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Despite maximal surgical resection and chemoradiation, glioblastoma (GBM) continues to be associated with significant morbidity and mortality. Novel therapeutic strategies are urgently needed. Given success in treating multiple other forms of cancer, checkpoint inhibitor immunotherapy remains foremost amongst novel therapeutic strategies that are currently under investigation. Through a systematic review of both published literature and the latest preliminary data available from ongoing clinical studies, we provide an up-to-date discussion on the immune system in the CNS, a detailed mechanistic evaluation of checkpoint biology in the CNS along with evidence for disruption of these pathways in GBM, and a summary of available preclinical and clinical data for checkpoint blockade in GBM. We also include a discussion of novel, emerging targets for checkpoint blockade which may play an important role in GBM immunotherapy. Evidence indicates that while clinical success of checkpoint blockade for the treatment of GBM has been limited to date, through improved preclinical models, optimization in the context of standard of care therapies, assay standardization and harmonization, and combinatorial approaches which may include novel targets for checkpoint blockade, checkpoint inhibitor immunotherapy may yield a safe and effective therapeutic option for the treatment of GBM. [ABSTRACT FROM AUTHOR]

Introduction: Immunotherapy embodies any approach that manipulates the immune system for therapeutic benefit. In this regard, various clinical trials have employed direct vaccination with patient-specific dendritic cells or adoptive T cell therapy to target highly aggressive tumors. Both modalities have demonstrated great specificity, an advantage that is unmatched by other treatment strategies. However, their full potential has yet to be realized. Areas covered: In this review, we provide an overview of chemokines in pathogen and anti-tumor immune responses and discuss further improving immunotherapies by arming particular chemokine axes. Expert commentary: The chemokine macrophage inflammatory protein-1 alpha (MIP-1α, CCL3) has emerged as a potent activator of both innate and adaptive responses. Specifically, CCL3 plays a critical role in recruiting distinct immune phenotypes to intratumoral sites, is a pivotal player in regulating lymph node homing of dendritic cell subsets, and induces antigen-specific T cell responses. The recent breadth of literature outlines the various interactions of CCL3 with these cellular subsets, which have now served as a basis for immunotherapeutic translation. [ABSTRACT FROM PUBLISHER]

Introduction: Glioblastoma is the most common primary brain tumor in adults and prognosis remains poor with a median survival of approximately 15–17 months. This review provides an overview of recent advances in the field of glioblastoma immunotherapy. Areas covered: Recent advances in dendritic cell vaccination immunotherapy are showing encouraging results in clinical trials and promise to extend patient survival. In this report we discuss current scientific knowledge regarding dendritic cell (DC) vaccines, including approaches to differentiating, priming, and injecting dendritic cells to achieve maximal anti-tumor efficacy in glioblastoma. These findings are compared to recently completed and currently ongoing glioblastoma clinical trials. Novel methods such as ‘fastDCs’ and vaccines targeting DCsin-vivomay offer more effective treatment when compared to traditional DC vaccines and have already entered the clinic. Expert commentary: Finally, we discuss the challenges of T-cell dysfunctions caused by glioblastoma immunosuppression and how they affect dendritic cell vaccinations approaches. [ABSTRACT FROM PUBLISHER]

While advanced surgical techniques, radiation therapy and chemotherapeutic regimens provide a tangible benefit for patients with glioblastoma (GBM), the average survival from the time of diagnosis remains less than 15 months. Current therapy for GBM is limited by the nonspecific nature of treatment, prohibiting therapy that is aggressive and prolonged enough to eliminate all malignant cells. As an alternative, bispecific antibodies can redirect the immune system to eliminate malignant cells with exquisite potency and specificity. We have recently developed an EGF receptor variant III (EGFRvIII)-targeted bispecific antibody that redirects T cells to eliminate EGFRvIII-expressing GBM. The absolute tumor specificity of EGFRvIII and the lack of immunologic crossreactivity with healthy cells allow this therapeutic to overcome limitations associated with the nonspecific nature of the current standard of care for GBM. Evidence indicates that the molecule can exert therapeutically significant effects in the CNS following systemic administration. Additional advantages in terms of ease-of-production and off-the-shelf availability further the clinical utility of this class of therapeutics. [ABSTRACT FROM AUTHOR]

Outcome for glioblastoma (GBM), the most common primary CNS malignancy, remains poor. The overall survival benefit recently achieved with immunotherapeutics for melanoma and prostate cancer support evaluation of immunotherapies for other challenging cancers, including GBM. Much historical dogma depicting the CNS as immunoprivileged has been replaced by data demonstrating CNS immunocompetence and active interaction with the peripheral immune system. Several glioma antigens have been identified for potential immunotherapeutic exploitation. Active immunotherapy studies for GBM, supported by preclinical data, have focused on tumor lysate and synthetic antigen vaccination strategies. Results to date confirm consistent safety, including a lack of autoimmune reactivity; however, modest efficacy and variable immunogenicity have been observed. These findings underscore the need to optimize vaccination variables and to address challenges posed by systemic and local immunosuppression inherent to GBM tumors. Additional immunotherapy strategies are also in development for GBM. Future studies may consider combinatorial immunotherapy strategies with complimentary actions. [ABSTRACT FROM AUTHOR]

Objectives: While convection enhanced delivery (CED) is an effective delivery method that bypasses the blood–brain barrier, its utility is limited by infusate leakage due to catheter misplacement. Therefore, it is critical to evaluate drug distribution during CED infusion. Gadolinium conjugated to diethylenetriamine penta-acetic acid (Gd-DTPA) is a common, readily available MRI contrast agent, which may be able to predict and actively monitor drug distribution. In this study, we assess the long-term safety and toxicity of intracerebrally infused Gd-DTPA along with an experimental targeted agent PRX321. Methods: Fifty-four immunocompetent rats were implanted with intracerebral cannulas linked to subcutaneously placed osmotic pumps. After pump implantation, the rats were randomized into six groups of nine rats each in order to assess the toxicities of six different concentrations of human serum albumin (HSA) with and without Gd-DTPA and PRX321. The rats were monitored clinically for 6 weeks before they were autopsied and assessed for histological toxicity to their central nervous system (CNS). Results: There was one unexplained death in a group infusing low concentration HSA, Gd-DTPA and PRX321. Upon microscopic examination of the CNS in that animal, no unexpected histological toxicity was found. Additionally, there were no signs of clinical or histological toxicity in any of the remaining rats, which all survived until the end of the 6 week observation period. Discussion: Free Gd-DTPA can be safely infused via CED in a pre-clinical animal model. Future studies should include its use in predicting and actively monitoring CED drug infusions in early phase human clinical trials. [ABSTRACT FROM AUTHOR]

Angiogenesis, the growth of new blood vessels from previously existing vasculature, is a requirement for tumor growth and metastasis. The first US FDA-approved drugs targeting angiogenesis have shown potential in the treatment of malignant gliomas. Immunotherapy as a treatment modality lends itself well to specifically targeting angiogenesis in tumors and may represent a powerful tool in the treatment of malignant gliomas. This review focuses on developments in immunotherapy targeting angiogenesis and tumor-vascular-specific endothelial cells using a variety of immunotherapeutic strategies including monoclonal antibodies and conjugated immunotoxins, as well as cellular, peptide, DNA and dendritic cell vaccines. [ABSTRACT FROM AUTHOR]

The authors reflect on the study on oncolytic viruses in the treatment of malignant glioma. They cite the genetic herpes simplex virus type 1 recombinants as the first to be considered for use in glioma oncolysis, re-engineered polioviruses and adenovirus. According to them, oncolytic viruses in combination with other experimental treatment modalities indicate a great promise but are still under preliminary investigation.

Despite their promise, tumor-specific peptide vaccines have limited efficacy. CD27 is a costimulatory molecule expressed on CD4+ and CD8+ T cells that is important in immune activation. Here we determine if a novel CD27 agonist antibody (αhCD27) can enhance the antitumor T cell response and efficacy of peptide vaccines. We evaluated the effects of αhCD27 on the immunogenicity and antitumor efficacy of whole protein, class I-restricted, and class II-restricted peptide vaccines using a transgenic mouse expressing human CD27. We found that αhCD27 preferentially enhances the CD8+ T cell response in the setting of vaccines comprised of linked class I and II ovalbumin epitopes (SIINFEKL and TEWTSSNVMEERKIKV, respectively) compared to a peptide vaccine comprised solely of SIINFEKL, resulting in the antitumor efficacy of adjuvant αhCD27 against intracranial B16.OVA tumors when combined with vaccines containing linked class I/II ovalbumin epitopes. Indeed, we demonstrate that this efficacy is both CD8- and CD4-dependent and αhCD27 activity on ovalbumin-specific CD4+ T cells is necessary for its adjuvant effect. Importantly for clinical translation, a linked universal CD4+ helper epitope (tetanus P30) was sufficient to instill the efficacy of SIINFEKL peptide combined with αhCD27, eliminating the need for a tumor-specific class II-restricted peptide. This approach unveiled the efficacy of a class I-restricted peptide vaccine derived from the tumor-associated Trp2 antigen in mice bearing intracranial B16 tumors. CD27 agonist antibodies combined with peptide vaccines containing linked tumor-specific CD8+ epitopes and tumor-specific or universal CD4+ epitopes enhance the efficacy of active cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) is an effective immunotherapy for B-cell malignancies but has failed in some solid tumors clinically. Intracerebral tumors may pose challenges that are even more significant. In order to devise a treatment strategy for patients with glioblastoma (GBM), we evaluated CARs as a monotherapy in a murine model of GBM. CARs exhibited poor expansion and survival in circulation and failed to treat syngeneic and orthotopic gliomas. We hypothesized that CAR engraftment would benefit from host lymphodepletion prior to immunotherapy and that this might be achievable by using temozolomide (TMZ), which is standard treatment for these patients and has lymphopenia as its major side effect. We modelled standard of care temozolomide (TMZSD) and dose-intensified TMZ (TMZDI) in our murine model. Both regimens are clinically approved and provide similar efficacy. Only TMZDI pretreatment prompted dramatic CAR proliferation and enhanced persistence in circulation compared to treatment with CARs alone or TMZSD + CARs. Bioluminescent imaging revealed that TMZDI + CARs induced complete regression of 21-day established brain tumors, which correlated with CAR abundance in circulation. Accordingly, TMZDI + CARs significantly prolonged survival and led to long-term survivors. These findings are highly consequential, as it suggests that GBM patients may require TMZDI as first line chemotherapy prior to systemic CAR infusion to promote CAR engraftment and antitumor efficacy. On this basis, we have initiated a phase I trial in patients with newly diagnosed GBM incorporating TMZDI as a preconditioning regimen prior to CAR immunotherapy (NCT02664363). [ABSTRACT FROM AUTHOR]

While RNA-pulsed dendritic cell (DC) vaccines have shown promise, the advancement of cellular therapeutics is fraught with developmental challenges. To circumvent the challenges of cellular immunotherapeutics, we developed clinically translatable nanoliposomes that can be combined with tumor-derived RNA to generate personalized tumor RNA-nanoparticles (NPs) with considerable scale-up capacity. RNA-NPs bypass MHC restriction, are amenable to central distribution, and can provide near immediate immune induction. We screened commercially available nanoliposomal preparations and identified the cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) as an efficient mRNA courier to antigen-presenting cells (APCs). When administered intravenously, RNA-NPs mediate systemic activation of APCs in reticuloendothelial organs such as the spleen, liver, and bone marrow. RNA-NPs increase percent expression of MHC class I/II, B7 co-stimulatory molecules, and maturation markers on APCs (all vital for T-cell activation). RNA-NPs also increase activation markers on tumor APCs and elicit potent expansion of antigen-specific T-cells superior to peptide vaccines formulated in complete Freund's adjuvant. We demonstrate that both model antigen-encoding and physiologically-relevant tumor-derived RNA-NPs expand potent antitumor T-cell immunity. RNA-NPs were shown to induce antitumor efficacy in a vaccine model and functioned as a suitable alternative to DCs in a stringent cellular immunotherapy model for a radiation/temozolomide resistant invasive murine high-grade glioma. Although cancer vaccines have suffered from weak immunogenicity, we have advanced a RNA-NP formulation that systemically activates host APCs precipitating activated T-cell frequencies necessary to engender antitumor efficacy. RNA-NPs can thus be harnessed as a more feasible and effective immunotherapy to re-program host-immunity. [ABSTRACT FROM AUTHOR]

Bispecific T-cell engagers (BiTE s) may break multiple barriers that currently limit the use of immunotherapy in glioblastoma patients. We have recently described a novel BiTE specific for a mutated form of the epidermal growth factor receptor, EGFRvIII, that exerts potent antineoplastic effects against established invasive tumors of the brain. [ABSTRACT FROM AUTHOR]

Conventional treatment for cancer routinely includes surgical resection and some combination of chemotherapy and radiation. These approaches are frequently accompanied by unintended and highly toxic collateral damage to healthy tissues, which are offset by only marginal prognostic improvements in patients with advanced cancers. This unfortunate balance has driven the development of novel therapies that aim to target tumors both safely and efficiently. Over the past decade, mounting evidence has supported the therapeutic utility of T-cell-centered cancer immunotherapy, which, in its various iterations, has been shown capable of eliciting highly precise and robust antitumor responses both in animal models and human trials. The identification of tumor-specific targets has further fueled a growing interest in T-cell therapies given their potential to circumvent the non-specific nature of traditional treatments. Of the several strategies geared toward achieving T-cell recognition of tumor, bispecific antibodies (bsAbs) represent a novel class of biologics that have garnered enthusiasm in recent years due to their versatility, specificity, safety, cost, and ease of production. Bispecific T-cell Engagers (BiTEs) are a subclass of bsAbs that are specific for CD3 on one arm and a tumor antigen on the second. As such, BiTEs function by recruiting and activating polyclonal populations of T-cells at tumor sites, and do so without the need for co-stimulation or conventional MHC recognition. Blinatumomab, a well-characterized BiTE, has emerged as a promising recombinant bscCD19×CD3 construct that has demonstrated remarkable antitumor activity in patients with B-cell malignancies. This clinical success has resulted in the rapid extension of BiTE technology against a greater repertoire of tumor antigens and the recent US Food and Drug Administration's (FDA) accelerated approval of blinatumomab for the treatment of a rare form of acute lymphoblastic leukemia (ALL). In this review, we dissect the role of T-cell therapeutics in the new era of cancer immunotherapy, appraise the value of CAR T-cells in the context of solid tumors, and discuss why the BiTE platform may rescue several of the apparent deficits and shortcomings of competing immunotherapies to support its widespread clinical application. [ABSTRACT FROM AUTHOR]

In adoptive T cell transfer therapy (ACT), the antitumor efficacy of cytotoxic CD8+T lymphocytes (CTLs) has been limited by tumor-induced immunosuppression. We have demonstrated that miR-23a blockade in tumor-specific CTLs conferred resilience to TGFβ-mediated immunosuppression, resulting in superior tumor control. Our studies highlight miR-23a in tumor-specific CTLs as a clinically relevant target to enhance ACT. [ABSTRACT FROM PUBLISHER]

First-line chemotherapy to combat primary malignant brain cancer is often accompanied by lymphopenic immunologic deficiency. Although counterintuitive, chemotherapy-induced lymphopenia can provide excellent host conditioning that may actually be leveraged to potentiate antitumor immunotherapy. We discuss here our preclinical and clinical experiences applying immunotherapy against glioblastoma, the most common and lethal primary malignant brain tumor, as well as the use of immunotherapeutics in the setting of standard-of-care temozolomide chemotherapy. [ABSTRACT FROM PUBLISHER]

CAR therapy has shown promise in treating cancer, but at the cost of unexpected toxicity against normal tissues, not predicted by preclinical testing. We are working to generate more physiologically relevant models for preclinical CAR toxicity testing, and in doing so, have discovered that CAR therapy induces immunogenic cell death, with the potential for cures. [ABSTRACT FROM PUBLISHER]

Human cytomegalovirus (CMV) is purportedly present in glioblastoma (GBM) while absent from the normal brain, making CMV antigens potentially ideal immunological anti-GBM targets. We recently demonstrated that patient-derived CMV pp65-specific T cells are capable of recognizing and killing autologous GBM tumor cells. This data supports CMV antigen-directed immunotherapies against GBM. [ABSTRACT FROM PUBLISHER]