Brain Tumor Immunotherapy Research Articles

Brain Tumor Immunotherapy: Current Advances and Future Prospects

Malignant brain tumors, particularly gliomas and glioblastoma multiforme (GBM), remain among the most lethal cancers due to their aggressive nature, genetic complexity, and resistance to conventional therapies. Immunotherapy has emerged as a promising approach to combat these tumors by harnessing the immune system’s capacity to target and destroy cancer cells. This review explores the current advances in brain tumor immunotherapy, including immune checkpoint inhibitors, chimeric antigen receptor (CAR) T-cell therapy, cancer vaccines, and oncolytic viruses. Despite significant progress, challenges such as the immunosuppressive tumor microenvironment, the blood-brain barrier, and tumor heterogeneity hinder the efficacy of these treatments. The review also delves into the unique immunological landscape of the brain, examining the role of microglia, astrocytes, and infiltrating immune cells, and their involvement in tumor-immune evasion. Prominent tumor-associated antigens like EGFRvIII, HER2, and survivin are discussed as key targets for immunotherapeutic strategies. Finally, the review outlines future prospects and research directions aimed at overcoming current obstacles and enhancing the effectiveness of immunotherapy for brain tumors Keywords: Brain Tumor, Immunotherapy, Current Advances, Future Prospects

T lymphocyte recruitment to melanoma brain tumors depends on distinct venous vessels

To improve immunotherapy for brain tumors, it is important to determine the principal intracranial site of Tcell recruitment from the bloodstream and their intracranial route to brain tumors. Using intravital microscopy in mouse models of intracranial melanoma, we discovered that circulating Tcells preferably adhered and extravasated at a distinct type of venous blood vessel in the tumor vicinity, peritumoral venous vessels (PVVs). Other vascular structures were excluded as alternative Tcell routes to intracranial melanomas. Anti-PD-1/CTLA-4 immune checkpoint inhibitors increased intracranial Tcell motility, facilitating migration from PVVs to the tumor and subsequently inhibiting intracranial tumor growth. The endothelial adhesion molecule ICAM-1 was particularly expressed on PVVs, and, in samples of human brain metastases, ICAM-1 positivity of PVV-like vessels correlated with intratumoral Tcell infiltration. These findings uncover a distinct mechanism by which the immune system can access and control brain tumors and potentially influence other brain pathologies.

Open-Source Throttling of CD8+ T Cells in Brain with Low-Intensity Focused Ultrasound-Guided Sequential Delivery of CXCL10, IL-2, and aPD-L1 for Glioblastoma Immunotherapy.

Improving clinical immunotherapy for glioblastoma (GBM) relies on addressing the immunosuppressive tumor microenvironment (TME). Enhancing CD8+ T cell infiltration and preventing its exhaustion holds promise for effective GBM immunotherapy. Here, a low-intensity focused ultrasound (LIFU)-guided sequential delivery strategy is developed to enhance CD8+ T cells infiltration and activity in the GBM region. The sequential delivery of CXC chemokine ligand 10 (CXCL10) to recruit CD8+ T cells and interleukin-2 (IL-2) to reduce their exhaustion is termed an "open-source throttling" strategy. Consequently, up to 3.39-fold of CD8+ T cells are observed with LIFU-guided sequential delivery of CXCL10, IL-2, and anti-programmed cell death 1 ligand 1 (aPD-L1), compared to the free aPD-L1 group. The immune checkpoint inhibitors (ICIs) therapeutic efficacy is substantially enhanced by the reversed immunosuppressive TME due to the expansion of CD8+ T cells, resulting in the elimination of tumor, prolonged survival time, and long-term immune memory establishment in orthotopic GBM mice. Overall, LIFU-guided sequential cytokine and ICIs delivery offers an "open-source throttling" strategy of CD8+ T cells, which may present a promising strategy for brain-tumor immunotherapy.

Toxoplasma gondii infection supports the infiltration of T cells into brain tumors

Few T cells infiltrate into primary brain tumors, fundamentally hampering the effectiveness of immunotherapy. We hypothesized that Toxoplasma gondii, a microorganism that naturally elicits a Th1 response in the brain, can promote T cell infiltration into brain tumors despite their immune suppressive microenvironment. Using a mouse genetic model for medulloblastoma, we found that T. gondii infection induced the infiltration of activatable T cells into the tumor mass and led to myeloid cell reprogramming toward a T cell-supportive state, without causing severe health issues in mice. The study provides a concrete foundation for future studies to take advantage of the immune modulatory capacity of T. gondii to facilitate brain tumor immunotherapy.

A Self-Cascade Penetrating Brain Tumor Immunotherapy Mediated by Near-Infrared II Cell Membrane-Disrupting Nanoflakes via Detained Dendritic Cells.

Immunotherapy can potentially suppress the highly aggressive glioblastoma (GBM) by promoting T lymphocyte infiltration. Nevertheless, the immune privilege phenomenon, coupled with the generally low immunogenicity of vaccines, frequently hampers the presence of lymphocytes within brain tumors, particularly in brain tumors. In this study, the membrane-disrupted polymer-wrapped CuS nanoflakes that can penetrate delivery to deep brain tumors via releasing the cell-cell interactions, facilitating the near-infrared II (NIR II) photothermal therapy, and detaining dendritic cells for a self-cascading immunotherapy are developed. By convection-enhanced delivery, membrane-disrupted amphiphilic polymer micelles (poly(methoxypoly(ethylene glycol)-benzoic imine-octadecane, mPEG-b-C18) with CuS nanoflakes enhances tumor permeability and resides in deep brain tumors. Under low-power NIR II irradiation (0.8 W/cm2), the intense heat generated by well-distributed CuS nanoflakes actuates the thermolytic efficacy, facilitating cell apoptosis and the subsequent antigen release. Then, the positively charged polymer after hydrolysis of the benzoic-imine bond serves as an antigen depot, detaining autologous tumor-associated antigens and presenting them to dendritic cells, ensuring sustained immune stimulation. This self-cascading penetrative immunotherapy amplifies the immune response to postoperative brain tumors but also enhances survival outcomes through effective brain immunotherapy.

Discovery of immunotherapy targets for pediatric solid and brain tumors by exon-level expression

Immunotherapy with chimeric antigen receptor T cells for pediatric solid and brain tumors is constrained by available targetable antigens. Cancer-specific exons present a promising reservoir of targets; however, these have not been explored and validated systematically in a pan-cancer fashion. To identify cancer specific exon targets, here we analyze 1532 RNA-seq datasets from 16 types of pediatric solid and brain tumors for comparison with normal tissues using a newly developed workflow. We find 2933 exons in 157 genes encoding proteins of the surfaceome or matrisome with high cancer specificity either at the gene (n = 148) or the alternatively spliced isoform (n = 9) level. Expression of selected alternatively spliced targets, including the EDB domain of fibronectin 1, and gene targets, such as COL11A1, are validated in pediatric patient derived xenograft tumors. We generate T cells expressing chimeric antigen receptors specific for the EDB domain or COL11A1 and demonstrate that these have antitumor activity. The full target list, explorable via an interactive web portal (https://cseminer.stjude.org/), provides a rich resource for developing immunotherapy of pediatric solid and brain tumors using gene or AS targets with high expression specificity in cancer.

Immunotherapy for Brain Tumors: Where We Have Been, and Where Do We Go From Here?

Immunotherapy for glioblastoma (GBM) remains an intensive area of investigation. Given the seismic impact of cancer immunotherapy across a range of malignancies, there is optimism that harnessing the power of immunity will influence GBM as well. However, despite several phase 3 studies, there are still no FDA-approved immunotherapies for GBM. Importantly, the field has learned a great deal from the randomized studies to date. Today, we are continuing to better understand the disease-specific features of the microenvironment in GBM-as well as the exploitable antigenic characteristic of the tumor cells themselves-that are informing the next generation of immune-based therapeutic strategies. The coming phase of next-generation immunotherapies is thus poised to bring us closer to treatments that will improve the lives of patients with GBM.

A blood–brain barrier- and blood–brain tumor barrier-penetrating siRNA delivery system targeting gliomas for brain tumor immunotherapy

Glioma is recognized as the most infiltrative and lethal form of central nervous system tumors and is known for its limited response to standard therapeutic interventions, high recurrence rate, and unfavorable prognosis. Recent progress in gene and immunotherapy presents a renewed sense of optimism in the treatment of glioblastoma. However, the barriers to overcome include the blood–brain barrier (BBB) and the blood–brain tumor barrier (BBTB), as well as the suppressive immune microenvironment. Overcoming these barriers remains a significant challenge. Here, we developed a lipid nanoparticle platform incorporating a dual-functional peptide (cholesterol-DP7-ACP-T7-modified DOTAP or DAT-LNP) capable of targeting glioma across the BBB and BBTB for brain tumor immunotherapy. This system was designed to achieve two key functions. First, the system could effectively penetrate the BBB during accumulation within brain tissue following intravenous administration. Second, this system enhances the maturation of dendritic cells, the polarization of M1 macrophages, and the activation of cytotoxic CD8+ T cells. This multifaceted approach effectively mitigates the immunosuppressive tumor microenvironment of glioma and promotes robust antitumor immune responses. Overall, the intravenous administration of the delivery system designed in this study demonstrates significant therapeutic potential for glioma and holds promising applications in the field of cancer immunotherapy.

Abstract LB310: Single-cell transcriptomics and TCR clonality reveal a role for immunotherapy in pediatric brain tumors

Abstract Central nervous system tumors are the most common solid tumors and the leading cause of cancer-related deaths in children. Outcomes remain dismal for a significant proportion of patients despite aggressive multimodal therapy and survivors suffer from treatment-related morbidity and neurological deficits. Despite their remarkable success in adult cancers, immunotherapies are not approved for pediatric brain tumors. Several factors like the relatively smaller patient population, a tumor location that makes them difficult to access through biopsies and poorly-studied tumor immune microenvironment (TME) have posed challenges in advancing immunotherapeutic options for these patients. Immune checkpoint blockers (ICB) tested in unstratified cohorts of children with brain tumors have not shown promising results; therefore, the role of immunotherapy remains unclear. Because the magnitude and nature of pre-existing T cell responses in the tumor has been shown to correlate with response to ICB, we asked if pediatric brain tumors show evidence of such favorable T cell responses. In the current study, we address this question using an unbiased approach to analyze the clonal relationship and transcriptional status of T cells present in tumor tissue of children with brain tumors using paired single-cell RNA-sequencing and TCR-sequencing. Our results demonstrate that a large fraction of T cells in the tumor tissue are clonally expanded with potential to recognize tumor antigens. Such clonally-expanded T cells display states linked to anti-tumor immunity, express higher levels of transcripts encoding for molecules linked to T cell activation, effector functions, immune cell recruitment, tissue-residency, immune checkpoints, and importantly, show significant enrichment of signatures linked to neoantigen-specific T cells and immunotherapy response. Notably, we identify several neoantigens in pediatric brain tumors, and show that neoantigen-specific T cell gene signatures are linked to better survival outcomes in high-grade glioma. We further show that PD1-expressing CD8+ T cells in pediatric brain tumors are indeed functional as evidenced by their capacity for cytotoxicity, cytokine production and proliferation. Among the patients in our cohort, we observe substantial heterogeneity in the degree of clonal expansion and expression of transcripts encoding immune checkpoints in tumor-infiltrating T cells. Overall, our findings suggest that accurate characterization of intra-tumoral T cell responses for features linked to immune check point therapy (ICB) response may enable selection of patients where immunotherapy is likely to be beneficial, an approach that requires prospective validation in future clinical trials. Citation Format: Anusha Preethi Ganesan, Aditi Upadhye, Kevin Meza Landeros, Ciro Ramírez-Suástegui1, Benjamin Schmiedel, Edwin Woo, Serena J. Chee, Denise Malicki, Nicole Coufal, David Gonda, Michael Levy, Jason Greenbaum, Gregory Seumois, John Crawford, William Roberts, Stephen Schoenberger, Hilde Cheroutre, Christian Ottensmeier, Pandurangan Vijayanand. Single-cell transcriptomics and TCR clonality reveal a role for immunotherapy in pediatric brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB310.

Abstract PR-001: Beta-adrenergic blockade licenses the use of immunotherapy in primary brain tumors and brain metastases

Abstract Immunotherapy is less effective against intracranial metastases compared to extracranial metastases and ineffective against primary brain tumors such as glioblastoma. Brain tumors present a unique challenge to in the context of immunotherapy, as these patients are immunosuppressed not just locally at the tumor, but also outside the CNS. Importantly, systemic immunosuppression observed in brain tumor patients limits the capacity of the immune system to respond to immunotherapy. Through this work we present a novel axis of immunosuppression in patients with intracranial tumors and demonstrate that overactive adrenergic signaling is a major barrier to immunotherapeutic success. Our data indicate that combining beta-adrenergic blockade with immunotherapy provides a survival benefit in the setting of brain tumors, where immunotherapy alone has proven ineffective. We demonstrate that this survival benefit is driven by a remodeling of the tumor microenvironment, increasing NF-kB activity and resulting in an increase in cDC1s and CD8+ T cells, as well as an increase in CD40-CD40L signaling, suggesting the immune system is poised to respond to immunotherapy. Further, we demonstrate that beta-adrenergic blockade can overcome systemic immunosuppression to restore the capacity of T cells to respond to an immune stimulus. Using the SEER-Medicaid database, we retrospectively examined outcomes in patients with melanoma and lung adenocarcinoma brain metastasis who received checkpoint blockade therapy alone vs those concurrently receiving beta-blocker therapy. We found that patients receiving combination therapy showed increased overall survival compared to those receiving checkpoint blockade alone. We then validated these findings in preclinical models of glioma, demonstrating that combining immunotherapy and propranolol, a widely prescribed FDA-approved beta-blocker, extended survival. Moving forward, we proffer that combination therapy with beta-blocker and immunotherapy, particularly checkpoint blockade, represents a promising translational treatment platform for patients with primary or metastatic intracranial malignancies. Citation Format: Selena Lorrey, Lucas Wachsmuth, Mackenzie Price, Corey Neff, Quinn Ostrom, Peter Fecci. Beta-adrenergic blockade licenses the use of immunotherapy in primary brain tumors and brain metastases [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr PR-001.

The unique immune ecosystems in pediatric brain tumors: integrating single-cell and bulk RNA-sequencing.

The significant progress of immune therapy in non-central nervous system tumors has sparked interest in employing the same strategy for adult brain tumors. However, the advancement of immunotherapy in pediatric central nervous system (CNS) tumors is not yet on par. Currently, there is a lack of comprehensive comparative studies investigating the immune ecosystem in pediatric and adult CNS tumors at a high-resolution single-cell level. In this study, we comprehensively analyzed over 0.3 million cells from 171 samples, encompassing adult gliomas (IDH wild type and IDH mutation) as well as four major types of pediatric brain tumors (medulloblastoma (MB), ependymoma (EPN), H3K27M-mutation (DIPG), and pediatric IDH-mutation glioma (P-IDH-M)). Our approach involved integrating publicly available and newly generated single-cell datasets. We compared the immune landscapes in different brain tumors, as well as the detailed functional phenotypes of T-cell and myeloid subpopulations. Through single-cell analysis, we identified gene sets associated with major cell types in the tumor microenvironment (gene features from single-cell data, scFes) and compared them with existing gene sets such as GSEA and xCell. The CBTTC and external GEO cohort was used to analyze and validate the immune-stromal-tumor patterns in pediatric brain tumors which might potentially respond to the immunotherapy. From the perspective of single-cell analysis, it was observed that major pediatric brain tumors (MB, EPN, P-IDH-M, DIPG) exhibited lower immune contents compared with adult gliomas. Additionally, these pediatric brain tumors displayed diverse immunophenotypes, particularly in regard to myeloid cells. Notably, the presence of HLA-enriched myeloid cells in MB was found to be independently associated with prognosis. Moreover, the scFes, when compared with commonly used gene features, demonstrated superior performance in independent single-cell datasets across various tumor types. Furthermore, our study revealed the existence of heterogeneous immune ecosystems at the bulk-RNA sequencing level among different brain tumor types. In addition, we identified several immune-stromal-tumor patterns that could potentially exhibit significant responses to conventional immune checkpoint inhibitors. The single-cell technique provides a rational path to deeply understand the unique immune ecosystem of pediatric brain tumors. In spite of the traditional attitudes of "cold" tumor towards pediatric brain tumor, the immune-stroma-tumor patterns identified in this study suggest the feasibility of immune checkpoint inhibitors and pave the way for the upcoming tide of immunotherapy in pediatric brain tumors.

IMG-02. VISUALIZATION OF TIGIT IN THE GLIOMA MICROENVIRONMENT: THE CREATION OF A PET IMAGING TRACER

Abstract Pediatric high-grade gliomas (HGGs) are aggressive tumors and are one of the drivers of pediatric brain tumor mortality. Few effective treatment options exist for pediatric HGGs beyond surgery and chemoradiation. Additionally, some HGGs, such as diffuse midline glioma, are often surgically inaccessible and respond poorly to chemotherapy leaving radiotherapy as the only treatment for this disease. While immune checkpoint inhibitors (ICIs) have seen success in treating cancers outside the CNS, ICIs for gliomas have shown limited efficacy. TIGIT is an IC receptor that is expressed on activated T-cells and has a critical role in suppressing T-cell and NK cell function. Prior work by our group has shown TIGIT to be a promising target for adult gliomas. These studies included analysis of transcriptomic data, and preclinical studies in glioma-bearing mice. We therefore assessed pediatric glioma transcriptomic datasets and identified via optimal cutoff analysis that at a specific mRNA threshold, TIGIT expression is associated with worsened survival. As TIGIT expression may be both prognostic and a biomarker for anti-TIGIT ICI therapy, we created a radiolabeled immunoPET tracer capable of binding TIGIT antigen that could be visualized via PET imaging. Referred to as “89Zr-DFO-TIGIT”, we found this tracer bound TIGIT with moderate immunoreactivity (57.7% ± 3.5%) as determined by bead-based immunoreactivity assays. As proof of feasibility, we injected glioma-bearing mice (GL261 cell line) with 89Zr-DFO-TIGIT which enabled the visualization of TIGIT in the tumor microenvironment via PET imaging. Thereafter, we performed biodistribution studies which found there to be significantly increased 89Zr-DFO-TIGIT in mouse tumor-bearing hemispheres as compared to non-tumor-bearing hemispheres. PET imaging also showed tracer-to-tumor uptake increased from day one to day eight. Our findings demonstrate the capability of 89Zr-DFO-TIGIT to visualize and quantify TIGIT in the glioma microenvironment, highlighting how this tracer may be of value in pediatric brain tumor immunotherapy studies.

Recruiting T-Cells toward the Brain for Enhanced Glioblastoma Immunotherapeutic Efficacy by Co-Delivery of Cytokines and Immune Checkpoint Antibodies with Macrophage-Membrane-Camouflaged Nanovesicles.

Immunotherapy with immune checkpoint inhibitors (CPIs) shows promising prospects for glioblastoma multiforme (GBM) but with restricted results, mainly attributed to the immunosuppressive tumor microenvironment (TME) and the limited antibody permeability of the blood-tumor barrier (BTB) in GBM. Here, nanovesicles with amacrophage-mimicking membrane are described, that co-deliverchemotactic CXC chemokine ligand 10 (CXCL10), to pre-activate the immune microenvironment, and anti-programmed death ligand 1 antibody (aPD-L1), to interrupt the immune checkpoint, aiming to enhance the effect of GBM immunotherapy. Consequently, the tumor tropism of the macrophage membrane and the receptor-mediated transcytosis of the angiopep-2 peptide allowthe nanovesicle to effectively cross the BTB and target the GBM region, with 19.75-fold higher accumulation of antibodies compared to the free aPD-L1 group. The CPI therapeutic efficacy is greatly enhanced by CXCL10-induced T-cells recruitment with significant expansion of CD8+ T-cells and effector memory T-cells, leading to the elimination of tumor, prolonged survival time, and long-term immune memory in orthotopic GBM mice. The nanovesicles, that relieve the tumor immunosuppressive microenvironment by CXCL10 to enhance aPD-L1 efficacy, may present a promising strategy for brain-tumor immunotherapy.

The Current Landscape of Immune Checkpoint Inhibitor Immunotherapy for Primary and Metastatic Brain Tumors

Antibodies against immune checkpoint inhibitors (ICIs) have revolutionized the treatment of multiple aggressive malignancies, including melanoma and non-small cell lung cancer. ICIs for the treatment of primary and metastatic brain tumors have been used with varying degrees of success. Here, we discuss the available evidence for the use of ICIs in the treatment of primary and metastatic brain tumors, highlighting challenges and opportunities for furthering this type of cancer immunotherapy in neuro-oncology.

The prognostic significance of Nectin-2 and Nectin-4 expression in glial tumors

Glial tumors are the most frequent neoplasms of the central nervous system in adults and despite recent advances in diagnosis and treatment of the disease, the prognosis of glioma is poor. Therefore, there is a great need to identify new prognostic factors and potential immunotherapeutic targets. Members of the Nectin family of proteins are gaining significant attention as possible diagnostic and immunotherapeutic targets in many solid tumors, but they have not been extensively investigated in glial tumors. The aim of the present study was to evaluate the expression of Nectin-2 and Nectin-4 in glial tumors of different grades, and to assess their prognostic value. The results showed heterogeneous expression of Nectin-2 and Nectin-4 in tumor cells and neuropil, with significantly higher Nectin-2 expression compared to Nectin-4, but without differences among tumor grades. In addition, the expression of Nectin-2 and Nectin-4 was associated with shorter survival times in patients with grade II/III gliomas. These results suggest that Nectin-2 and Nectin-4 expression may be used as an independent prognostic indicator for patients with II/III gliomas. This study contributes to the development of personalized care for patients with glioma and provides a basis for further research on nectin-based immunotherapy for brain tumors.

Immunotherapy associated central nervous system complications in primary brain tumors.

Advances clarifying the genetics and function of the immune system within the central nervous system (CNS) and brain tumor microenvironment have led to increasing momentum and number of clinical trials using immunotherapy for primary brain tumors. While neurological complications of immunotherapy in extra-cranial malignancies is well described, the CNS toxicities of immunotherapy in patients with primary brain tumors with their own unique physiology and challenges are burgeoning. This review highlights the emerging and unique CNS complications associated with immunotherapy including checkpoint inhibitors, oncolytic viruses, adoptive cell transfer/chimeric antigen receptor (CAR) T cell and vaccines for primary brain tumors, as well as reviews modalities that have been currently employed or are undergoing investigation for treatment of such toxicities.

Smart Nanosensitizers for Activatable Sono‐Photodynamic Immunotherapy of Tumors by Redox‐Controlled Disassembly

AbstractTumor‐targeted and stimuli‐activatable nanosensitizers are highly desirable for cancer theranostics. However, designing smart nanosensitizers with multiple imaging signals and synergistic therapeutic activities switched on is challenging. Herein, we report tumor‐targeted and redox‐activatable nanosensitizers (1‐NPs) for sono‐photodynamic immunotherapy of tumors by molecular co‐assembly and redox‐controlled disassembly. 1‐NPs show a high longitudinal relaxivity (r1=18.7±0.3 mM−1 s−1), but “off” dual fluorescence (FL) emission (at 547 and 672 nm), “off” sono‐photodynamic therapy and indoleamine 2,3‐dioxygenase 1 (IDO1) inhibition activities. Upon reduction by glutathione (GSH), 1‐NPs rapidly disassemble and remotely release small molecules 2‐Gd, Zn‐PPA‐SH and NLG919, concurrently switching on (1) dual FL emission, (2) sono‐photodynamic therapy and (3) IDO1 inhibition activities. After systemic injection, 1‐NPs are effective for bimodal FL and magnetic resonance (MR) imaging‐guided sono‐photodynamic immunotherapy of orthotropic breast and brain tumors in mice under combined ultrasound (US) and 671‐nm laser irradiation.

Smart Nanosensitizers for Activatable Sono-Photodynamic Immunotherapy of Tumors by Redox-Controlled Disassembly.

Tumor-targeted and stimuli-activatable nanosensitizers are highly desirable for cancer theranostics. However, designing smart nanosensitizers with multiple imaging signals and synergistic therapeutic activities switched on is challenging. Herein, we report tumor-targeted and redox-activatable nanosensitizers (1-NPs) for sono-photodynamic immunotherapy of tumors by molecular co-assembly and redox-controlled disassembly. 1-NPs show a high longitudinal relaxivity (r1 =18.7±0.3 mM-1 s-1 ), but "off" dual fluorescence (FL) emission (at 547 and 672 nm), "off" sono-photodynamic therapy and indoleamine 2,3-dioxygenase 1 (IDO1) inhibition activities. Upon reduction by glutathione (GSH), 1-NPs rapidly disassemble and remotely release small molecules 2-Gd, Zn-PPA-SH and NLG919, concurrently switching on (1) dual FL emission, (2) sono-photodynamic therapy and (3) IDO1 inhibition activities. After systemic injection, 1-NPs are effective for bimodal FL and magnetic resonance (MR) imaging-guided sono-photodynamic immunotherapy of orthotropic breast and brain tumors in mice under combined ultrasound (US) and 671-nm laser irradiation.

Photodynamic Opening of the Blood-Brain Barrier and the Meningeal Lymphatic System: The New Niche in Immunotherapy for Brain Tumors.

Photodynamic therapy (PDT) is a promising add-on therapy to the current standard of care for patients with glioblastoma (GBM). The traditional explanation of the anti-cancer PDT effects involves the PDT-induced generation of a singlet oxygen in the GBM cells, which causes tumor cell death and microvasculature collapse. Recently, new vascular mechanisms of PDT associated with opening of the blood-brain barrier (OBBB) and the activation of functions of the meningeal lymphatic vessels have been discovered. In this review, we highlight the emerging trends and future promises of immunotherapy for brain tumors and discuss PDT-OBBB as a new niche and an important informative platform for the development of innovative pharmacological strategies for the modulation of brain tumor immunity and the improvement of immunotherapy for GBM.

Immunotherapy for brain metastases and primary brain tumors

During the V Siena Immuno-Oncology (IO) Think Tank meeting in 2021, conditions were discussed which favor immunotherapy responses in either primary or secondary brain malignancies. Core elements of these discussions have been reinforced by important publications in 2021 and 2022. In primary brain tumors (such as glioblastoma) current immunotherapies have failed to deliver meaningful clinical benefit. By contrast, brain metastases frequently respond to current immunotherapies. The main differences between both conditions seem to be related to intrinsic factors (e.g., type of driver mutations) and more importantly extrinsic factors, such as the blood brain barrier and immune suppressive microenvironment (e.g., T cell counts, functional differences in T cells, myeloid cells). Future therapeutic interventions may therefore focus on rebalancing the immune cell population in a way which enables the host to respond to current or future immunotherapies.