Journal for Immunotherapy of Cancer最新文献

Background: B7 homolog 3 (B7-H3), an overexpressed antigen across multiple solid cancers, represents a promising target for CAR T cell therapy. This study investigated the expression of B7-H3 across various solid tumors and developed novel monoclonal antibodies (mAbs) targeting B7-H3 for CAR T cell therapy.

Methods: Expression of B7-H3 across various solid tumors was evaluated using RNA-seq data from TCGA, TARGET, and GTEx datasets and by flow cytometry staining. B7-H3-specific mAbs were developed by immunizing mice with human B7-H3, screening with ELISA, and analyzing kinetics with surface plasmon resonance. These mAbs were used to create second-generation CAR constructs, which were evaluated in vitro and in vivo for their antitumor function.

Results: We identified four mAb clones from immunized mice, with three demonstrating high specificity and affinity. The second-generation B7-H3 CAR T cells derived from these mAbs exhibited robust cytotoxicity against B7-H3-positive targets and successfully infiltrated and eliminated tumor spheroids in vitro. In a xenograft mouse model of glioblastoma, these CAR T cells, particularly those derived from clone A2H4, eradicated the primary tumor, and effectively controlled rechallenge tumor, resulting in prolonged survival of the xenograft mice. In vivo T cell trafficking revealed high accumulation and persistence of A2H4-derived CAR T cells at the tumor site.

Conclusions: Our results provide novel B7-H3-targeted CAR T cells with high efficacy, paving the way for clinical translation of solid tumor treatment.

Chimeric antigen receptor T cell (CAR-T) therapies are now standard-of-care for several B-cell malignancies, and additional indications are being evaluated. In this review, we survey data on how outcomes after CAR-T therapies vary according to age, race, and ethnicity. We also review the representation of age, racial, and ethnic groups in key CAR-T clinical trials. We focus on B-cell acute lymphoblastic leukemia, B-cell non-Hodgkin's lymphoma, and multiple myeloma.

Neoadjuvant (presurgical) anti-programmed cell death protein-1 (PD-1)-based immunotherapy as a new approach to cancer treatment has been developing on an accelerated trajectory since the seminal clinical trial results from studies in lung cancer and melanoma were published in 2018. Groundbreaking regulatory approvals in triple-negative breast cancer, non-small cell lung cancer and melanoma will certainly be followed by additional approvals in other disease indications, as clinical and basic research are burgeoning globally in hundreds of clinical trials across dozens of cancer types. As this field is evolving, it is addressing gaps in our understanding of biological mechanisms underlying PD-1 pathway blockade and their synergy with other antineoplastic drugs, probing mechanisms of response and resistance to neoadjuvant immunotherapy, optimizing efficacious clinical strategies, and analyzing commonalities and differences across cancer types. Knowledge gained thus far provides a firm foundation from which to launch the next phase of translational research in this expanding arena of biomedical investigation.

Extracellular vesicles (EVs) are produced by all living cells and are present in all body fluids. EVs are heterogeneous in size, biogenesis, molecular/genetic content and functions. They constitute a part of the intercellular communication system. Among them, a subset of small EVs (sEVs) (30-150 nm) originating in the tumor cell endosomes and often referred to as "tumor cell-derived exosomes" have been of special interest. Tumors have adapted sEV they produce to promoting their own survival. Plasma of patients with cancer contains variably elevated numbers of tumor-derived sEV called "TEX," which differ from circulating sEV produced by non-malignant cells by the immunosuppressive phenotype and the molecular/genetic content. Immunosuppressive molecular profiles and abilities to signal, enter and functionally reprogram a variety of recipient cells enable TEX to exert pro-tumor effects that promote tumor resistance to immunotherapy. This review describes phenotypic and functional attributes of TEX that underline their reprogramming capabilities. It also considers mechanisms responsible for TEX pro-tumor activities and the potential significance of TEX signaling for responses of patients with cancer to immune therapies.

The application of messenger RNA (mRNA) technology in antigen-based immuno-oncology therapies represents a significant advancement in cancer treatment. Cancer vaccines are an effective combinatorial partner to sensitize the host immune system to the tumor and boost the efficacy of immune therapies. Selecting suitable tumor antigens is the key step to devising effective vaccinations and amplifying the immune response. Tumor neoantigens are de novo epitopes derived from somatic mutations, avoiding T-cell central tolerance of self-epitopes and inducing immune responses to tumors. The identification and prioritization of patient-specific tumor neoantigens are based on advanced computational algorithms taking advantage of the profiling with next-generation sequencing considering factors involved in human leukocyte antigen (HLA)-peptide-T-cell receptor (TCR) complex formation, including peptide presentation, HLA-peptide affinity, and TCR recognition. This review discusses the development and clinical application of mRNA vaccines in oncology, with a particular focus on recent clinical trials and the computational workflows and methodologies for identifying both shared and individual antigens. While this review centers on therapeutic mRNA vaccines targeting existing tumors, it does not cover preventative vaccines. Preclinical experimental validations are crucial in cancer vaccine development, but we emphasize the computational approaches that facilitate neoantigen selection and design, highlighting their role in advancing mRNA vaccine development. The versatility and rapid development potential of mRNA make it an ideal platform for personalized neoantigen immunotherapy. We explore various strategies for antigen target identification, including tumor-associated and tumor-specific antigens and the computational tools used to predict epitopes capable of eliciting strong immune responses. We address key design considerations for enhancing the immunogenicity and stability of mRNA vaccines, as well as emerging trends and challenges in the field. This comprehensive overview highlights the therapeutic potential of mRNA-based cancer vaccines and underscores ongoing research efforts aimed at optimizing these therapies for improved clinical outcomes.

Background: ATOR-1017 (evunzekibart) is a human agonistic immunoglobulin G4 antibody targeting the costimulatory receptor 4-1BB (CD137). ATOR-1017 activates T cells and natural killer cells in the tumor environment, leading to immune-mediated tumor cell death.

Methods: In this first-in-human, multicenter, phase I study, ATOR-1017 was administered intravenously every 21 days as a monotherapy to patients with advanced, unresectable solid tumors having received multiple standard-of-care treatments. The study used single patient cohorts for rapid dose escalation up to 40 mg; thereafter a modified 3+3 design up to 900 mg. Escalating doses were given until disease progression, unacceptable toxicity, or withdrawal of consent. The primary objective of the study included determination of the maximum tolerated dose (MTD) via assessment of adverse events and dose-limiting toxicities (DLTs). Secondary objectives included determination of the pharmacokinetics, immunogenicity and clinical efficacy assessed with CT scans using immune Response Evaluation Criteria in Solid Tumors. Exploratory objectives included pharmacodynamic (PD) assessment of immune system biomarkers.

Results: Of the 27 patients screened, 25 received treatment with ATOR-1017. The median time on study was 13.1 weeks (range 4.3-92.3). The MTD of ATOR-1017 was not reached. Treatment-related adverse events (TRAEs) were reported in 13 (52%) of 25 patients; most common (≥10%) were fatigue (n=4 (16.0%) patients) and neutropenia (n=3 (12.0%) patients). Five patients experienced a severe (≥ grade 3) TRAE; neutropenia (n=2), febrile neutropenia (n=1), chest pain (n=1), increased liver enzymes (n=1), and leukopenia and thrombocytopenia (n=1). No patients discontinued due to TRAEs and no DLTs were observed. Pharmacokinetic data demonstrated approximate dose-proportional kinetics. Dose-dependent increases in PD biomarkers, including soluble 4-1BB, are indicative of target-mediated biological activity. Best response was stable disease in 13 out of 25 patients (52%), maintained for 6 months or longer in six patients (24%).

Conclusions: Treatment with ATOR-1017 was safe and well tolerated at all dose levels and demonstrated biological activity. Furthermore, almost one-third of patients experienced long-lasting stable disease in this heavily pretreated population. The encouraging safety and preliminary efficacy data warrant further clinical development of ATOR-1017, possibly in combination with other anticancer agents.

Background: More efficient therapeutic options for non-small cell lung cancer (NSCLC) are needed as the survival at 5 years of metastatic disease is near zero. In this regard, we used a preclinical model of metastatic lung adenocarcinoma (SV2-OVA) to assess the safety and efficacy of novel radio-immunotherapy combining hypofractionated radiotherapy (HRT) with muPD1-IL2v immunocytokine and muFAP-CD40 bispecific antibody.

Methods: We evaluated the changes in the lung immune microenvironment at multiple timepoints following combination therapies and investigated their underlying antitumor mechanisms. Additionally, we analyzed the tumor clonal heterogeneity upon the combination treatments to explore potential mechanisms associated with the lack of complete response.

Results: The combination of HRT with muPD1-IL2v had a potent antitumor effect and increased survival in the SV2-OVA lung cancer model. Importantly, this combination therapy was devoid of measurable toxicity. It induced remodeling of the immune contexture through the increase of CD8⁺ T and natural killer (NK) cells. The addition of muFAP-CD40 to the combination treatment further increased infiltrating CD8⁺ T cells, expressing high levels of effector molecules, both in the periphery and core tumor regions. An accumulation of CD8⁺ PD-1⁺ TOX⁺ (exhausted) T cells, already at the 'early' timepoint, is consistent with the limited clinical benefits provided by the various combination treatments in this model. The study of the clonal dynamics of tumor cells during disease progression and therapy highlighted a clonal selection upon HRT+muPD1-IL2v therapy.

Conclusions: We demonstrated that HRT+muPD1-IL2v combination is a potent therapeutic strategy to delay tumor growth and increase survival in a metastatic lung cancer model, but additional studies are required to completely understand the resistance mechanisms associated with the lack of complete response in this model.

Background: Chordoma is a slow-growing, primary malignant bone tumor that arises from notochordal tissue in the midline of the axial skeleton. Surgical excision with negative margins is the mainstay of treatment, but high local recurrence rates are reported even with negative margins. High-dose radiation therapy (RT), such as with proton or carbon ions, has been used as an alternative to surgery, but late local failure remains a problem. B7-H3 is an immune checkpoint, transmembrane protein that is dysregulated in many cancers, including chordoma. This study explores the efficacy of B7-H3 chimeric antigen receptor T (CAR-T) therapy in vitro and in vivo.

Methods: Chordoma cancer stem cells (CCSCs) were identified using flow cytometry, sphere formation, and western blot analysis. The expression of B7-H3 in paraffin-embedded chordoma tissue was determined by immunohistochemical staining, and the expression of B7-H3 in chordoma cells was measured by flow cytometry. Retroviral particles containing either B7-H3 or CD19 CAR-expressing virus were transduced into T cells derived from peripheral blood mononuclear cells isolated from healthy human donor blood to prepare CAR-T cells. Animal bioluminescent imaging was used to evaluate the killing effect of CAR-T cells on chordoma cells in vivo. An irradiator was used for all irradiation (IR) experiments.

Results: The combination of B7-H3 CAR-T cell therapy and IR has a greater killing effect on killing radiation-resistant CCSCs and bulk chordoma cells compared with CAR-T cell or IR monotherapy. Additionally, increased expression of B7-H3 antigens on CCSCs and bulk tumor cells is associated with enhanced CAR-T cell killing in vitro and in vivo xenograft mouse models. Upregulation of B7-H3 expression by IR increases CCSCs sensitivity to B7-H3 CAR-T cell-mediated killing.

Conclusions: Our preliminary data show that IR and B7-H3 CAR-T cell therapy is synergistically more effective than either IR or CAR-T cell monotherapy in killing chordoma cells in vitro and in a xenograft mouse model. These results provide preclinical evidence for further developing this combinatorial RT and B7-H3 CAR-T cell therapy model in chordoma.

Background: Endogenous retrovirus (ERV) elements are genomic footprints of ancestral retroviral infections within the human genome. While the dysregulation of ERV transcription has been linked to immune cell infiltration in various cancers, its relationship with immune checkpoint inhibitor (ICI) response in solid tumors, particularly metastatic clear-cell renal cell carcinoma (ccRCC), remains inadequately explored.

Methods: This study analyzed patients with metastatic ccRCC from two prospective clinical trials, encompassing 181 patients receiving nivolumab in the CheckMate trials (-009 to -010 and -025) and 48 patients treated with the ipilimumab-nivolumab combination in the BIONIKK trial. ERV expression was quantified using the ERVmap algorithm from RNA sequencing data. Our primary objective was to correlate ERV expression with progression-free survival, with overall survival and time-to-second-treatment survival as secondary endpoints. We used bootstrap methods with univariate Cox regression on 666 substantially expressed ERVs to evaluate their prognostic significance and stability.

Results: Our analysis centered on two ERVs, E4421_chr17 and E1659_chr4, which consistently exhibited opposing prognostic impacts across both cohorts. We developed a stratification system based on their median expression levels, categorizing patients into four ERV subgroups. These subgroups were further consolidated into a three-tier risk model that significantly correlated with ICI treatment outcomes. The most responsive ERV risk category showed enhanced endothelial cell infiltration, whereas the resistant category was characterized by higher levels of myeloid dendritic cells, regulatory T cells, myeloid-derived suppressor cells, and markers of T-cell exhaustion. Notably, this ERV-based classification outperformed traditional transcriptomic signatures in predicting ICI efficacy and showed further improvement when combined with epigenetic DNA methylation markers.

Conclusions: Our findings introduce a dual ERV-based stratification system that effectively categorizes patient risk and predicts clinical outcomes for ccRCC patients undergoing ICI therapy. Beyond enhancing the predictive precision of existing transcriptomic models, this system paves the way for more targeted and individualized approaches in the realm of precision oncology.

Background: ACKR2 is an atypical chemokine receptor that plays a significant role in regulating inflammation by binding to inflammatory CC chemokines and facilitating their degradation. Previous findings suggest that the genetic absence of ACKR2 leads to heightened tumor growth in inflammation-driven models. Conversely, mice lacking ACKR2 exhibit protection against lung metastasis in melanoma and breast cancer models. This study aims to explore the specific cell types expressing ACKR2 and their relative contributions to the protection against lung metastasis.

Methods: ACKR2 expression was studied by the generation of an inducible and conditional knockout (KO) mouse expressing two reporter genes, luciferase and TdTomato visible by In Vivo Imaging System, flow cytometry and immunofluorescence. Gene expression in lung endothelial cells (ECs) was investigated by RNA sequencing analysis. In vivo models of lung metastasis and inflammation were performed in wild-type (WT) and conditional KO mice by intravenous injection of melanoma and colon cancer cell lines; the induction of acute lung injury model was done by intranasal injection of lipopolysaccharide (LPS). Leukocytes infiltrating lung metastasis were studied by fluorescence-activated cell sorting (FACS) analysis. The serum chemokine levels were studied with a multiplex ELISA.

Results: The analysis of the reporter mouse revealed that ACKR2 is expressed by lymphatic endothelial cells (LECs) in most murine organs. However, uniquely in the lungs, ACKR2 expression is observed in blood endothelial cells (BECs), specifically in capillaries known as aerocytes specialized for regulating leukocyte trafficking. Selective deletion of Ackr2 from ECs (ACKR2^ΔCdh5 mice) but not from LECs (ACKR2^ΔProx1 mice) resulted in protection in models of melanoma and colorectal cancer lung metastasis. This protection was associated with an increased presence of activated T lymphocytes infiltrating the lungs compared with WT mice. Additionally, in a model of acute lung injury, mice with selective deletion from the endothelial compartment exhibited heightened extravasation of T lymphocytes compared with both ACKR2 KO and WT mice.

Conclusions: These results indicate that ACKR2 is selectively expressed by lung vascular capillaries (aerocytes) that are devoted to the regulation of leukocyte extravasation. Selective ACKR2 targeting in this compartment, by modulating chemokine availability, promotes T lymphocyte extravasation resulting in reduced lung metastases.