Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30‒50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3‒4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90‒100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO’s MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC.

Predicting whether a patient with cancer will benefit from immune checkpoint inhibitors (ICIs) without resorting to advanced genomic or immunologic assays is an important clinical need. To address this, we developed and evaluated SCORPIO, a machine learning system that utilizes routine blood tests (complete blood count and comprehensive metabolic profile) alongside clinical characteristics from 9,745 ICI-treated patients across 21 cancer types. SCORPIO was trained on data from 1,628 patients across 17 cancer types from Memorial Sloan Kettering Cancer Center. In two internal test sets comprising 2,511 patients across 19 cancer types, SCORPIO achieved median time-dependent area under the receiver operating characteristic curve (AUC(t)) values of 0.763 and 0.759 for predicting overall survival at 6, 12, 18, 24 and 30 months, outperforming tumor mutational burden (TMB), which showed median AUC(t) values of 0.503 and 0.543. Additionally, SCORPIO demonstrated superior predictive performance for predicting clinical benefit (tumor response or prolonged stability), with AUC values of 0.714 and 0.641, compared to TMB (AUC = 0.546 and 0.573). External validation was performed using 10 global phase 3 trials (4,447 patients across 6 cancer types) and a real-world cohort from the Mount Sinai Health System (1,159 patients across 18 cancer types). In these external cohorts, SCORPIO maintained robust performance in predicting ICI outcomes, surpassing programmed death-ligand 1 immunostaining. These findings underscore SCORPIO’s reliability and adaptability, highlighting its potential to predict patient outcomes with ICI therapy across diverse cancer types and healthcare settings.

CD4⁺ T cells can "help” or "license” conventional type 1 dendritic cells (cDC1s) to induce CD8⁺ cytotoxic T lymphocyte (CTL) anticancer responses, as proven in mouse models. We recently identified cDC1s with a transcriptomic imprint of CD4⁺ T-cell help, specifically in T-cell-infiltrated human cancers, and these cells were associated with a good prognosis and response to PD-1-targeting immunotherapy. Here, we delineate the mechanism of cDC1 licensing by CD4⁺ T cells in humans. Activated CD4⁺ T cells produce IFNβ via the STING pathway, which promotes MHC-I antigen (cross-)presentation by cDC1s and thereby improves their ability to induce CTL anticancer responses. In cooperation with CD40 ligand (L), IFNβ also optimizes the costimulatory and other functions of cDC1s required for CTL response induction. IFN-I-producing CD4⁺ T cells are present in diverse T-cell-infiltrated cancers and likely deliver “help” signals to CTLs locally, according to their transcriptomic profile and colocalization with “helped/licensed” cDCs and tumor-reactive CD8⁺ T cells. In agreement with this scenario, the presence of IFN-I-producing CD4⁺ T cells in the TME is associated with overall survival and the response to PD-1 checkpoint blockade in cancer patients.

To dissect the effect of neoadjuvant PD-1 and CTLA4 blockade on intratumoral T cells in treatment-naive head and neck squamous cell carcinoma, we analyzed primary tumor immune infiltrates from responding and nonresponding patients. At baseline, a higher ratio between active (4-1BB/OX40+) and inactive regulatory CD4+ T cells was associated with immunotherapy response. Furthermore, upon therapy, this active regulatory T-cell (Treg) population showed a profound decrease in responding patients. In an analogous process, intratumoral dysfunctional CD8+ T cells displayed decreased expression of activity and dysfunction-related genes in responding patients, whereas in clinical nonresponders, natural killer cells showed an increased cytotoxic profile early upon treatment. These data reveal immunologic changes in response to dual PD-1/CTLA4 blockade, including a parallel remodeling of presumed tumor-reactive Treg and CD8+ T-cell compartments in responding patients, and indicate that the presence of activated Tregs at baseline may be associated with response. Significance: In head and neck squamous cell carcinoma, neoadjuvant PD-1/CTLA4 blockade has shown substantial response rates (20%–35%). As recognition of tumor antigens by T cells appears to be a critical driver of therapy response, a better understanding of alterations in T-cell state that are associated with response and resistance is of importance. This article is featured in Selected Articles from This Issue, p. 2109

BACKGROUND. Recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) is often an incurable disease, with patients experiencing median survival of under ten months and significant morbidity. While immune checkpoint blockade (ICB) drugs are effective in ~20% of patients, the remaining experience limited clinical benefit and are exposed to potential adverse effects and financial costs. Clinically approved biomarkers, such as tumor mutational burden (TMB), have modest predictive value in HNSCC. METHODS. We analyze clinical and genomic features, generated using whole-exome sequencing, in 133 ICB-treated R/M HNSCC patients, of whom 69 had virus-associated and 64 had non-virus-associated tumors. RESULTS. Hierarchical clustering of genomic data revealed six molecular subtypes characterized by a wide range of objective response rates and survival after ICB therapy. The prognostic importance of these 6 subtypes was validated in an external cohort. A random forest-based predictive model, using several clinical and genomic features, predicted progression-free survival (PFS), overall survival (OS), and response with greater accuracy than a model based on TMB alone. Recursive partitioning analysis identified three features (systemic inflammatory response index, TMB, and smoking signature) that classified patients into risk groups with accurate discrimination of PFS and OS. CONCLUSION. These findings shed light on the immunogenomic characteristics of HNSCC tumors that drive differential response to ICB and identify a clinical-genomic classifier that outperforms the current clinically approved biomarker of TMB. This validated predictive tool may help with clinical risk stratification in patients with R/M HNSCC for whom ICB is being considered.