Journal for Immunotherapy of Cancer最新文献

Background: Glioblastoma is an aggressive tumor with poor prognosis and limited treatment options due to its resistance to chemotherapy and radiotherapy, high heterogeneity, and ability to evade the immune system. Nevertheless, immunotherapy and oncolytic virotherapy are emerging as promising strategies. This study aimed to evaluate the therapeutic efficacy of an engineered oncolytic Herpes Simplex Virus for glioblastoma treatment.

Methods: We investigated the efficacy of R-115, a retargeted oncolytic Herpes Simplex Virus directed against the human epidermal growth factor receptor 2 (HER2) and engineered to express murine interleukin-12, in an immunocompetent glioblastoma model that recapitulates HER2 tumor heterogeneity. We tested the translatability and reliability of R-115 by assessing overall survival in HER2⁺ or HER2⁺/HER2^- mixed tumors treated with different schedules. We assessed the potential of the treatment to elicit an antitumor vaccination effect by rechallenging previously treated mice with HER2-negative cells in the absence of any further therapy. Additionally, we characterized both the immune and tumor components by analyzing immune cells' proliferation, activation and the resulting tumor cells reduction.

Results: R-115 exhibited potent cytotoxic and immune-stimulatory effects, significantly prolonging survival and eradicating tumors in approximately 25% of treated mice independently from tumor composition and treatment schedule. Furthermore, it induced long-term immune memory, enabling the eradication of secondary transplanted tumors, effectively acting as a tumor-agnostic vaccination. Notably, in addition to the direct oncolysis mediated by the virus, R-115 treatment induced an immune response even against HER2-negative glioblastoma cells, potentially via cross-presentation or epitope spreading.

Conclusions: Our findings candidate R-115 as a promising alternative to standard glioblastoma treatments and support further investigation to advance its clinical application.

Background: Stearoyl-CoA desaturase 1 (SCD1) is a key enzyme in fatty acid (FA) metabolism that catalyzes the addition of a cis double bond to palmitic and stearic saturated FAs, producing palmitoleic and oleic monounsaturated FAs, respectively. Interleukin (IL)9-secreting CD4⁺ T-helper lymphocytes (Th9) exert antitumoral activity in preclinical cancer models. In the present study, we evaluated the role of SCD1 in Th9 differentiation and their antitumoral properties.

Results: A specific monounsaturated FA profile is found in Th9 lymphocytes compared with Th1, Th2, Th17 and regulatory T cell (Treg) lymphocyte subsets and is correlated to the induction of SCD1 expression in mouse and human Th9 differentiated in vitro with TGFβ1 and IL4. The expression of SCD1 is also detected in tumor-draining lymph nodes and tumor-infiltrating Th9 lymphocytes of mice. The canonical Smad3 and non-canonical Pi3K members of the TGFβ signaling drive SCD1 expression in combination with IL4 during Th9 polarization. The invalidation of SCD1 gene expression or inhibition of its activity blocks Th9 differentiation by disrupting Smad2/3 activation. Furthermore, the lipidomic analysis between Th9 and Th9 invalidated for SCD1 gene or activity reveals a change in the FA profile, specifically a decrease in palmitoleic and oleic acids. Nevertheless, only oleic acid restores Th9 differentiation in CD4⁺ T lymphocytes invalidated for SCD1 gene or activity under TGFβ1 and IL4 polarizing conditions. Finally, invalidation of the SCD1 gene or its activity leads to the loss of Th9 antitumoral functions and promotes tumor growth through the production of TGFβ1.

Conclusion: We demonstrate that SCD1 contributes to Th9 differentiation and their antitumoral activity via the regulation of Smad2/3 signaling.

Background: Cergutuzumab amunaleukin (CA) is an immunocytokine comprising an anticarcinoembryonic antigen (CEA) linked to an interleukin-2 (IL-2) variant. CA does not bind to CD25 (IL-2 receptor α) and was designed to maintain the T and natural killer (NK) cell stimulatory effect, while avoiding stimulating effects on regulatory T cells (Tregs). In mouse models, CA previously demonstrated superior tumor targeting to CEA surface expression-positive (CEA+) tumors and increased CD8+ T cells and NK cell numbers in peripheral blood and tumor tissue when compared with wild-type IL-2. We present biomarker data from the first-in-human, open-label, multicenter, phase I, dose-escalation study investigating CA in patients with metastatic/unresectable CEA+ solid tumors (NCT02004106).

Methods: Patients received ascending doses of CA intravenously weekly (qw: 6/10/20 mg) or every 2 weeks (q2w: 10/20/30/40 mg). Flow cytometry determined absolute numbers/mL of CD4+ and CD8+ T cells, NK cells, macrophages/monocytes, Tregs, and B cells and their expression of activation and proliferation markers in circulation. Sequential pretreatment and on-treatment paired tumor biopsies were studied by flow cytometry, multicolor immunohistochemistry, and bulk RNA sequencing. Antitumor activity was used for correlative studies.

Results: Biomarker data were collected from 55 patients. After treatment, peripheral blood samples showed increased proliferating NK cells, CD8+ T cells, and CD4+ T cells, without an apparent dose effect. Levels of circulating soluble CD25 increased in patients with intermediate/high CA doses on-treatment; levels of cytokines, such as tumor necrosis factor, also increased with high CA dose levels. On-treatment tumor samples showed increases in total and proliferating CD8+ T cells as well as CD3+ perforin+ T cells but, importantly, not in Tregs. Notably, increases in the ratio of CD8+/CD4+ T cells were more pronounced for qw than for q2w dosing, while programmed death ligand-1-positive CD14+ cells increased, particularly for the q2w schedule. Higher on-treatment circulating levels of cytokines correlated with longer progression-free survival (PFS). Apart from the positive correlation with NK cell density, no other correlations between PFS and infiltrating immune cell populations in the tumor were observed.

Conclusions: CA-induced immune pharmacodynamic effects in peripheral blood and in the tumor microenvironment without preferential Treg cell activation in patients with metastatic/unresectable CEA+ solid tumors.

Trial registration number: NCT02004106; BP28920.

Background: Patients with non-small cell lung cancer (NSCLC) exhibit heterogeneous responses to immunotherapy (IT) with high resistance rates, highlighting the need for precise biomarkers of treatment outcomes.

Methods: In a prospective cohort study, we longitudinally assessed liquid biopsy samples from patients with NSCLC undergoing IT at four distinct time points (T1 pretreatment, T2 post-second cycle, T3 6 months, and T4 1 year). We profiled plasma-derived cell-free DNA methylation and extracellular vesicle-associated microRNAs from 79 patients with metastatic NSCLC treated with immune checkpoint inhibitors (ICIs). High-dimensional omics data were integrated using Multi-Omics Factor Analysis (MOFA2) to uncover latent molecular subtypes, which we termed MOFA-Derived Clusters (MDCs), independently established at baseline (MDC-T1) and post-second cycle (MDC-T2). Differential expression and methylation analyses, pathway enrichment, and immune phenotyping via flow cytometry were used to characterize the molecular and immunological landscape of each MDC. External validation was performed using independent NSCLC cohorts for miRNAs (Genova et al, 2024, n=54) and methylation (SMC Cohort, GSE119144, n=57).

Results: MDCs captured divergent survival outcomes and reflected biologically coherent processes including angiogenesis, cytoskeletal remodeling, and immune signaling. Projection of MDCs onto later time points (T3, T4) supported the temporal relevance of early molecular signatures. MDCs also displayed immunological correlates via circulating immune cell subsets. Importantly, MDC classifiers demonstrated consistent survival stratification in external cohorts, particularly MDC-T2.

Conclusion: This study defines a multiomic, liquid biopsy-based framework for molecular subtyping in NSCLC to manage ICI treatment. Our MDC signatures reveal clinically meaningful, treatment-informative biology and offer a path toward minimally invasive patient stratification in immuno-oncology.

B cell acute lymphoblastic leukemia (B-ALL) is the most common cancer of childhood. Outcomes for B-ALL have steadily improved over the last five decades, most recently due to impressive activity of chimeric antigen receptor modified T (CAR-T) cells and bispecific antibodies targeting CD19. In contrast, progress against other pediatric cancers has largely stalled. Significant academic effort is underway to expand the reach of CAR T cell therapy in pediatric cancer beyond B-ALL to other hematologic malignancies, solid cancers and brain tumors. Promising clinical activity using CAR-modified T cells has already been demonstrated in neuroblastoma and diffuse midline glioma by targeting the GD2 ganglioside, in pediatric sarcomas by targeting Her2, in Hodgkin's disease by targeting CD30, in T cell lymphoblastic leukemia by targeting CD5 or CD7, and in CAR19 refractory B-ALL by targeting CD22. Comprehensive surfaceome profiling of pediatric tumors is revealing additional novel candidate CAR targets expressed on pediatric cancers, including oncofetal cell surface antigens such as GPC2 and GPC3, which are expressed broadly on pediatric solid and brain tumors, and major histocompatibility complex bound peptides from oncofetal intracellular proteins such as PHOX2B Next-generation CAR T cell therapeutics that incorporate suicide domains, regulatory circuits, logic gating and potency enhancements as well as combination immunotherapies are expected to further augment efficacy while maintaining safety. Current trials are administering CAR T cells in patients with refractory disease, but future studies are warranted to determine whether adjuvant use of CAR T cells could deliver cures with lower intensity standard therapy regimens and thereby reduce long-term toxicities in pediatric cancer survivors. Despite this scientific and clinical progress, the high cost of developing CAR T cells through the traditional biopharma pathway is limiting late-stage clinical development, necessitating the creation of new business models to commercialize CAR T cells for these small markets. CAR T cells hold great promise for improving outcomes for pediatric patients with cancer, but substantial additional research and clinical development is needed if this promise is to be realized for children afflicted with cancer.

Background: Atypical tumor response patterns associated with immunotherapies pose significant challenges for assessing treatment response and clinical decision-making. We characterized the epidemiology, clinical impact, and molecular determinants of pseudo-stability/progression after atezolizumab with and without bevacizumab across several histologies.

Methods: Post hoc individual-level analysis of 2980 patients across eight randomized trials of atezolizumab in non-small cell lung cancer, urothelial carcinoma, renal cell carcinoma (RCC), and hepatocellular carcinoma.

Results: Analyses of the temporal characteristics of atypical responses revealed two distinct patterns including primary and secondary pseudo-stability/progression. Primary pseudo-stability/progression is characterized by initial disease progression and subsequent regression, which occurs in 7.7%-12.5% of patients according to cancer type. In contrast, secondary progression is characterized by initial disease control with subsequent radiographic progression followed by tumor regression, and this occurs in 4.4%-10.8% of patients according to cancer type. Compared with patients matched by the same initial radiographic response, primary and secondary pseudo-stability/progression could be associated with similar or inferior overall survival outcomes depending on the cancer type and classification of the initial tumor response. Exploratory analyses indicate that clinical factors are not predictive of atypical responses, but pseudo-stability/progression could be associated with distinct genomic alterations including TSC1/2 in RCC.

Conclusions: Primary and secondary pseudo-stability/progression occur in a non-trivial proportion of patients across cancer types. Outcomes after pseudo-stability/progression are dependent on cancer type and initial response. Uncovering the clinical and molecular features of pseudo-stability/progression subtypes may guide treatment decisions and identify patients who may benefit from continued immunotherapy despite radiographic progression.

Background: IGSF9, immunoglobulin superfamily member 9, has been reported to inhibit T cell proliferation and activation, thereby promoting tumor immune escape. Tumor-associated macrophages (TAMs), the most abundant tumor-infiltrating immune cells, play a crucial role in forming the immunosuppressive tumor microenvironment. We find that IGSF9 strongly binds to TAMs, however, how it affects TAMs function remains unreported.

Methods: The spatial transcriptomics dataset (GSE189487) was analyzed to clarify the relationship among IGSF9, senescent TAMs, and T cells. RNA-seq revealed differentially expressed genes. Flow cytometry was employed to assess the binding of IGSF9-ECD proteins to macrophages. Macrophage-educated by IGSF9 were co-cultured with T cells, and the phagocytosis was observed. Membrane-system yeast two-hybrid screening, GST pull-down, and co-IP were used to identify the binding partner of IGSF9. Cellular senescence markers and the senescence-associated secretory phenotype (SASP) were assessed by flow cytometry and immunofluorescence. LL/2-control or LL/2-Igsf9 cells were injected into C57BL/6, NSG, and monocytes-depleted C57BL/6 mice. Similarly, MC38-OVA-control or MC38-OVA-Igsf9 cells were inoculated into OT-II mice. Finally, anti-IGSF9 and its LALA-PG-mutant variant were administered to C57BL/6 mice to monitor tumor growth and SASP expression.

Results: The spatial transcriptomics dataset (GSE189487) revealed that the level of IGSF9 in tumor cells was positively correlated with the senescence of TAMs, and RNA-seq revealed the differentially expressed genes which were related to senescence. Macrophage educated by IGSF9 exhibited distinct senescence phenotypes and immunosuppressive features, and IGSF9 bound to TMUB1 to activate the IL-6/STAT3 signal pathway to trigger the above phenotype. In vivo data showed that IGSF9 could induce TAM senescence, leading to inhibition of T cell activity and formation of an immunosuppressive microenvironment, then promoting tumor immune escape. Treatment with anti-IGSF9, including the LALAPG-mutant variant that reduces antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis, mitigated TAM senescence and immunosuppression, activated T cells, and suppressed tumor growth.

Conclusions: TMUB1 as a binding protein of IGSF9 is first discovered, and TAMs educated by IGSF9 exhibit senescent and suppressive phenotype to orchestrate an inhibitory tumor microenvironment, which can be reversed by anti-IGSF9 to suppress tumor progression.

Background: Given the success of checkpoint inhibitor therapy in the advanced Merkel cell carcinoma (MCC) setting, there is interest in exploring immunotherapy as a neoadjuvant approach. We report the primary results of a neoadjuvant study of lenvatinib plus pembrolizumab in resectable MCC.

Methods: In this single-center, phase II open-label trial, resectable stage II-IV MCC patients received 6 weeks of neoadjuvant therapy with lenvatinib 20 mg orally daily plus pembrolizumab 200 mg intravenous dose every 3 weeks. Following local therapy, patients received continued adjuvant pembrolizumab monotherapy to complete a total treatment duration of 1 year. Pathological complete response (pCR) rate was the primary endpoint of the study.

Results: 26 patients were enrolled, including 5 (19.2%) with clinical stage II disease, 20 (76.9%) with stage III, and 1 (3.8%) with stage IV. Following neoadjuvant treatment, 2 patients (7.7%) were unable to undergo planned surgery, one due to progressive disease and one due to toxicity. On intention to treat, 15 of the 26 patients (57.7%) achieved pCR. Among 22 radiographically evaluable patients, 16 (72.7%) achieved an objective response. At a median follow-up of 20.0 months, median progression-free survival (PFS) has not been reached. PFS significantly correlated with radiographic response to neoadjuvant therapy. pCR was associated with superior PFS, though this result was not statistically significant (p=0.22). Grade 3 treatment-related adverse events (TRAEs) occurred in 14 patients (53.8%), most commonly grade 3 hypertension in 11 patients (42.3%). No grade 4-5 TRAEs were observed.

Conclusions: Lenvatinib plus pembrolizumab demonstrated encouraging efficacy with anticipated toxicity when used as neoadjuvant therapy for MCC. Further investigation of these promising findings is warranted.

Trial registration number: NCT04869137.