Joshua D. Brody

The exquisite antigen specificity of T cells is one foundation of modern cancer immunotherapy. The therapeutic efficacy of checkpoint blockade, cancer vaccines, and engineered T-cell therapies, all appear to depend on T cells capable of recognizing specific antigens displayed by tumor cells. In a recent issue of Nature Immunology, Smith and colleagues challenge this paradigm by demonstrating that local activation of virus-specific memory T cells can eliminate tumors without direct tumor-cell recognition. Instead, activated T cells initiate a multicellular inflammatory response involving IFNγ, TNF, nitric oxide and recruited myeloid cells that collectively induce tumor-cell death. These findings separate the antigen specificity required for T-cell activation from that required for tumor killing and expand the role of T cells from direct cytotoxic effectors to organizers of a broader antitumor response. Together, these findings broaden the potential scope of T-cell-mediated antitumor immunity beyond the constraints of direct tumor-antigen recognition.

Patients with newly diagnosed large B-cell lymphoma (LBCL) and International Prognostic Index (IPI) scores ≥3 have inferior outcomes with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). We evaluated efficacy and safety of epcoritamab plus R-CHOP in newly diagnosed LBCL in Arm 1 of the phase 1b/2 EPCORE NHL-2 trial. Adults with CD20+ LBCL and IPI scores 3-5 received R-CHOP (6 cycles) plus epcoritamab for a total of 1 year of treatment. Primary endpoint was investigator-assessed overall response rate (ORR). Key secondary endpoints included complete response (CR) rate, duration of CR (DOCR), progression-free survival (PFS), overall survival (OS), minimal residual disease (MRD) negativity, and safety. Forty-seven patients were treated. Median age was 64 years, 89% had Ann Arbor stage IV, and 53% had bulky disease (≥7 cm). ORR was 98% (95% CI, 89-100) and CR rate 85% (95% CI, 72-94). At median follow-up of 44.2 months, median DOCR, PFS and OS were not reached (NR; 95% CI, NR-NR); estimated 2-year PFS and OS rates were 80% (95% CI, 65-89) and 87% (95% CI, 73-94), respectively. MRD-negativity was achieved in 100% of MRD-evaluable patients. Most common adverse events were neutropenia (74%), anemia (72%), and cytokine release syndrome (CRS; 60%). CRS events were predominantly grade 1-2; all resolved. Epcoritamab plus R-CHOP induced high response rates in patients with newly diagnosed LBCL and IPI scores 3-5. These promising findings support the ongoing phase 3 evaluation of this treatment regimen. This trial was registered at ClinicalTrials.gov (NCT04663347).

First‐line (1L) bendamustine plus rituximab (BR) leads to high response rates in follicular lymphoma (FL), but maintaining durable remissions remains challenging. We report the 3‐year follow‐up from arm 3 of the phase 1b/2 EPCORE NHL‐2 trial (NCT04663347) of epcoritamab, a subcutaneously administered CD3×CD20 bispecific antibody, combined with BR in patients with newly diagnosed FL. Twenty‐five patients received epcoritamab plus BR, followed by epcoritamab monotherapy for up to 2 years. At a median follow‐up of 41.3 months, the best overall response and CR rates were both 96%. The median time to CR was 1.5 (range 1–6) months. At 3 years, 87% of responders maintained CR. High CR rates were observed across subgroups, including 100% of patients with bulky disease (≥7 cm), 93% with Follicular Lymphoma International Prognostic Index score ≥3, and 100% with bone marrow involvement. The three‐year progression‐free survival and overall survival rates were 83% and 96%, respectively. Three patients progressed within 24 months of initiating treatment. Long‐term data were consistent with prior reports and the known safety profiles of the individual agents, with no high‐grade cytokine release syndrome or immune effector cell‐associated neurotoxicity syndrome events. Infections occurred in 92% of patients; COVID‐19 was the most common (84%). Overall, 1L FL treatment with epcoritamab plus BR resulted in deep, durable responses beyond 3 years with a consistent safety profile. These results compare favorably with BR alone, although they require confirmation in further studies, and highlight the versatility of epcoritamab in combination with various standards of care and in improving outcomes in FL.

Tertiary lymphoid structures (TLSs) are associated with immunotherapy response, yet the mechanisms controlling their formation and maintenance remain unclear. Using spatial transcriptomics and multiplex imaging across human tumors, we found that CCR7 ⁺ mature dendritic cells (DCs) accumulate in TLSs. In a mouse non–small cell lung cancer model that forms mature TLSs, we show that early TLS development requires interferon-γ (IFN-γ)–driven type 1 conventional dendritic cell (cDC1) maturation, migration to tumor-draining lymph nodes (tdLNs), and T cell recruitment. As tumors progress, TLSs persist independently of tdLN T cell egress, coinciding with cDC1 accumulation within intratumoral CCL19 stromal hubs. There, cDC1–major histocompatibility complex class 1 (MHC-I) and –MHC-II concomitant antigen presentation, along with CD40 signaling, sustain TLS, T follicular helper (T _FH ) cell pool, germinal centers, and tumor-specific immunoglobulin G (IgG). These findings highlight local mature cDC1s as key TLS orchestrators and potential targets to enhance antitumor TLS function.

Proteins encoded by mRNA vaccines can be expressed by a diversity of transfected cell types but how cell-type-specific expression influences immunity is poorly understood. To investigate this, we incorporated synthetic microRNA target sites (miRT) into lipid nanoparticle (LNP)-delivered mRNA vaccines to silence mRNA expression specifically in professional antigen-presenting cells (pAPCs), hepatocytes or myocytes. We found that mRNA expression in pAPCs was dispensable for priming antigen-specific T cells, whereas mRNA expression in myocytes induced similar or stronger immune responses, including for SARS-CoV-2, suggesting that antigen cross-presentation or cross-dressing may be more impactful than direct mRNA expression in pAPCs. In contrast, mRNA expression in hepatocytes suppressed the antigen-specific T cell response, partly through PD1/PDL1. In mice bearing tumor-associated antigen (TAA)-expressing lymphoma cells, miRT-mediated hepatocyte-silenced TAA mRNA vaccine enhanced immune response and reduced tumor burden. Thus, non-pAPC expression shapes immunity to mRNA-encoded protein and inclusion of miRTs can boost or blunt mRNA-LNP immunogenicity.

Epcoritamab and glofitamab are CD20-directed bispecific antibodies (BsAbs) approved in the United States for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Limited data exist for patients treated outside of trials. Patients with R/R DLBCL receiving commercial epcoritamab or glofitamab between 1 January 2023 and 15 October 2024 were collected from 21 United States institutions. Among 245 patients, 156 received epcoritamab and 89 received glofitamab, 113 were refractory to front-line therapy, 40 had MYC and BCL2 and/or BCL6 rearrangements, 147 received prior chimeric antigen receptor T-cell therapy, and 174 patients would have been ineligible for registrational trials. The overall response rate (ORR) for epcoritamab and glofitamab was 51% (23% complete response, [CR]) and 53% (30% CR), respectively. Median progression-free survival (PFS) was 2.6 months (95% confidence interval [CI], 2.0-3.8 months), and median overall survival (OS) was 7.8 months (95% CI, 6.2-11.0 months). The 6-month PFS was 36% (95% CI, 30-44) and the 6-month OS was 60% (95% CI, 54-67). Both trial ineligibility and undetectable CD20 pre-BsAbs portended shorter PFS and OS. Of 17 individuals with paired biopsies, 15 (88.2%) lost CD20 expression after BsAbs with a median time to progression of 3.7 months. This analysis including patients with R/R DLBCL shows the ORR to CD3/CD20 BsAbs was comparable to pivotal trials, although PFS and OS were lower. Baseline undetectable levels of CD20 were associated with poor outcomes. These results demonstrate the activity of BsAbs in R/R DLBCL, and underscore the importance of target antigen expression.

Purpose: We report results from two clinical trials of the cyclic dinucleotide stimulator of IFN genes (STING) agonist ulevostinag. Patients and Methods: In a phase I study (NCT03010176) with an accelerated titration design/modified toxicity probability interval method, participants with advanced/metastatic solid tumors or lymphomas received intratumoral ulevostinag (±intravenous pembrolizumab). In an expansion phase, participants with head and neck squamous cell carcinoma (HNSCC) or triple-negative breast cancer received the combination. Primary objectives were safety/tolerability and identifying the recommended phase II dose; biomarkers were exploratory. In a randomized phase II study (NCT04220866), participants with untreated metastatic or unresectable, recurrent HNSCC received intravenous pembrolizumab (±ulevostinag 540 µg). The primary objective was antitumor activity. Pembrolizumab 200 mg was administered every 3 weeks in both studies. Results: In the phase I study (NCT03010176; N = 156), the most common adverse event was pyrexia (70%). Plasma ulevostinag concentrations increased dose-dependently. Circulating levels of C-X-C motif chemokine 10, IFNγ, and IL-6 showed elevation at 2 to 4 hours, peak at 6 to 8 hours, and plateau/partial resolution at 24 hours but, beyond the 540 µg dose, did not show a clear dose–effect relationship. Ten participants experienced dose-limiting toxicities; the recommended phase II dose for intratumoral ulevostinag was 540 µg. In the phase II study (NCT04220866), 4 of 8 participants treated with combination therapy and 1 of 10 treated with pembrolizumab monotherapy had a complete or partial response. The most common adverse event was pyrexia (n = 5). Conclusions: Intratumoral ulevostinag (±pembrolizumab) had manageable toxicity, dose-dependent pharmacokinetics, and evidence of STING activation and target engagement. Combination therapy showed antitumor activity in participants with untreated metastatic or unresectable, recurrent HNSCC.