Colorectal carcinoma (CRC) is frequently typified by chronic inflammation and high levels of immunosuppression that render it resistant to immunotherapy. The multimodal immunostimulatory mechanisms of oncolytic virotherapy make it an attractive strategy for priming tumors for immune-checkpoint blockade (ICB). Here, we present an emerging oncolytic virotherapeutic, rAPMV-4, with previously described efficacy in preclinical models of CRC and melanoma.

We expand on the established efficacy of APMV-4 by characterizing responses to the virotherapy in preclinical single and bilateral MicroSatellite Stable CRC tumor models. To investigate local and systemic effects of the virus, we characterized responses in tumors, draining lymph nodes, and sera using RNA-seq, high-dimensional flow cytometry, and cytokine analysis.

rAPMV-4 induced rapid, yet transient, interferon signaling, and early signatures of antigen presentation and T cell activation. Comparison with a human CRC cohort revealed a transcriptomic shift induced by the virus from a mesenchymal CMS4 to an "immune-high" CMS1 subtype predicted to respond well to ICB. Leveraging these signatures of response and resistance to the virotherapy, we designed a rational combinatorial approach with low-dose anti-CTLA-4, which reversed Treg activation and alleviated CD4 and CD8 dysfunction, leading to more potent systemic tumor elimination.

This work supports the further clinical development of rAPMV-4, either alone or in combination, as an efficacious therapy for CRC.

Patients with advanced non-small cell lung cancer who progress on immune checkpoint inhibitors (ICIs) face limited options and poor survival. Aglatimagene besadenovec (CAN-2409), a replication-defective adenoviral vector encoding herpes simplex virus-thymidine kinase, plus valacyclovir, has been shown to induce immunogenic cell death and systemic immune activation.

In this open-label, phase 2a clinical trial, 76 patients were enrolled (intention-to-treat population) and 73 received at least one dose of aglatimagene besadenovec (safety population); 46 patients who received two intratumoral aglatimagene besadenovec injections, completed protocol-defined valacyclovir exposure, and underwent a 12-week imaging comprised the evaluable (per-protocol) population. Endpoints included clinical and immunological outcomes.

In the 73 patients included in the safety analysis (including patients who did not receive a second injection due to apparent pseudoprogression), median OS was 14.3 months. In the evaluable (per-protocol) population of 46 patients who completed protocol-defined treatment and week-12 imaging, median OS was 24.5 months (95% CI 16.0 to 33.8). Among the 41 evaluable patients in cohort 2, 15 (37%) were alive at ≥24 months and 5 (12%) at ≥40 months. In the 46-patient evaluable population, the objective response rate was 10.9% (5/46; 95% CI 4.7% to 23.0%) and the disease control rate was 71.7% (33/46; 95% CI 57.5% to 82.7%). In the 73 patients included in the safety analysis (including patients who did not receive a second injection due to apparent pseudoprogression) median overall survival was 14.3 months. Exploratory biomarkers demonstrated systemic immune reactivation, including cytotoxic T-cell expansion and regression of uninjected lesions, with stronger signals in non-squamous histology. No grade 4 treatment-related adverse events or treatment-related deaths were reported. Most treatment-related adverse events were grade 1-2; 10/73 patients (13.7%) experienced grade 3 treatment-related adverse events. Six patients discontinued because of adverse events, including two with events considered possibly related to treatment (including ongoing ICI).

In this single-arm phase 2a study, aglatimagene besadenovec plus valacyclovir with ongoing ICI was associated with systemic immune remodeling and encouraging survival. Because comparisons with historical controls are descriptive and vulnerable to selection and other biases, efficacy requires confirmation in a randomized controlled clinical trial, which has been initiated.

NCT04495153.

Oncolytic viruses represent a promising immunotherapeutic strategy for converting pancreatic and other immunologically cold tumors. While their ability to stimulate innate immune signaling and promote antitumor immunity is established, mechanisms enabling durable adaptive responses remain poorly defined.

We used CRISPR-Cas9-based homologous recombination to generate a thymidine kinase (TK) and B2R double-deleted backbone virus, VV∆TK∆B2R (VV-DD). On this backbone, we engineered VV∆TKmp40∆B2Rmp19 (VV-DDIL23), which expresses the p40 and p19 subunits of interleukin-23 (IL-23) separately to mimic natural heterodimer assembly. Its antitumor efficacy was evaluated in immunosuppressive pancreatic ductal adenocarcinoma models and compared with a single-chain IL-23 fusion construct (VV-DDIL23F). In parallel, unbiased single-cell RNA sequencing was employed to systematically dissect the immune mechanisms underlying the potent antitumor activity of VV-DDIL23.

VV-DDIL23 exhibited potent antitumor efficacy and significantly outperformed VV-DDIL23F. Single-cell RNA sequencing revealed that VV-DDIL23 enhanced antigen processing and presentation in macrophages, characterized by elevated major histocompatibility complex-II expression, upregulation of co-stimulatory molecules, and production of cytokines including interferon-I and IL-1β. This was accompanied by the emergence of a distinct population of tumor-infiltrating CD4⁺ T cells that mediated long-term memory immune surveillance against tumors. Mechanistically, VV-DDIL23 infection triggered tumor cell-mediated activation of the macrophage inflammasome, leading to IL-1β release. Notably, IL-1β synergized with virally encoded IL-23 to promote the differentiation of Th17-skewed Cxcr6⁺Rora⁺ CD4⁺ T cells with sustained antitumor functions.

This work reveals a previously unrecognized pathway linking innate viral recognition by macrophages to CD4⁺ T cell-directed differentiation and tumor clearance, providing a novel therapeutic strategy to overcome immunosuppression in pancreatic cancer.

Novel therapies to prevent lethal castration-resistant prostate cancer in response to standard-of-care androgen deprivation therapy (ADT) are required. Unfortunately, most prostate cancers are "immune cold" and fail to respond to checkpoint inhibitors (CPIs). To assess whether ADT induces changes that enable more effective CPI therapy, we examined the tumor immune microenvironment (TiME) following neoadjuvant ADT (nADT).

Radical prostatectomy specimens from 43 nADT-treated patients were stratified into three duration groups and compared with each other and with matched controls. RNA sequencing and quantitative multispectral immunofluorescence (qmIF) staining were performed to analyze transcriptomic and TiME abundance and cellular spatial relationship differences after nADT.

Immune and inflammatory pathways, particularly of antigen presentation and adaptive immune response, were increased, most notably in tumors receiving 3-5 months nADT. qmIF revealed a complex temporal response in the TiME, with a dramatic influx of cytotoxic T lymphocytes (CTLs) and T-helper cells after 3-5 months of nADT. However, after 6 months nADT, M2-like tumor-associated macrophages (TAMs) and regulatory T cells were strikingly increased while CTLs decreased. Spatially, CTLs and T-helper cells clustered near tumor cells at 3-5 months nADT, but were replaced by M2-TAMs in tumors receiving ≥6 months of nADT.

These data reveal the induction of a bi-phasic response in the TiME: robust CTL activation 3-5 months after nADT is initiated, followed by myeloid immunosuppression in tumors receiving prolonged nADT. This ADT-induced reprogramming of the TiME suggests a critical window of opportunity where short-duration ADT might augment CPI efficacy, converting cold into immunologically responsive tumors.

Central retinal artery occlusion (CRAO) is a vision-threatening vascular emergency that often causes permanent monocular visual loss. We report a woman in her late seventies with metastatic hormone receptor-positive, HER2-negative breast cancer and multiple myeloma who developed sudden, painless right monocular vision loss while receiving long-term abemaciclib and lenalidomide. Funduscopic examination showed diffuse retinal whitening, attenuated retinal arterioles and a cherry-red spot, confirming CRAO. She presented approximately 20 hours after symptom onset, outside the window for hyperacute intervention and severe visual impairment persisted. Evaluation showed severe hypertension and extensive cardiovascular comorbidity but no high-grade carotid stenosis, large-vessel occlusion or definite cardiac embolic source. Abemaciclib and lenalidomide have each been associated predominantly with venous thromboembolism. Given the patient's multiple vascular and malignancy-related risk factors, a treatment-related contribution, including a possible synergistic interaction, cannot be excluded.

Although lymphoma may involve the adrenal glands as part of a generalised disease process, primary adrenal lymphoma is a rare entity. We present the case of a man in his late 60s who was admitted via the emergency department with clinical features consistent with adrenal failure. Initial investigations demonstrated anaemia, hypercalcaemia and adrenal insufficiency. Further biochemical work-up showed no evidence of an autoimmune or congenital aetiology of adrenal failure, and diagnostic imaging revealed bilateral adrenal enlargement. Adrenal biopsy revealed a diagnosis of diffuse large B-cell lymphoma. The patient achieved complete metabolic remission following first-line immunochemotherapy, though adrenal function remained compromised. We review the published literature and discuss diagnostic challenges in patients presenting with adrenal insufficiency of unclear aetiology.

Malignant melanomas have an intrinsic ability to present in a variety of ways necessitating biopsies, immunohistological staining and next-generation sequencing for an accurate diagnosis. A dedifferentiated melanoma by virtue of its transformation from its typical morphohistological features represents a rare aggressive form with poor responses to immunotherapy and targeted therapy. Dedifferentiation along with metastasis may lead to changes in goals of care, with treatments shifting from curative intent towards palliation. Our patient, a man in his early 60s, presented with a slow growing skin lesion on the back over two decades along with a recently noticed right axillary mass. During our investigations, a rapid deterioration in the patient's functional status necessitated hospitalisation and intensive care. We present this rare atypical rapid course to emphasise the value of diagnosis and palliation by a multidisciplinary team to improve quality of life for such patients.

Glomus tumours (GTs) are rare mesenchymal neoplasms originating from modified myoid cells of the glomus body which is involved in thermoregulation and skin circulation. Primary renal involvement is exceedingly rare and has been reported only sporadically in the medical literature. Although typically benign, these tumours can occasionally exhibit aggressive or malignant behaviour. This article presents two cases of renal GT with uncertain malignant potential. Both patients, elderly individuals presenting with abdominal pain, were found to have large parenchymal renal masses on radiological evaluation. They underwent nephrectomy, followed by detailed histopathological and immunohistochemical analysis. While the tumours displayed atypical features, they did not meet the established criteria for malignancy. Postoperative follow-up revealed a benign clinical course, with no signs of local recurrence or metastasis.

The gut microbiome is increasingly recognised as a clinically modifiable determinant of efficacy and toxicity across systemic cancer therapies, with the most mature evidence in patients receiving immune checkpoint inhibitors (ICIs). The composition and function of intestinal microbes can influence treatment outcomes by affecting immune priming, antigen presentation, host-microbial co-metabolism, drug biotransformation, and epithelial barrier integrity. In melanoma, non-small-cell lung cancer, and renal cell carcinoma, higher microbial diversity, ecological stability, and enrichment of immunostimulatory pathways have been associated with improved ICI response and survival. By contrast, antibiotics and proton pump inhibitors are linked to inferior outcomes because they disrupt the microbiome. Microbiome-directed interventions, including faecal microbiota transplantation, dietary modifications, prebiotics, probiotics, and live biotherapeutic products, are undergoing clinical testing but remain at the investigational stage. This Review synthesises current evidence linking the intestinal microbiome to anticancer therapy outcomes, evaluates strategies and challenges for therapeutic modulation of the microbiome, and introduces emerging insights into the mycobiome.

Appendiceal neoplasms represent less than 1% of all gastrointestinal cancers. Epithelial mucinous neoplasms of the appendix are classified as low grade, high grade, or adenocarcinoma. Pseudomyxoma peritonei, the peritoneal dissemination of these tumors, is a common clinical presentation. The management of peritoneal carcinomatosis is complex and involves cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy, a modality associated with significant surgical morbidity and resource demands. Nevertheless, cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy remains the standard of care.

To evaluate overall survival and disease-free survival following cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy for appendiceal tumors in a Latin American cancer center.

We conducted a retrospective observational cohort study including patients aged 18-75 years who underwent cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy between 2001 and 2021. Survival analysis was performed using Kaplan-Meier estimates and the log-rank test to compare overall survival and disease-free survival up to 10 years or until last follow-up or death. Cox proportional hazards models were applied to identify risk factors associated with recurrence and mortality.

A total of 139 patients were included; 45.3% were male, with a mean age of 49.8 years. Fifty-four patients had mucinous neoplasms, and 85 patients had adenocarcinomas. The mean peritoneal cancer index was 14.9, and complete cytoreductive surgery was achieved in 133 patients (95.6%). The most commonly used chemotherapy agents were mitomycin (74.8%) and oxaliplatin (25.2%). At 10 years, overall survival and disease-free survival were 64.8% and 55.2%, respectively. Histology was significantly associated with prognosis (P = .04 for overall survival and P = .02 for disease-free survival at 10 years). In multivariable Cox regression, the use of oxaliplatin was associated with an increased risk of recurrence (hazard ratio, 2.71; 95% confidence interval, 1.26-5.53). Poorly differentiated or signet-ring cell histology was associated with a 3.5-fold increased risk of recurrence (hazard ratio, 3.54; 95% confidence interval, 1.44-8.68) and a 3-fold increased risk of death (hazard ratio, 2.9; 95% confidence interval, 1.14-7.26).

Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy is a complex but effective treatment for appendiceal neoplasms, providing favorable long-term survival rates with acceptable mortality when performed at experienced referral centers. Our study suggests that both the hyperthermic intraperitoneal chemotherapy drug and histological subtype influenced disease-free survival. These findings underscore the importance of careful patient selection and specialized multidisciplinary care to optimize outcomes.