphoblastic Leukemia (B-ALL) compared to Consolidation Chemotherapy in Iran. Based on the results of the phase III randomized 20120215 trial (NCT02393859) the cost-utility analysis, was evaluated over a lifetime using the Parietal Survival model with three health states. The model considered both direct and indirect costs from a societal perspective. The incremental cost-effectiveness ratio (ICER) was calculated by determining the cost per quality-adjusted life year (QALY) gained. Costs and QALYs were discounted annually at 5.8% and 5%, respectively. Deterministic sensitivity analysis (DSA) and Probabilistic sensitivity analysis (PSA) were performed to assess the model's robustness. The study estimated that blinatumomab is a cost-effective treatment option, with a probability of 57.2%. Blinatumomab was associated with a higher cost ($42,481 versus $21,355) and higher QALYs gained (13.14 versus 8.06) compared to Consolidation Chemotherapy with an ICER of USD 4,160, which is below the willingness-to-pay (WTP) threshold of 4,210 USD in Iran. Blinatumomab is a cost-effective treatment strategy for pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia B-ALL from an Iranian societal perspective.

With the rapid advancements in oncology, immunology, and molecular biology, immunotherapy has emerged as a cornerstone of anti-tumor treatment, complementing traditional modalities such as surgery, radiotherapy, and chemotherapy. Among the many immunotherapy strategies, adoptive cell therapy (ACT) is the most representative one. A key technology within ACT is chimeric antigen receptor (CAR) T-cell therapy, a precision-targeted treatment that leverages genetic engineering to modify T cells, enabling them to express antigen-specific receptors independent of major histocompatibility complex (MHC) restrictions. In recent years, continuous optimization of CAR-T therapy has been leading to remarkable clinical outcomes in oncology. However, its efficacy is significantly compromised by T-cell exhaustion, characterized by reduced proliferative capacity, attenuated anti-tumor activity, and limited persistence. Notably, CAR-T cell exhaustion is primarily driven by repeated tumor antigen stimulation, sustained autonomous activation of CAR constructs, and the immunosuppressive tumor microenvironment (TME), collectively contributing to disease relapse in hematologic malignancies and limited efficacy in solid tumors. Therefore, it is important to elucidate and inhibit the mechanism of CAR-T cell dysfunction to improve its efficacy. Overcoming these challenges will facilitate the development of CAR-T cells with sustained proliferative potential and tumor clearance.

Although PD-1 checkpoint inhibition has improved outcomes for some cancer types, a substantial proportion of solid tumors still do not respond, in part due to inadequate cytotoxic CD8+ T-cell infiltration and survival within the tumor microenvironment (TME). CD25+ regulatory T-cells (Tregs) are a subset of T-cells that play a key role in suppressing CD8+ T-cell activity. Depletion of Tregs in the TME could thus enhance anti-cancer immune responses. Here, we present the experience of a patient with platinum-resistant ovarian carcinoma who achieved a durable partial response on a phase 1 clinical trial of an anti-CD25 antibody-drug conjugate combined with pembrolizumab. Notably, her tumor response correlated with a reduction in CD25+ Tregs on paired tumor biopsies and further deepened after treatment discontinuation. This case provides early proof-of-concept that Treg depletion combined with PD-1/PD-L1 inhibitors can lead to anti-cancer efficacy in refractory diseases and offers key lessons to guide future development of anti-Treg therapeutics.