Journal for Immunotherapy of Cancer最新文献

Background: Antitumor immune responses induced by oncolytic immunotherapy (OI) are often followed by upregulation of programmed death-ligand 1 (PD-L1). As such, the combination of OI with blockade of the programmed cell death protein-1 (PD-1)/PD-L1 axis has demonstrated therapeutic activity in preclinical and clinical trials. The purpose of this study is to understand further the immune-mediated mechanism of interaction between oncolytic viruses and anti-PD-1 therapy.

Methods: Tumor cells and immune cells (splenocytes) were cultured separately, or in co-culture with vusolimogene oderparepvec, an oncolytic herpes simplex virus expressing the fusogenic gibbon-ape leukemia virus-fusogenic membrane glycoprotein protein (GALV) and granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as RP1. Viral replication, interferon (IFN) responses and PD-L1 expression were analyzed using wild-type, IFNAR1, TNFAR1 and STING knockout splenocytes. In vivo studies evaluated immune cell infiltrates into the tumor following RP1 administration with anti-PD-1 therapy.

Results: RP1 replication was evident in tumor cells but not splenocytes. This was also accompanied by upregulated IFN expression in cultured splenocytes that was absent in cultured tumor cells. However, when these cell types were co-cultured, splenocytes mediated an interferon response to RP1 via STING that was transmitted to tumor cells in a non-touch-dependent manner. Tumor cells responded to these input signals via upregulation of cell surface major histocompatibility complex-I and PD-L1 through tumor intrinsic JAK-STAT signaling. In vivo, an IFN signature was observed following intratumoral injection of RP1, both in injected and non-injected tumors, which was further increased when combined with anti-PD-1 therapy. Marked upregulation of PD-L1 was observed in tumors injected with RP1 accompanied by the recruitment of CD11b+Ly6G+neutrophils into the tumor microenvironment, which stained positive for PD-L1.

Conclusion: Overall, the data demonstrate that RP1 remodels the tumor microenvironment through a combination of direct and indirect effects on both tumor and immune cells, resulting in an overall more inflamed phenotype.

Local immunotherapy comprises broad classes of therapeutics that aim to trigger a robust "in situ" immune response that can ultimately generate systemic antitumor immunity. These agents are appealing as resistance to standard immune checkpoint inhibitors has been linked to a lack of baseline immune activity or immune suppressive elements in the tumor microenvironment. By administering agents directly to the tumor microenvironment, local immune therapies can both stimulate immune response and attempt to "reprogram" or subvert the effects of immune suppressive cell populations. Proof of concept for the benefit of local immune therapy has been demonstrated by several Food and Drug Administration-approved therapies.A "Summit on Intralesional Immunotherapy" was held in September 2024, which comprised lectures and discussion from an international panel of experts on local immune therapy. In this consensus paper, we will discuss unique considerations for local immunotherapy development across the continuum from pre-clinical and early-stage investigation through registration intent clinical trials.Early phase trials offer an opportunity to gain understanding of the biologic activity of candidate therapies and determine optimal dosing schedules. For local immunotherapies, it is most informative to measure the direct effect of the therapy in the tumor microenvironment at both injected and non-injected tumor sites. Carefully planned pharmacodynamic endpoints using on-treatment biopsies and novel imaging strategies to track immune cell activity will maximize the insights from early phase trials. For promising local therapies, selecting the proper patient population and treatment setting are critical. In order to intervene before the tumor microenvironment has reached a fixed immune suppressive state, local immunotherapies may best be suited as part of neoadjuvant or frontline metastatic therapy regimens. We also highlight several specific classes of local immunotherapy under investigation including oncolytic viruses, radiation, messenger RNA, Toll-like receptor agonists, stimulator of interferon gene agonists, CD40 agonists and cytokines.Novel local therapies currently being investigated are poised to expand the field and show promising activity in generating systemic antitumor immunity. Thoughtful trial design in both early stage as well as registration intent settings will accelerate the advancement of this field.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, offering durable responses and prolonged survival. However, these therapies also present unique challenges, particularly with the onset of immune-related adverse events (irAEs), which can manifest during treatment either acutely and/or become chronic or emerge long after treatment cessation. Delayed, chronic, and re-emergent irAEs often require tailored survivorship care, including coordination across multiple disciplines focused on oncology, specialty care, and primary care. Despite the increased usage of ICIs, there is limited longitudinal data guiding the surveillance, diagnosis, attribution, and management of irAEs after ICI treatment. To address these gaps, the Society for Immunotherapy of Cancer convened an Expert Panel to deliberate best practices and identify research opportunities for improving post-treatment care. This paper outlines these expert insights into irAE surveillance, coordination and continuity across care transitions and settings, and clinical management strategies. The paper also underscores the importance of clinicians' understanding of irAE onset patterns, multidisciplinary coordination, and the urgent need in the field for the development of a comprehensive irAE registry. By addressing these critical gaps, the oncology community can better support the growing population of ICI-treated cancer survivors, ensuring improved quality of life and care outcomes.

Background: For patients with high-risk melanoma who are unresponsive or intolerant to immune checkpoint inhibitors, cancer vaccines may provide benefit with a favorable toxicity profile. CD4⁺ T cells provide essential help to dendritic cells (DCs) for optimal CD8⁺ T cell priming in the antitumor response, and induction of tumor-cognate CD4⁺ T cell responses may enhance vaccine efficacy. We report on a first-in-human approach to treat patients with high-risk melanoma using a vaccine composed of six non-mutated melanoma-specific helper peptides (6MHP) and a shared mutated BRAF-V600E neoantigen helper peptide (mBRAF) co-administered locally with a TLR3 agonist (poly-ICLC) and agonistic CD40 antibody (CDX-1140).

Methods: Adults with high-risk melanoma arising from cutaneous, mucosal, or ocular primary sites who were rendered clinically free of disease after definitive treatment were enrolled to this nonrandomized phase I/II trial (NCT04364230) designed to assess safety and immunogenicity. Participants received vaccine (6MHP+mBRAF+poly-ICLC) with a dose-escalation allocation of CDX-1140 into the vaccine mixture at one of four dose levels (50, 200, 800, 3000 μg). Vaccines were administered at 3-week intervals for four doses. Primary endpoints were safety and peripheral CD4⁺ T cell response. Exploratory analysis to characterize the vaccine site microenvironment was performed.

Results: Of 22 eligible participants, 11 (50%) had ocular melanoma. Sixteen (73%) received the maximum CDX-1140 dose. Toxicities were limited to grade 1 or 2 treatment-related adverse events, with no dose-limiting toxicities reported. Peripheral CD4⁺ T cell responses to 6MHP were found ex vivo in six (27%, 95% CI 11% to 50%), including four with the maximum CDX-1140 dose. One had a durable and persistent T cell response to week 25. T cell responses to mBRAF did not meet criteria for positivity ex vivo, but one participant had a durable response after in vitro stimulation, with expansion of multifunctional Th1-polarized CD4⁺ T cells. Favorable immune-related changes were observed at the vaccine site, including CDX-1140-mediated increases in mature (DC-LAMP⁺) DCs.

Conclusions: The vaccine was safe, well-tolerated, and immunogenic. Optimization of vaccines that include agonistic CD40 antibody is needed to enhance immunogenicity. Induction of a multifunctional CD4⁺ T cell response to mBRAF supports targeting shared mutated neoantigens with melanoma vaccines.

Trial registration number: NCT04364230.

T-cell receptors (TCRs) are generated through somatic recombination of variable (V), diversity (D), and joining (J) gene segments, resulting in an extraordinarily diverse receptor repertoire that is essential for immune surveillance and host defense. TCR sequencing (TCR-seq) has emerged as a powerful tool for comprehensive characterization of the adaptive immune repertoire, offering deep insights into T-cell diversity, antigen specificity, and clonal dynamics.TCR-seq enables the tracking of T-cell clones across both temporal and spatial dimensions. From a longitudinal perspective, it allows for the monitoring of clonal dynamics before and after therapeutic interventions or over the course of disease progression. Temporal shifts in clonal composition can reveal the persistence, contraction, or expansion of specific T-cell populations, thereby providing valuable information on the durability of immune responses and the efficacy of treatments. From a spatial standpoint, TCR-seq facilitates comparative analyses of repertoires across distinct anatomical compartments, including tumors, blood, and lymph nodes. Such analyses yield insights into tissue-specific immune responses, T-cell trafficking, and infiltration patterns. Moreover, the ability to track antigen-specific T-cell clones enables the visualization and quantification of tumor-specific immune responses. Advances in spatial TCR-seq now integrate spatial context with clonal identity and repertoire diversity, further illuminating complex immune architecture within tissue microenvironments. Nonetheless, despite the development of various approaches for antigen specificity prediction, further advances are needed to improve their accuracy and generalizability.A wide range of TCR-seq platforms are currently available, including DNA-based and RNA-based protocols, short-read and long-read sequencing technologies, and bulk and single-cell approaches. Each method presents unique advantages in terms of resolution, throughput, cost, and biological relevance. For instance, DNA-based TCR-seq is well suited for longitudinal tracking of clonal populations, whereas RNA-based approaches are advantageous for detecting actively transcribed, antigen-responsive clones. Short-read sequencing offers high-throughput capabilities, while long-read and paired-chain sequencing provide comprehensive structural and functional information on TCRs. Additionally, computational methods, including machine learning algorithms and motif-based clustering, are increasingly employed to infer antigen specificity directly from TCR-seq data.In this review, we examine the current landscape of TCR-seq through the lenses of what, when, where, why, and how, highlighting recent technological developments and emerging applications that are shaping the field of immune repertoire analysis.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by limited treatment options and poor prognosis. Immune checkpoint blockade, particularly via programmed cell death protein-1/programmed death-ligand 1 inhibition, has improved outcomes in selected patients with TNBC; however, resistance remains a major barrier. Recent studies have identified B7-H3 (CD276) as a key immune-suppressive molecule overexpressed in TNBC, correlating with poor prognosis and immune exclusion. Jiang et al demonstrate that B7-H3 inhibition triggers a compensatory metabolic adaptation in TNBC cells, marked by upregulation of fatty acid synthesis and β-oxidation, particularly via the AKT-SREBP1-FASN signaling axis. This metabolic reprogramming promotes survival and immune evasion, limiting the efficacy of B7-H3-targeted therapies. Dual inhibition of B7-H3 and fatty acid synthase synergistically enhances tumor cell apoptosis, suppresses proliferation and migration, and promotes CD8⁺ T-cell infiltration in vitro and in vivo. These findings reveal a novel immune-metabolic resistance mechanism in TNBC and provide a compelling rationale for combinatorial strategies targeting both immune checkpoints and metabolic pathways.

Objective: Metadherin (MTDH) is a recognized oncogene involved in the progression and metastasis of various cancers. However, further studies are needed to elucidate the biological role of MTDH, which is expressed in macrophages during tumor progression.

Methods: Mouse colorectal cancer and melanoma cells were subcutaneously and intravenously injected into myeloid-specific Mtdh knockout mice to evaluate tumor growth and lung metastases. The effects of macrophage with Mtdh knockout on angiogenesis and fibrosis were examined using mass spectrometry, immunofluorescence staining, analyses of data from The Cancer Genome Atlas (TCGA) colon adenocarcinoma and melanoma cohorts, and western blotting. A thrombospondin (TSP-1) blocking peptide was used to inhibit transforming growth factor β1 (TGF-β1) activation for suppression of fibrosis in vivo and in vitro. The molecular mechanisms were investigated using RNA sequencing data from the Gene Expression Omnibus database, ELISA, immunoprecipitation, chromatin immunoprecipitation assay, quantitative real-time PCR, and western blotting.

Results: Mtdh-deficient macrophages suppressed lung metastasis but, unexpectedly, promoted subcutaneous tumor growth of both cancer cell types. This discordant effect was attributed to increased production of TSP-1, an angiogenesis inhibitor that also regulates fibrosis through TGF-β1 activation. Mtdh knockout in macrophages inhibited angiogenesis in both lung metastatic and subcutaneous tumors, whereas enhanced fibrosis was observed only in subcutaneous tumors. In TCGA colon adenocarcinoma data, higher TSP-1 expression correlated with advanced pathological T stage and cancer-associated fibroblasts abundance. Furthermore, Mtdh loss in macrophages induced activation of latent TGF-β1 in tumor cells, promoting fibroblast-to-myofibroblast transition, fibrosis, and unexpected tumor growth through the TSP-1/TGF-β1 axis. Mechanistically, MTDH deficiency led to nuclear retention of murine double minute-2 (MDM2), disruption of the MDM2-p53 interaction, and enhanced p53-dependent TSP-1 transcription.

Conclusions: We found that macrophage Mtdh deficiency discordantly regulates tumor metastasis and growth through either TSP-1-mediated anti-angiogenic effect or a TSP-1/TGF-β1-mediated pro-fibrotic effect. This study, therefore, provides novel insights into the mechanisms underlying the discordance between tumor growth and metastasis.

Tumor-associated macrophages are key myeloid cells in the tumor microenvironment (TME), acting as essential orchestrators of innate and adaptive immune responses. The efficacy of current antitumoral treatments can be promoted by macrophages, thanks to their phagocytosis, tumoricidal activity, and eliciting of adaptive immunity; or restricted by their expression of inhibitory counter-receptors (such as programmed death-ligand 1 or signal regulatory protein alpha). Furthermore, the continuous recruitment of these myelomonocytic cells into tumor tissues makes them attractive candidates for cell therapy with the development of chimeric antigen receptor (CAR) effector cells. This evidence highlights the strong therapeutic potential of macrophage engineering for the treatment of solid tumors. In this line of research, Du et al developed pArg1-CD47 CAR-Mφ based on intrinsic Arg1 promoter responsiveness for TME-specific activation of cytotoxicity, effectively overcoming SIRPα inhibition against CD47+cancer cells. In preclinical murine models of breast and gastric cancer, this macrophage cell therapy demonstrated significant regression of established tumors with minimal toxicity towards erythrocytes. Although translating this work from mice to humans remains a significant challenge, it provides hope for the design of myeloid cell therapies with antitumoral efficacy and safe profile for solid tumors.

T cell engagers (TCEs) recruit T cells to the tumor microenvironment (TME) to induce antitumor immune responses. TCEs have demonstrated promising clinical responses in patients with metastatic castration-resistant prostate cancer and have advanced into phase 3 clinical trials. Here we provide an overview of the mechanisms of action of TCEs, including both CD3-targeted and CD28-targeted agents, and review the clinical development of these agents for prostate cancer. We propose a path forward for TCEs in prostate cancer, in which innovative clinical trials will facilitate a biological understanding of mechanisms of efficacy and toxicity to inform: (1) development of predictive biomarkers for patient selection; (2) rational combination strategies; and (3) targeted treatments for toxicity management, ultimately delivering broad clinical benefit for patients with lethal prostate cancer.

Background: At diagnosis, ~80% of pancreatic ductal adenocarcinomas (PDAC) have metastasized. Relapse is thus common even among patients who undergo surgical resection, the only curative option. PDAC progresses rapidly, and existing immunotherapies have been ineffective. We hypothesized that natural killer (NK) cell immunotherapies could be effective against PDAC because they recognize conserved and heterogeneous features associated with cellular stress and transformation and can seek out metastases distal to the primary tumor site. Here, we aim to define the key features of NK cells as effective agents for PDAC immunotherapy.

Methods: We used The Cancer Genome Atlas Program (TCGA) PDAC Firehose data and flow cytometry to predict and measure the most common activating or inhibitory ligands available on PDAC for NK cell activation. To ascertain how the tumor might alter expression of these ligands during treatment, inflammation or immune pressure, we measured expression of NK ligands at rest, or after exposure to immune cells or inflammation. To test and rank the functional importance of these dynamic ligands in the recognition, killing and control of PDAC we used co-culture, antibody-blocking and an NK-competent humanized mouse model.

Results: Leveraging the known sequential acquisition of mutations as a surrogate for disease progression, we observed a progressive loss of transcript expression for activating NK cell ligands and chemoattractants. Exposure of PDAC to NK cells or interferon-γ, an inflammatory stimulus, drove dynamic changes in expression of both activating and inhibitory ligands. In vitro co-culture assays revealed a redundancy in the activating receptors engaged in NK:PDAC interactions, but that human leukocyte antigens (HLA)-killer immunoglobulin-like receptors (KIR) signaling dominantly interrupted anti-PDAC activity. In NK-competent humanized mice, adoptively transferred, unselected, unmodified NK cells slowed tumor growth in a dose-dependent manner, but NK cells selected to avoid HLA I-driven inhibition were the most competent effectors for PDAC control.

Conclusions: Although there is redundancy among activating ligand:receptor pairs for recognizing PDAC tumors, interactions between KIR and HLA define the extent to which antitumor activity can proceed. During tumor progression and in response to immunotherapy, NK:tumor interactions drive upregulation of HLA I molecules. Thus, educated NK cells from HLA I-disparate donors may be the more effective allogeneic NK immunotherapy for PDAC.