Adoptive T Cell Therapy Research Articles

Identification and structural characterization of a mutant KRAS-G12V specific TCR restricted by HLA-A3.

Mutations in KRAS are some of the most common across multiple cancer types and are thus attractive targets for therapy. Recent studies demonstrated that mutant KRAS generates immunogenic neoantigens that are targetable by adoptive T-cell therapy in metastatic diseases. To expand mutant KRAS-specific immunotherapies, it is critical to identify additional HLA-I allotypes that can present KRAS neoantigens and their cognate T-cell receptors (TCR). Here, we identified a murine TCR specific to a KRAS-G12V neoantigen (7VVVGAVGVGK16) using a vaccination approach with transgenic mice expressing HLA-A*03:01 (HLA-A3). This TCR demonstrated exquisite specificity for mutant G12V and not WT KRAS peptides. To investigate the molecular basis for neoantigen recognition by this TCR, we determined its structure in complex with HLA-A3(G12V). G12V-TCR CDR3β and CDR1β formed a hydrophobic pocket to interact with p6 Val of the G12V but not the WT KRAS peptide. To improve the tumor sensitivity of this TCR, we designed rational substitutions to improve TCR:HLA-A3 contacts. Two substitutions exhibited modest improvements in TCR binding avidity to HLA-A3 (G12V) but did not sufficiently improve T-cell sensitivity for further clinical development. Our study provides mechanistic insight into how TCRs detect neoantigens and reveals the challenges in targeting KRAS-G12V mutations.

Recent advances in immunotherapy and its combination therapies for advanced melanoma: a review.

The incidence of melanoma is increasing year by year and is highly malignant, with a poor prognosis. Its treatment has always attracted much attention. Among the more clinically applied immunotherapies are immune checkpoint inhibitors, bispecific antibodies, cancer vaccines, adoptive cell transfer therapy, and oncolytic virotherapy. With the continuous development of technology and trials, in addition to immune monotherapy, combinations of immunotherapy and radiotherapy have shown surprising efficacy. In this article, we review the research progress of immune monotherapy and combination therapy for advanced melanoma, with the aim of providing new ideas for the treatment strategy for advanced melanoma.

Scalable intracellular delivery via microfluidic vortex shedding enhances the function of chimeric antigen receptor T-cells.

Adoptive chimeric antigen receptor T-cell (CAR-T) therapy is transformative and approved for hematologic malignancies. It is also being developed for the treatment of solid tumors, autoimmune disorders, heart disease, and aging. Despite unprecedented clinical outcomes, CAR-T and other engineered cell therapies face a variety of manufacturing and safety challenges. Traditional methods, such as lentivirus transduction and electroporation, result in random integration or cause significant cellular damage, which can limit the safety and efficacy of engineered cell therapies. We present hydroporation as a gentle and effective alternative for intracellular delivery. Hydroporation resulted in 1.7- to 2-fold higher CAR-T yields compared to electroporation with superior cell viability and recovery. Hydroporated cells exhibited rapid proliferation, robust target cell lysis, and increased pro-inflammatory and regulatory cytokine secretion in addition to improved CAR-T yield by day 5 post-transfection. We demonstrate that scaled-up hydroporation can process 5 x 108 cells in less than 10 s, showcasing the platform as a viable solution for high-yield CAR-T manufacturing with the potential for improved therapeutic outcomes.

Prospective study of successful autologous dendritic cell therapy in dogs with splenic stage II hemangiosarcoma

Hemangiosarcoma is an aggressive tumour that most frequently occurs in larger, middle-aged dogs of certain breeds. The spleen is the most commonly affected organ. The aim of this prospective therapy study was to evaluate the clinical effect of autologous, monocyte-derived dendritic cell (DC) therapy in canine hemangiosarcoma stage II after splenectomy. Dogs (n=452) diagnosed with splenic hemangiosarcoma that underwent splenectomy were enrolled. Of these, 42 dogs with stage II entered the DC therapy study. The median survival time for the total group of 42 dogs was 203 days. The median survival for the group (n=34) that received the full DC therapy (≥3 vaccines) was 256 days, with a 29 % one-year survival rate and a hazard ratio of 0.30, adjusted to age and bodyweight (P=0.010). We further observed a significant increase in DC yield after each application and demonstrated that DC yield at the beginning of treatment is significantly related to patient survival. While further evidence is needed, we conclude that autologous, monocyte-derived DC therapy is a viable alternative to standard treatment methods of canine splenic stage II hemangiosarcoma.

Clinical research progress of telomerase targeted cancer immunotherapy: a literature review.

Telomerase is activated or overexpressed in 85-90% of tumors, which maintains the length of telomere and has become an important anti-cancer target. Increasing clinical and preclinical data suggest that telomerase-targeted cancer immunotherapy could achieve effective killing of tumor cells in vivo. This article reviews the research progress of telomerase targeted cancer immunotherapy in clinical and pre-clinical trials, aiming to provide a reference for further clinical research and treatment of cancers. We investigated the research progress of telomerase immunotherapy in the last 20 years from four electronic databases. Telomerase-targeted immunotherapies have been developed with the arising of a new era in immuno-oncology, including peptide vaccines, DNA vaccines, dendritic cells (DCs), adoptive cell transfer (ACT) therapies, antibodies, etc. Some of them have been approved for undergoing clinical trials by the Food and Drug Administration (FDA) for the treatment of various cancers, such as pancreatic cancer, non-small cell lung cancer, melanoma, leukaemia. Of all the treatment modalities, vaccines are the primary treatment methods, some of which have been even entered into phase III clinical trials. The main clinical application direction of telomerase vaccine is the combination with other drugs and treatment modalities, including combination with other vaccines targeting human telomerase reverse transcriptase (hTERT), traditional chemotherapy drugs and immunosuppressors. We also summarized the recent findings of immunotherapy targeting hTERT, focusing on various vaccines and the current status of associated clinical trials. We further discussed the advantages, disadvantages and potential developmental directions of various telomerase-targeted immunotherapies. Telomerase-targeted cancer immunotherapy has promising prospects in improving patient survival expectancy. This review may provide data support and design ideas for all researchers and pharmaceutical enterprises in this field.

Novel Autologous Dendritic Cell Therapy AVT001 for Type 1 Diabetes

BackgroundCD8+ T regulatory (Treg) cells that recognize the nonclassical class 1b molecule Qa-1/human leukocyte antigen E (Q/E CD8+ Treg cells) are important in maintaining self-tolerance. We sought to investigate the role that these T cells play in type 1 diabetes (T1D) pathogenesis and whether an intervention targeting this mechanism may delay T1D progression.MethodsWe conducted a phase 1/2, randomized, double-blind, placebo-controlled trial of the autologous dendritic cell therapy AVT001 that included participants at least 16 years of age, within 1 year of T1D diagnosis, and with ex vivo evidence of a defect in Q/E CD8+ Treg function. Patients were randomly assigned in a 2:1 ratio to AVT001 or placebo, which was administered in three monthly intravenous infusions. The primary end point was safety; efficacy end points included changes from baseline in C-peptide area under the curve (AUC) during a 4-hour mixed meal, hemoglobin A1c (HbA1c), and insulin dose.ResultsSixteen patients received AVT001, and nine received placebo. Similar rates and severity of adverse events were observed in both groups. None of the patients in the AVT001 group had serious adverse events through visit day 360. Compared with placebo, treatment with ATV001 was associated with less decline from baseline log-transformed C-peptide AUC (nmol/l), with the treatment effect between AVT001 and placebo at day 150 of 0.09 (95% confidence interval [CI], 0.03 to 0.15) and at day 360 of 0.10 (95% CI, 0.04 to 0.15). No clear differences in change in HbA1c and insulin dose from baseline were observed between groups. Estimated treatment effects of AVT001 versus placebo at day 360 were −0.17% (95% CI, −0.60 to 0.26%) for HbA1c and −0.06 U/kg/day (95% CI, −0.14 to 0.02) for daily insulin dose.ConclusionsIn this phase 1/2 trial, AVT001 did not result in dose-limiting adverse events. Potential signals of efficacy observed here warrant further evaluation in a fully powered trial. (Funded by Avotres Inc. and the Division of Diabetes, Endocrinology, and Metabolic Diseases; ClinicalTrials.gov number, NCT03895996.)

The Evolving Role of Bispecific Antibodies in Diffuse Large B-Cell Lymphoma.

The advent of targeted therapies such as monoclonal antibodies, adoptive T-cell therapies, and antibody-drug conjugates (ADCs) dramatically changed the treatment landscape of diffuse large B-cell lymphoma (DLBCL) over the last two decades. Rituximab was the first one approved. Chimeric antigen receptor T-cells are currently approved as second-line treatment in patients with DLBCL refractory to first-line chemo-immunotherapy. Polatuzumab, a CD79b-targeting ADC, is approved as first-line treatment in high-risk patients in combination with chemo-immunotherapy. Bispecific antibodies (BsAbs) are a novel category of drugs that are also changing the treatment paradigm of patients with DLBCL. They are engineered to bind to two different targets at the same time. To date, two BsAbs (glofitamab and epcoritamab) are approved as monotherapy in third-line treatment in DLBCL. Combination strategies with chemotherapy, immunotherapy, and ADCs are currently under investigation with encouraging results in first-line or subsequent lines of treatment. In the following review, we focus on the structure of BsAbs, the mechanism of action, clinical efficacy, and the mechanisms of resistance to BsAbs.

Intratumoral immune triads are required for immunotherapy-mediated elimination of solid tumors

Tumor-specific CD8+ Tcells are frequently dysfunctional and unable to halt tumor growth. We investigated whether tumor-specific CD4+ Tcells can be enlisted to overcome CD8+ Tcell dysfunction within tumors. We find that the spatial positioning and interactions of CD8+ and CD4+ Tcells, but not their numbers, dictate anti-tumor responses in the context of adoptive Tcell therapy as well as immune checkpoint blockade (ICB): CD4+ Tcells must engage with CD8+ Tcells on the same dendritic cell during the effector phase, forming a three-cell-type cluster (triad) to license CD8+ Tcell cytotoxicity and cancer cell elimination. When intratumoral triad formation is disrupted, tumors progress despite equal numbers of tumor-specific CD8+ and CD4+ Tcells. Inpatients with pleural mesothelioma treated with ICB, triads are associated with clinical responses. Thus,CD4+ Tcells and triads are required for CD8+ Tcell cytotoxicity during the effector phase and tumor elimination.

Risk of Second Tumors and T-Cell Lymphoma after CAR T-Cell Therapy

BackgroundThe risk of second tumors after chimeric antigen receptor (CAR) T-cell therapy, especially the risk of T-cell neoplasms related to viral vector integration, is an emerging concern.MethodsWe reviewed our clinical experience with adoptive cellular CAR T-cell therapy at our institution since 2016 and ascertained the occurrence of second tumors. In one case of secondary T-cell lymphoma, a broad array of molecular, genetic, and cellular techniques were used to interrogate the tumor, the CAR T cells, and the normal hematopoietic cells in the patient.ResultsA total of 724 patients who had received T-cell therapies at our center were included in the study. A lethal T-cell lymphoma was identified in a patient who had received axicabtagene ciloleucel therapy for diffuse large B-cell lymphoma, and both lymphomas were deeply profiled. Each lymphoma had molecularly distinct immunophenotypes and genomic profiles, but both were positive for Epstein–Barr virus and were associated with DNMT3A and TET2 mutant clonal hematopoiesis. No evidence of oncogenic retroviral integration was found with the use of multiple techniques.ConclusionsOur results highlight the rarity of second tumors and provide a framework for defining clonal relationships and viral vector monitoring. (Funded by the National Cancer Institute and others.)

Grooved Microneedle Patch Augments Adoptive T Cell Therapy Against Solid Tumors via Diverting Regulatory T Cells.

The efficacy of adoptive T cell therapy (ACT) for the treatment of solid tumors remains challenging. In addition to the poor infiltration of effector T (Teff) cells limited by the physical barrier surrounding the solid tumor, another major obstacle is the extensive infiltration of regulatory T (Treg) cells, a major immunosuppressive immune cell subset, in the tumor microenvironment. Here, this work develops a grooved microneedle patch for augmenting ACT, aiming to simultaneously overcome physical and immunosuppressive barriers. The microneedles are engineered through an ice-templated method to generate the grooved structure for sufficient T-cell loading. In addition, with the surface modification of chemokine CCL22, the MNs could not only directly deliver tumor-specific T cells into solid tumors through physical penetration, but also specifically divert Treg cells from the tumor microenvironment to the surface of the microneedles via a cytokine concentration gradient, leading to an increase in the ratio of Teff cells/Treg cells in a mouse melanoma model. Consequently, this local delivery strategy of both T cell receptor T cells and chimeric antigen receptor T cells via the CCL22-modified grooved microneedles as a local niche could significantly enhance the antitumor efficacy and reduce the on-target off-tumor toxicity of ACT.

Subcutaneous biodegradable scaffolds for restimulating the antitumour activity of pre-administered CAR-T cells.

The efficacy of adoptive T-cell therapies based on chimaeric antigen receptors (CARs) is limited by the poor proliferation and persistence of the engineered T cells. Here we show that a subcutaneously injected biodegradable scaffold that facilitates the infiltration and egress of specific T-cell subpopulations, which forms a microenvironment mimicking features of physiological T-cell activation, enhances the antitumour activity of pre-administered CAR-T cells. CAR-T-cell expansion, differentiation and cytotoxicity were driven by the scaffold's incorporation of co-stimulatory bound ligands and soluble molecules, and depended on the types of co-stimulatory molecules and the context in which they were presented. In mice with aggressive lymphoma, a single, local injection of the scaffold following non-curative CAR-T-cell dosing led to more persistent memory-like T cells and extended animal survival. Injectable biomaterials with optimized ligand presentation may boost the therapeutic performance of CAR-T-cell therapies.

Adenovirus- and cytomegalovirus-specific adoptive T-cell therapy in the context of hematologic cell transplant or HIV infection - A single-center experience.

Reactivation of viral infections, in particular cytomegalovirus (CMV) and adenovirus (ADV), cause morbidity and non-relapse-mortality in states of immune deficiency, especially after allogeneic hematopoietic cell transplantation (allo-HCT). Against the background of few available pharmacologic antiviral agents, limited by toxicities and resistance, adoptive transfer of virus-specific T-cells (VST) is a promising therapeutic approach. We conducted a single-center retrospective analysis of adult patients treated with ADV- or CMV-specific T-cells in 2012-2022. Information was retrieved by review of electronic health records. Primary outcome was a response to VST by decreasing viral load or clinical improvement. Secondary outcomes included overall survival and safety of VST infusion, in particular association with graft-versus-host disease (GVHD). Ten patients were included, of whom four were treated for ADV, five for CMV, and one for ADV-CMV-coinfection. Cells were derived from stem cell donors (6/10) or third-party donors (4/10). Response criteria were met by six of 10 patients (4/4 ADV, 2/5 CMV, and 0/1 ADV-CMV). Overall survival was 40%. No infusion related adverse events were documented. Aggravation of GVHD after adoptive immunotherapy was observed in two cases, however in temporal association with a conventional donor lymphocyte infusion and a stem cell boost, respectively. In this cohort, CMV- and ADV-specific T-cell therapy appear to be safe and effective. We describe the first reported case of virus-specific T-cell therapy for CMV reactivation not associated with transplantation but with advanced HIV infection. This encourages further evaluation of adoptive immunotherapy beyond the context of allo-HCT.

FOXP3+ Regulatory T Cells Require TBET to Regulate Activated CD8+ T Cells During Recovery from Influenza Infection.

FOXP3+ regulatory T (Treg) cells are necessary to coordinate resolution of lung inflammation and a return to homeostasis after respiratory viral infections, but the specific molecular requirements for these functions and the cell types governed by Treg cells remain unclear. This question holds significance as clinical trials of Treg cell transfer therapy for respiratory viral infection are being planned and executed. Here, we report causal experiments in mice determining that Treg cells are necessary to control the numbers of activated CD8+ T cells during recovery from influenza infection. Using a genetic strategy paired with adoptive transfer techniques, we determined that Treg cells require the transcription factor TBET to regulate these potentially pro-inflammatory CD8+ T cells. Surprisingly, we found that Treg cells are dispensable for the generation of CD8+ lung tissue resident-memory T (Trm) cells yet similarly influence the transcriptional programming of CD8+ Trm and activated T cells. Our study highlights the role of Treg cells in regulating the CD8+ T cell response during recovery from influenza infection.

A phase 2 study of regorafenib in metastatic/unresectable, refractory synovial sarcomas.

e23551 Background: Current therapeutic options for advanced synovial sarcomas remain limited. Adoptive T-cell therapies against NY-ESO-1 and MAGE-4 benefit a subset of patients, but is of limited value in Asian patients due to the absence of the HLA-A*02 genotype. Methods: The trial had a single arm, Simon two-stage design that included patients with advanced synovial sarcomas who had progressed on 2 lines of therapy, one of which could be an anti-VEGF therapy. Regorafenib was administered orally in a continuous regimen with 80mg and 120 mg doses on alternate days. The primary end point was 3-month progression-free rate (PFR). A 3-month PFR of greater than 40% was taken to be a marker of drug efficacy. Secondary end points included median PFS, OS and safety analysis. Quality of life assessment was carried out at baseline and at 3 months using the EORTC C-30 questionnaire. Radiological responses were assessed using RECIST 1.1 criteria after independent review by 2 radiologists. Results: A total of 22 patients were included in the study during the period from January 2022 to December 2023 with baseline characteristics as shown in Table 1. 18 patients were eligible for assessment of the primary outcome. The 3-month PFR with regorafenib was 57% with an ORR of 5%. At a median follow up of 9 months, the median PFS was 5.0 (2.9-7.0) months, and the median OS was 10.0 (7.8-11.2) months. In an exploratory analysis, the subset of patients previously exposed to pazopanib showed a 3-month PFR of 46% and a median PFS of 3 months. The grade ¾ toxicities seen included HFSR (52%), diarrhea (5%) and oral mucositis (5%). The quality-of-life analysis showed symptom burden to be highest in the fatigue, pain and financial difficulties domain at baseline. No worsening of symptom burden scores was seen over the study period. The global health status score showed a numerical improvement at 3 months. Conclusions: The study had a significant number of patients with poor PS. Regorafenib in the above-mentioned dosing regimen demonstrated meaningful clinical activity in a heavily pre-treated population of patients with synovial sarcoma, including those previously exposed to pazopanib, with a preserved quality of life. The treatment was associated with manageable toxicities and no new safety signals, albeit with higher HFSR rates. [Table: see text]

Primary and secondary resistance to immune checkpoint inhibitors in hepatocellular carcinoma.

e16209 Background: Immunotherapy have revolutionized the therapeutic landscape of hepatocellular carcinoma (HCC). However, clinical features affecting immune resistance remain largely unknown. This retrospective cohort study aims to investigate the outcomes and characteristics of pts with resistance to immunotherapy in HCC. Methods: Pts with HCC who received immune checkpoint inhibitors (ICIs) of PD-1/PD-L1 antibodies at Eastern Hepatobiliary Surgery Hospital between 2016 and 2021 were retrospectively enrolled and screened for eligibility. Recommended by the Society for Immunotherapy of Cancer (SITC), primary resistance was defined as when pts were exposed to ICIs therapy for at least 6 weeks and with the best overall response (BOR) of PD or SD for less than 6 months. Secondary resistance was defined as pts having disease progression after the initial objective response (CR/PR) or SD for more than 6 months. The durable response group consists of pts with the durable response (CR, PR, or SD) for more than 6 months without progression at data cutoff. Time to progression (TTP), overall survival (OS) and clinicopathological features of HCC pts were compared between groups. Subsequent management after resistance and post-progression survival (PPS) were also analyzed. Results: Of 496 pts included, 229 (46.2%) and 141 (28.4%) pts developed primary resistance and secondary resistance, and 126 (25.4%) pts achieved a durable response. The median follow-up was 22.8 months. For pts with primary resistance, secondary resistance, and durable response, the median TTP was 2.83 [2.56-3.09] months, 11.93 [10.45-13.40] months, and not reached, respectively. Whereas the median OS was 12.83 [10.36-15.30] months, 31.53 [28.09-34.97] months and not reached, respectively. Multivariate logistic regression revealed that the Child-Pugh score (Child-Pugh B versus A, OR 3.28 [1.51-7.13], p= 0.003), BCLC stage (BCLC B versus A, OR 3.55 [1.70-7.43], p= 0.001; BCLC C versus A, OR 2.88 [1.47-5.65], p= 0.002), and combinational therapies (ICIs+bevacizumab versus monotherapy, OR 0.14 [0.04-0.51], p= 0.003; ICIs plus lenvatinib+monotherapy, OR 0.43 [0.26-0.72], p= 0.001) were independently associated with primary resistance, and only the combination of ICIs plus bevacizumab (ICIs+bevacizumab versus monotherapy, OR 0.10 [0.01-0.52], p= 0.007) was independently associated with secondary resistance. AFP levels and post-progression therapies were independently associated with PPS in pts with primary resistance, while post-progression therapies were independently associated with PPS in pts with secondary resistance. Conclusions: Risk for resistance was significantly lower among pts who received ICIs plus bevacizumab.High AFP levels independently predict the survival of pts after primary resistance to immunotherapy. ICI-based maintenance therapy after resistance may provide a significant survival advantage for HCC pts.

Effect of blocking CD96 on CD8+ T cell–mediated elimination of tumor dormancy.

e14679 Background: Dormant tumor cells, characterized by quiescent state, exhibit superior tumorigenic capacity, chemotherapy resistance, and expression of stemness genes, along with reduced immune infiltration. Tumor recurrence frequently emerges from persistent dormant tumor cells, posing a formidable challenge for targeted intervention. Methods: In this study, we established a reporter gene system to isolate dormant tumor cells from implanted tumors and reimplanted them into C57BL/6 mice. The effectiveness of the anti-CD96 antibody against dormant tumor cells was assessed by measuring tumor volumes and survival. Subsequently, anti-EpCAM CAR-T cells with CD96 knockout were administered to NSG mice with established dormant tumor cells to evaluate their efficacy and toxicity in vivo. Results: In this study, we identify a novel therapeutic target for dormant tumor cells. Administering anti-CD96 antibodies, rather than anti-PD-1 antibodies, in a systemic treatment of mice effectively eradicates dormant tumor cell-mediated recurrence in a CD96 T cell-dependent manner. Notably, dormant tumor cells exhibit resistance to adoptive cell transfer therapy. Consequently, the blockade of CD96 in anti-EpCAM CAR-T cells, either through antibody treatment or knock-out approaches, holds promise for eliminating dormant tumor cells in colorectal cancer (CRC). Furthermore, knockout CD96 in CAR-T cells enhances CAR-T cell memory formation via regulating mitochondria function but also inhibits T cell exhaustion. Conclusions: In summary, targeting CD96 serves as a valuable checkpoint against dormant tumor cells, presenting a therapeutically actionable strategy for preventing disease relapse.

Dendritic Cell Immune Modulation via Polyphenol Membrane Coatings.

Cellular hitchhiking is an emerging strategy for the in vivo control of adoptively transferred immune cells. Hitchhiking approaches are primarily mediated by adhesion of nano and microparticles to the cell membrane, which conveys an ability to modulate transferred cells via local drug delivery. Although T cell therapies employing this strategy have progressed into the clinic, phagocytic cells including dendritic cells (DCs) are much more challenging to engineer. DC vaccines hold great potential for a spectrum of diseases, and the combination drug delivery is an attractive strategy to manipulate their function and overcome in vivo plasticity. However, DCs are not compatible with current hitchhiking approaches due to their broad phagocytic capacity. In this work, we developed and validated META (membrane engineering using tannic acid) to enable DC cellular hitchhiking for the first time. META employs the polyphenol tannic acid (TA) to facilitate supramolecular assembly of protein drug cargoes on the cell membrane, enabling the creation of cell surface-bound formulations for local drug delivery to carrier DCs. We optimized META formulations to incorporate and release protein cargoes with varying physical properties alone and in combination and to preserve DC viability and critical functions such as migration. We further show that META loaded with either a pro- or anti-inflammatory cargo can influence the carrier cell phenotype, thus demonstrating the flexibility of the approach for applications from cancer to autoimmune disease. Overall, this approach illustrates a new platform for the local control of phagocytic immune cells as a next step to advance DC therapies in the clinic.

Synergistic antitumor immune response mediated by paclitaxel-conjugated nanohybrid oncolytic adenovirus with dendritic cell therapy.

Dendritic cell (DC)-based vaccines have emerged as a promising strategy in cancer immunotherapy due to low toxicity. However, the therapeutic efficacy of DC as a monotherapy is insufficient due to highly immunosuppressive tumor environment. To address these limitations of DC as immunotherapeutic agent, we have developed a polymeric nanocomplex incorporating (1) oncolytic adenovirus (oAd) co-expressing interleukin (IL)-12 and granulocyte-macrophage colony-stimulating factor (GM-CSF) and (2) arginine-grafted bioreducible polymer with PEGylated paclitaxel (APP) to restore antitumor immune surveillance function in tumor milieu and potentiate immunostimulatory attributes of DC vaccine. Nanohybrid complex (oAd/APP) in combination with DC (oAd/APP+DC) induced superior expression level of antitumor cytokines (IL-12, GM-CSF, and interferon gamma) than either oAd/APP or DC monotherapy in tumor tissues, thus resulting in superior intratumoral infiltration of both endogenous and exogenous DCs. Furthermore, oAd/APP+DC treatment led superior migration of DC to secondary lymphoid organs, such as draining lymph nodes and spleen, in comparison with either monotherapy. Superior migration profile of DCs in oAd/APP+DC treatment group resulted in more prolific activation of tumor-specific T cells in these lymphoid organs and greater intratumoral infiltration of T cells. Additionally, oAd/APP+DC treatment led to lower subset of tumor infiltrating lymphocytes and splenocytes being immunosuppressive regulatory T cells than any other treatment groups. Collectively, oAd/APP+DC led to superior induction of antitumor immune response and amelioration of immunosuppressive tumor microenvironment to elicit potent tumor growth inhibition than either monotherapy.

Combination of percutaneous thermal ablation and adoptive Th9 cell transfer therapy against non-small cell lung cancer

BackgroundNon-small cell lung cancer (NSCLC) is one of the predominant malignancies globally. Percutaneous thermal ablation (PTA) has gained widespread use among NSCLC patients, with the potential to elicit immune responses but limited therapeutic efficacies for advanced-stage disease. T-helper type 9 (Th9) cells are a subset of CD4+ effector T cells with robust and persistent anti-tumor effects. This study proposes to develop PTA-Th9 cell integrated therapy as a potential strategy for NSCLC treatment.MethodsThe therapeutic efficacies were measured in mice models with subcutaneously transplanted, recurrence, or lung metastatic tumors. The tumor microenvironments (TMEs) were evaluated by flow cytometry. The cytokine levels were assessed by ELISA. The signaling molecules were determined by quantitative PCR and Western blotting. The translational potential was tested in the humanized NSCLC patient-derived xenograft (PDX) model.ResultsWe find that PTA combined with adoptive Th9 cell transfer therapy substantially suppresses tumor growth, recurrence, and lung metastasis, ultimately extending the survival of mice with NSCLC grafts, outperforming both PTA and Th9 cell transfer monotherapy. Analysis of TMEs indicates that combinatorial therapy significantly augments tumor-infiltrating Th9 cells, boosts anti-tumor effects of CD8+ T cells, and remodels tumor immunosuppressive microenvironments. Moreover, combinatorial therapy significantly strengthens the regional and circulation immune response of CD8+ T cells in mice with tumor lung metastasis and induces peripheral CD8+ T effector memory cells in mice with tumor recurrence. Mechanically, PTA reinforces the anti-tumor ability of Th9 cells primarily through upregulating interleukin (IL)-1β and subsequently activating the downstream STAT1/IRF1 pathway, which could be effectively blocked by intercepting IL-1β signaling. Finally, the enhanced therapeutic effect of combinatorial therapy is validated in humanized NSCLC PDX models.ConclusionsCollectively, this study demonstrates that combinatorial therapy displays robust and durable anti-tumor efficacy and excellent translational potential, offering excellent prospects for translation and emerging as a promising approach for NSCLC treatment.

Current immunotherapeutic approaches to diffuse intrinsic pontine glioma.

Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumour that occurs in the pons of the brainstem and accounts for over 80% of all brainstem gliomas. The median age at diagnosis is 6-7years old, with less than 10% overall survival 2years after diagnosis and less than 1% after 5years. DIPGs are surgically inaccessible, and radiation therapy provides only transient benefit, with death ensuing from relentless local tumour infiltration. DIPGs are now the leading cause of brain tumour deaths in children, with a societal cancer burden in years of life lost (YLL) of more than 67 per individual, versus approximately 14 and 16 YLL for lung and breast cancer respectively. More than 95 clinical drug trials have been conducted on children with DIPGs, and all have failed to improve survival. No single or combination chemotherapeutic strategy has been successful to date because of our inability to identify targeted drugs for this disease and to deliver these drugs across an intact blood-brain barrier (BBB). Accordingly, there has been an increased focus on immunotherapy research in DIPG, with explorations into treatments such as chimeric antigen receptor T (CAR-T) cells, immune checkpoint blockades, cancer vaccines, and autologous cell transfer therapy. Here, we review the most recent advances in identifying genetic factors influencing the development of immunotherapy for DIPG. Additionally, we explore emerging technologies such as Magnetic Resonance-guided Focused Ultrasound (MRgFUS) in potential combinatorial approaches to treat DIPG.