Omid Hamid

Regulatable membrane-bound IL-15 engineered TIL cell therapy for immune checkpoint inhibitor-resistant advanced melanoma: pooled analysis of phase 1 and 1/2 trials

Amsokigene autoleucel (amsoki-cel, OBX-115) is a tumor-infiltrating lymphocyte (TIL) cell therapy engineered to express acetazolamide (ACZ)-regulatable membrane-bound interleukin-15, abrogating the need for interleukin-2. In two single-arm trials (completed phase 1 single-center first-in-human (FIH) and ongoing phase 1/2 multicenter Agni-01), patients with immune checkpoint inhibitor (ICI)-resistant advanced melanoma received lymphodepletion and varying doses and schedules of amsoki-cel and ACZ. The primary objective of FIH and Agni-01 phase 1 was safety, tolerability and recommended phase 2 dose (RP2D); the primary objective of Agni-01 phase 2 was objective response rate (ORR) at the RP2D. The first patient treated experienced rapid lymphocyte expansion and vasogenic edema of a previously irradiated brain metastasis, prompting protocol modifications and dose deescalation in FIH, including 80% reduction in maximum amsoki-cel dose and 75% reduction in ACZ dose. After preliminary demonstration of safety at the lower dose, doses were increased in FIH, and reescalation was initiated in Agni-01. Across studies, 37 patients were treated (FIH, n = 17; Agni-01, n = 20). Post hoc pooled analysis demonstrated no dose-limiting toxicities, ICU care or treatment-related mortality. Most common grade 3 or higher treatment-emergent adverse events (TEAEs) included neutropenia (64.9% (24/37)), leukopenia/lymphopenia (56.8% (21/37) each) and anemia/thrombocytopenia (37.8% (14/37) each). Serious TEAEs were reported for 10 patients, including eight patients with grade 3 or higher events (non-hematologic, 13.5% (5/37); hematologic, 13.5% (5/37)). RP2D was selected based on overall safety and tolerability as well as preliminary anti-tumor activity in Agni-01 phase 1. The phase 2 preliminary ORR was 66.7% (6/9). In total, 15 patients were treated at RP2D and comprise the Key Efficacy Set (Agni-01: phase 1, n = 6; phase 2, n = 9), of which 10 patients (66.7%; 95% confidence interval 38−88%) achieved objective responses (including two complete responses). Amsoki-cel demonstrated favorable safety and promising early clinical activity in patients with ICI-resistant melanoma. A separate phase 2 pivotal Agni-01 cohort is ongoing. ClinicalTrials.gov identifiers: NCT05470283 and NCT06060613 . As presented at the Society for Immunotherapy of Cancer 2026 Annual Meeting, in a non-prespecified pooled analysis of two trials, amsokigene autoleucel, an autologous tumor-infiltrating lymphocyte therapy engineered to eliminate the need for IL-2, was successfully manufactured and well tolerated and showed a preliminary clinical efficacy signal in patients with immune checkpoint inhibitor-refractory melanoma.

OCT 1LongNature Medicine

Five-year survival with neoadjuvant therapy in melanoma: updated pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC)

Neoadjuvant immune checkpoint inhibitors (ICIs) are standard of care for resectable stage IIIB–D melanoma, but knowledge gaps remain regarding optimal treatment type, long-term survival, postsurgical management and clinical, histopathological or molecular subgroups. We analyzed 1,038 patients treated with neoadjuvant ICIs ( n = 735), BRAF and MEK inhibitors (BRAF/MEKis; n = 119) or ICI plus any targeted therapy (ICI + TT; n = 184) from 26 international sites in both trial (755, 72.7%) and nontrial (283, 27.3%) settings. ICI regimens included anti-programmed cell death protein 1 (PD-1) alone (PD-1 alone; n = 242) and anti-PD-1 plus other immuno-oncology agent(s) (PD-1 + IO; n = 489). Outcomes included major pathological response (MPR), recurrence-free survival (RFS) and overall survival (OS). An MPR was achieved in 57.8% of patients with ICIs, 51.4% with BRAF/MEKis and 44.6% with ICI + TT. PD-1 + IO elicited higher MPR rates than PD-1 alone (61.4% versus 49.5%). The 5-year RFS rate was 61.0% with PD-1 alone, 73.9% with PD-1 + IO, 37.4% with BRAF/MEKis and 76.4% with ICI + TT; the 5-year OS rates were 83.3%, 87.5%, 69.8% and 83.9%, respectively. ICI-treated patients with MPR had 5-year OS rates of 98.8% with PD-1 alone and 97.9% with PD-1 + IO and gained no benefit from continuing ICIs into the adjuvant setting. Neoadjuvant ICIs were active in BRAF -mutant melanoma (MPR, 46.3%), acral melanoma (38.1%), in-transit metastases (66.7%) and oligometastases (41.2%), although subgroup sizes and relative effectiveness varied. Survival outcomes were excellent with neoadjuvant ICIs, particularly in patients achieving MPR, but poor with BRAF/MEKis and mixed with ICI + TT. Predictive biomarker-driven trials, effective adjuvant strategies and subgroup-specific research are needed for nonresponders.

A Phase 1 First-Time-in-Human, Open-Label Study of Nelistotug Administered to Patients with Advanced Solid Tumors

Open-label phase 1 trial demonstrates acceptable safety but modest antitumor efficacy of nelistotug in advanced solid tumors, suggesting limited activity in heavily pretreated patients.

Safety and efficacy of intratumoral MEDI1191, an IL-12 mRNA lipid nanoparticle, plus intravenous durvalumab in patients with advanced solid tumors: a first-in-human study

Phase I trial demonstrates safety and systemic antitumor responses with intratumoral MEDI1191 and durvalumab in advanced solid tumors, indicating potential for combination immunotherapy.

Tryptophan degradation by intestinal Bacteroides induces anti-tumor immunity and limits melanoma growth

Defining mechanisms used by gut microbiota to control anti-tumor immunity may offer novel therapeutic modalities. Here, we demonstrate that Bacteroides rodentium and closely related Bacteroides uniformis species induce anti-tumor immunity and limit melanoma development when colonized in either germ-free (GF) mice, mice with a complex microbiome, or WT mice. Enhanced CD8 + T cell infiltration seen in tumors of mice harboring B. rodentium coincided with increased expression of immune-stimulating pathways and activation of bone marrow-derived dendritic cells that were co-cultured with the B. rodentium secretome. Metabolomic analyses of cecal samples from GF mice colonized with Altered Shedlar Flora (ASF) plus B. rodentium revealed lower tryptophan levels than in ASF-colonized controls, and WT mice fed a tryptophan-deficient diet exhibited inhibition of melanoma development. In silico genomic reconstruction of metabolic pathways revealed that both B. rodentium and B. uniformis harbor tryptophanase A ( TnaA ) and aromatic amino transferase ( ArAT ) genes, both of which function in tryptophan degradation. Administration of a B. uniformis harboring TnaA mutant failed to inhibit melanoma growth in gnotobiotic mice. Notably, administration of indoles, but not kynurenines, also effectively inhibited melanoma development, increasing immune cell infiltration into the tumors. Correspondingly, levels of bacterially encoded tryptophan-degrading enzymes were higher in cohorts of melanoma patients responding to immune checkpoint blockade. These findings highlight a novel mechanism of anti-tumor immunity and tumor growth inhibition dependent on the tryptophan degradation products, indoles, produced by intestinal Bacteroides species.

Translating ctDNA into cutaneous melanoma care: An international expert survey

BACKGROUND: Circulating tumor DNA (ctDNA) is a promising biomarker in melanoma, with higher sensitivity for tumor burden detection than conventional diagnostics. While well established in research, clinical routine implementation remains pending. Key global questions concern optimal clinical applications and barriers to adoption. METHODS: A web-based survey of 116 members of the Melanoma World Society Study Group assessed international expert opinions on ctDNA utility across predefined clinical scenarios. The questionnaire included 18 general questions on ctDNA use and 5 clinical vignettes with de-identified patient data and retrospectively obtained ctDNA results. RESULTS: ctDNA was rated most valuable for detecting minimal residual disease (mean score 3.63), surveillance of recurrent disease (3.85), and stage IV melanoma (3.82), with limited utility in early stages. Experts considered ctDNA superior to S100 and LDH for early relapse detection and identifying progressive disease. Most participants (80%) agreed that ctDNA correlates with radiographic response, and 82% favored its integration into routine follow-ups. In urgent high-tumor-burden settings, 82.8% would initiate BRAFi/MEKi therapy based on ctDNA if tissue analysis was pending, and 93.9% if unavailable. For central nervous system lesions, 62% did not support blood ctDNA, while 66% considered cerebrospinal fluid valuable. Pragmatic approaches with small to mid-size targeted panels and short turnaround times were preferred. Major barriers included the need for prospective trials (85%), standardized guidelines (83%), and reimbursement policies (82%). CONCLUSION: Key opinion leaders regarded ctDNA as a valuable adjunct selected melanoma scenarios. Validation through prospective studies, guideline development, and reimbursement frameworks are essential for broader clinical implementation.

Pre-vaccine immune profiling in cancer patients identifies correlates of COVID-19 vaccine responses

mRNA vaccines have been highly effective against SARS-CoV-2-related severe illness and are currently undergoing investigation as anti-cancer therapeutics. Our prior work has shown that patients undergoing cancer therapy have reduced immune responses to mRNA-based vaccines. Therefore, further investigation into immunologic responses in the setting of immune-altered hosts is warranted. In this study, we investigated pre-vaccination peripheral immune cell repertoire from a cohort of 66 patients with cancer on active treatment. Immune cell repertoire was characterized by mass cytometry to identify key immune subsets for COVID-19 vaccine response. Immunological populations were then assessed for their association with spike-specific antibody titers measured by ELISA and the breadth and depth of T-cell response to vaccine by TCR sequencing. Immune features significantly correlated with response were selected using an iterative bootstrapping model. We identified immunological features including abundance and functional state of T and B cells, expression of co-stimulatory and -inhibitory molecules, and presence of innate lymphoid cells, and myeloid-derived suppressor cells correlated with humoral and cellular responses. Our findings suggest that vaccine-induced immune responses could serve as biomarkers of immune fitness, in general and specifically for patients receiving anti-cancer mRNA vaccines, providing insights to tailor future therapeutic strategies for immune-altered patients.

Psychometric item/question analysis of multiple-choice questions in fixed prosthodontics exam

Item analysis shows improved reliability and psychometric performance in fixed prosthodontics exams, indicating the need for ongoing faculty training.

Advanced stage melanoma during pregnancy: recommendations from a retrospective, multicentre, registry-based study

Background Diagnosis and treatment of advanced melanoma during pregnancy represents a major challenge, with scarce data on outcome or management available. Therefore, the Melanoma Pregnancy Taskforce collected real-world data to understand the current management approaches. Methods This retrospective, multicenter database included patients who were either diagnosed with advanced melanoma (newly diagnosed or recurrent) during pregnancy (group 1) or conceived while on systemic treatment (group 2) between 01/01/2011 and 07/31/2024. Information regarding patient, primary tumor and advanced melanoma characteristics, intervention or treatment during pregnancy, and outcomes of mother and fetus were collected using a standardized, de-identified form. Findings 72 women from seven countries were identified. In group 1 (n = 63), nine pregnancies were terminated, and two miscarried. Median gestational age of live births was 34 weeks (IQR 32–37). Nine patients initiated systemic treatment during pregnancy; 56 (85%) of 66 switched or initiated new treatment after delivery. 5-year overall survival was 53% (95% CI 39–71), with median follow-up of 27 months (IQR 1.0–4.8 years). In group 2 (n = 10), four pregnancies were terminated, one miscarried. Of the six live births, median gestational age was 33 weeks (IQR 32–NR). Seven (63%) of nine initiated new or continued treatment after delivery. 5-year overall survival was 71% (95% CI 51–100), with median follow-up of 42 months (IQR 2.5–4.5 years). One neonate born at 26 weeks died after three days and one had a fatal congenital malformation. One child with third trimester vemurafenib-exposure had cardiac malformations, and two neonates experienced toxicity after in utero immunotherapy exposure. No children developed melanoma, despite five placentas with melanoma involvement. Interpretation Here, we present the data from the largest contemporary dataset of outcomes of women diagnosed with advanced stage melanoma during pregnancy and provide recommendations for the diagnosis and management of advanced melanoma during pregnancy.

Table 1 from First-in-Human Phase I/II Study of INCAGN01876, a Glucocorticoid-Induced Tumor Necrosis Factor Receptor Agonist, in Patients with Advanced or Metastatic Solid Tumors

First-in-human trial finds safety for glucocorticoid-induced TNF receptor agonist in advanced tumors, suggesting potential for further studies.

Supplementary data1 from First-in-Human Phase I/II Study of INCAGN01876, a Glucocorticoid-Induced Tumor Necrosis Factor Receptor Agonist, in Patients with Advanced or Metastatic Solid Tumors

First-in-human trial evaluates efficacy of a glucocorticoid-induced tumor necrosis factor receptor agonist in metastatic solid tumors, suggesting potential therapeutic benefits.

Data from First-in-Human Phase I/II Study of INCAGN01876, a Glucocorticoid-Induced Tumor Necrosis Factor Receptor Agonist, in Patients with Advanced or Metastatic Solid Tumors

First-in-human trial of INCAGN01876 shows potential in enhancing immune responses in patients with solid tumors, indicating possible benefits alongside checkpoint blockade therapy.

Figure 1 from First-in-Human Phase I/II Study of INCAGN01876, a Glucocorticoid-Induced Tumor Necrosis Factor Receptor Agonist, in Patients with Advanced or Metastatic Solid Tumors

Phase I/II study evaluates a glucocorticoid-induced TNF receptor agonist in patients with metastatic solid tumors, suggesting potential treatment avenues.

Figure 2 from First-in-Human Phase I/II Study of INCAGN01876, a Glucocorticoid-Induced Tumor Necrosis Factor Receptor Agonist, in Patients with Advanced or Metastatic Solid Tumors

Phase I/II trial investigates INCAGN01876 pharmacokinetics in patients with advanced tumors, revealing receptor occupancy patterns.

Figure 3 from First-in-Human Phase I/II Study of INCAGN01876, a Glucocorticoid-Induced Tumor Necrosis Factor Receptor Agonist, in Patients with Advanced or Metastatic Solid Tumors

Phase I/II trial evaluates INCAGN01876's effects on Tregs and CD4+ T cells in metastatic solid tumors, suggesting immune modulation.

Table 2 from First-in-Human Phase I/II Study of INCAGN01876, a Glucocorticoid-Induced Tumor Necrosis Factor Receptor Agonist, in Patients with Advanced or Metastatic Solid Tumors

Phase I/II study evaluates safety and efficacy of INCAGN01876 in patients with advanced tumors, indicating potential for treatment improvements.

Concurrent local therapy extends clinical benefit of tebentafusp in metastatic uveal melanoma patients

Retrospective study shows significant improvement in progression-free survival with concurrent local therapy, suggesting enhanced efficacy of tebentafusp in metastatic uveal melanoma.

SEP 2025LongNature Medicine

Neoadjuvant PD-1 and LAG-3-targeting bispecific antibody and other immune checkpoint inhibitor combinations in resectable melanoma: the randomized phase 1b/2 Morpheus-Melanoma trial

First-in-Human Phase I/II Study of INCAGN01876, a Glucocorticoid-Induced Tumor Necrosis Factor Receptor Agonist, in Patients with Advanced or Metastatic Solid Tumors

PURPOSE: Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) agonism in T cells may potentiate antitumor immune responses to immune checkpoint blockade therapy. This first-in-human, phase I/II dose escalation/expansion study assessed INCAGN01876, a humanized GITR-targeting agonistic mAb, for advanced solid tumors (NCT02697591). PATIENTS AND METHODS: Dose was escalated by 0.03 to 20 mg/kg every 2 weeks; flat doses of 400 mg every 4 weeks and 300 mg every 2 weeks were also evaluated. The primary objective was safety/tolerability; secondary objectives were pharmacokinetics and preliminary efficacy; and exploratory objectives were immunogenicity, GITR occupancy, and immune biomarker assessment. RESULTS: Among 100 patients enrolled [prior anti-PD-1/PD-L1 therapy, 47%; most common tumors: colorectal (19%) and melanoma (14%)], 2% had one dose-limiting toxicity (grade 4 hypoxia and grade 3 pleurisy). The MTD was not reached. Treatment-related adverse events (TRAE) occurred in 69% of patients, most frequently fatigue (17%) and pruritus (14%); 10% had grade ≥3 TRAEs, most commonly fatigue (3%); and 23% reported immune-related adverse events, most frequently generalized pruritus and generalized rash (7% each). Doses ≥5 mg/kg every 2 weeks resulted in full receptor occupancy at trough. INCAGN01876 elicited changes in immune parameters in some patients, including variable peripheral regulatory T-cell depletion and cytokine upregulation. Two patients achieved confirmed partial responses: one with appendiceal mucinous carcinoma and another with melanoma previously treated with pembrolizumab and glembatumumab; 36% of patients had disease control. CONCLUSIONS: INCAGN01876 was generally well tolerated; fatigue was the most frequent TRAE. INCAGN01876 elicited transient and variable regulatory T-cell depletion and limited antitumor activity. Future studies will explore combinatorial approaches.

Pan-cancer prediction of tumor immune activation and response to immune checkpoint blockade from tumor transcriptomics and histopathology

Accurately predicting which patients will respond to immune checkpoint blockade (ICB) remains a major challenge. Here, we present TIME_ACT, an unsupervised 66-gene transcriptomic signature of tumor immune activation derived from TCGA melanoma data. First, TIME_ACT scores accurately identify tumors with activated immune microenvironments across cancer types. Analysis of spatial features of the tumor microenvironment revealed that TIME_ACT-high regions exhibit dense lymphocyte infiltration near tumor cells, indicating localized immune activation. Second, in 15 anti-PD1 transcriptomic cohorts spanning six cancer types, TIME_ACT outperforms 22 established signatures and methods, achieving a mean AUC of 0.76 and a clinically meaningful mean odds ratio of 6.11. Thirdly, TIME_ACT scores can be accurately inferred from tumor histopathology slides. Finally, slide-inferred TIME_ACT scores predict ICB response across eight unseen cohorts, achieving a mean AUC of 0.72 and a mean odds ratio of 5.02. These findings establish TIME_ACT as a robust, pan-cancer, and low-cost predictor of ICB response.