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Efficacy of dendritic cell (DC) cancer vaccines is classically thought to depend on their antigen-presenting cell (APC) activity. Studies show, however, that DC vaccine priming of cytotoxic T lymphocytes (CTLs) requires the activity of endogenous DCs, suggesting that exogenous DCs stimulate antitumor immunity by transferring antigens (Ags) to endogenous DCs. Such Ag transfer functions are most commonly ascribed to monocytes, implying that undifferentiated monocytes would function equally well as a vaccine modality and need not be differentiated to DCs to be effective. Here, we used several murine cancer models to test the antitumor efficacy of undifferentiated monocytes loaded with protein or peptide Ag. Intravenously injected monocytes displayed antitumor activity superior to DC vaccines in several cancer models, including aggressive intracranial glioblastoma. Ag-loaded monocytes induced robust CTL responses via Ag transfer to splenic [CD8.sup.+] DCs in a manner independent of monocyte APC activity. Ag transfer required cell-cell contact and the formation of connexin 43- containing gap junctions between monocytes and DCs. These findings demonstrate the existence of an efficient gap junction-mediated Ag transfer pathway between monocytes and [CD8.sup.+] DCs and suggest that administration of tumor Ag-loaded undifferentiated monocytes may serve as a simple and efficacious immunotherapy for the treatment of human cancers., Introduction A major approach to cancer immunotherapy is the use of cellular vaccines to induce cytotoxic T lymphocyte (CTL) responses against specific tumor antigens (Ags) (1, 2). Among tumor vaccine [...]

BACKGROUND: The efficacy of carboplatin, irinotecan, and bevacizumab among recurrent glioblastoma (GBM) patients after prior progression on bevacizumab therapy in a phase 2, open-label, single-arm trial was evaluated. METHODS: Eligible patients received carboplatin (area under the plasma curve [AUC] 4 mg/ml-min) on day 1, whereas bevacizumab (10 mg/kg) and irinotecan (340 mg/m2 for patients on CYP3A enzyme-inducing anti-epileptics [EIAEDs] and 125 mg/m2 for patients not on EIAEDs) were administered on days 1 and 14 of every 28-day cycle. Patients were evaluated after each of the first 2 cycles and then after every other cycle. Treatment continued until progressive disease, unacceptable toxicity, noncompliance, or voluntary withdrawal. The primary end point was progression-free survival at 6 months (PFS-6), and secondary end points included safety and median overall survival (OS). RESULTS: All patients had progression on at least 1 prior bevacizumab regimen and 56% enrolled after either second or third overall progression. The median OS was 5.8 months (95% confidence interval [CI], 4.0-7.0 months) and PFS-6 rate was 16% (95% CI, 5.0%-32.5%). The most common grade 3 or 4 events were hematologic and occurred in 29% of cycles. Nine patients (38%) required dose modification. There were no treatment-related deaths. CONCLUSIONS: Carboplatin, irinotecan, and bevacizumab was associated with modest activity and adequate safety among recurrent GBM patients who progressed on bevacizumab previously. Cancer 2011;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Summary: The immunologic treatment of cancer has long been heralded as a targeted molecular therapeutic with the promise of eradicating tumor cells with minimal damage to surrounding normal tissues. However, a demonstrative example of the efficacy of immunotherapy in modulating cancer progression is still lacking for most human cancers. Recent breakthroughs in our understanding of the mechanisms leading to full T-cell activation, and recognition of the importance of overcoming tumor-induced immunosuppressive mechanisms, have shed new light on how to generate effective anti-tumor immune responses in humans, and sparked a renewed and enthusiastic effort to realize the full potential of cancer immunotherapy. The immunologic treatment of invasive malignant brain tumors has not escaped this re-invigorated endeavor, and promising therapies are currently under active investigation in dozens of clinical trials at several institutions worldwide. This review will focus on some of the most important breakthroughs in our understanding of how to generate potent anti-tumor immune responses, and some of the clear challenges that lie ahead in achieving effective immunotherapy for the majority of patients with malignant brain tumors. A review of immunotherapeutic strategies currently under clinical evaluation, as well as an outline of promising novel approaches on the horizon, is included to provide perspective on the active and stalwart progress toward effective immunotherapy for the treatment of malignant brain tumors. [Copyright &y& Elsevier]

The article presents a clinical trial in patients with recurrent or progressive malignant glioma (MG). The trial was intended to find the maximum tolerated dose (MTD) and toxicity of irinotecan (CPT-11) when distributed with O6-benzylguanine and temozolomide (TMZ). The trial shows that in both strata, the dose-fixing toxicities were hematologic and included in four leukopenia, neutropenia, thrombocytopenia and febrile neutropenia.

Brain tumors are horrific diseases with almost universally fatal outcomes; new therapeutics are desperately needed and will come from improved understandings of glioma biology. Exosomes are endosomally derived 30-100 nm membranous vesicles released from many cell types into the extracellular milieu; surprisingly, exosomes are virtually unstudied in neuro-oncology. These microvesicles were used as vaccines in other tumor settings, but their immunological significance is unevaluated in brain tumors. Our purpose here is to report the initial biochemical, proteomic, and immunological studies on murine brain tumor exosomes, following known procedures to isolate exosomes. Our findings show that these vesicles have biophysical characteristics and proteomic profiles similar to exosomes from other cell types but that brain tumor exosomes have unique features (e.g., very basic isoelectric points, expressing the mutated tumor antigen EGFRvIII and the putatively immunosuppressive cytokine TGF-β). Administration of such exosomes into syngeneic animals produced both humoral and cellular immune responses in immunized hosts capable of rejecting subsequent tumor challenges but failed to prolong survival in established orthotopic models. Control animals received saline or cell lysate vaccines and showed no antitumor responses. Exosomes and microvesicles isolated from sera of patients with brain tumors also possess EGFR, EGFRvIII, and TGF-β. We conclude that exosomes released from brain tumor cells are biochemically/biophysically like other exosomes and have immune-modulating properties. They can escape the blood-brain barrier, with potential systemic and distal signaling and immune consequences. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy in glioblastoma has so far failed to yield a survival benefit. This failure can be attributed to a paucity of immune cells at the tumor site which can be reinvigorated to kill tumor cells. Therefore, driving effector immune cells such as cytotoxic T lymphocytes to the tumor is a necessary pre-requisite of any effective immunotherapy approach. In this review, we will discuss therapeutic approaches possible for trafficking T cells from the periphery to travel through the blood–brain barrier and tissue of the brain to reach the tumor. Glioblastoma is an immunologically 'cold' tumor, which are characterized by absent or minimal numbers of tumor-infiltrating lymphocytes (TILs). For those tumors that have been invaded by lymphocytes, they are profoundly exhausted and ineffective. While many immunotherapy approaches seek to reinvigorate immune cells at the tumor, this requires TILs to be present. Therefore, to unleash the full potential of immunotherapy in glioblastoma, the trafficking of lymphocytes to the tumor is highly desirable. However, the process of T cell recruitment into the central nervous system (CNS) is tightly regulated. Naïve T cells may undergo an initial licensing process to enter the migratory phenotype necessary to enter the CNS. T cells then must express appropriate integrins and selectin ligands to interact with transmembrane proteins at the blood–brain barrier (BBB). Finally, they must interact with antigen-presenting cells and undergo further licensing to enter the parenchyma. These T cells must then navigate the tumor microenvironment, which is rich in immunosuppressive factors. Altered tumoral metabolism also interferes with T cell motility. In this review, we will describe these processes and their mediators, along with potential therapeutic approaches to enhance trafficking. We also discuss safety considerations for such approaches as well as potential counteragents. [ABSTRACT FROM AUTHOR]

Despite aggressive multi-modality therapy including surgery, radiation, and chemotherapy, the prognosis for patients with malignant primary brain tumors remains very poor. Moreover, the non-specific nature of conventional therapy for brain tumors often results in incapacitating damage to surrounding normal brain and systemic tissues. Thus, there is an urgent need for the development of therapeutic strategies that precisely target tumor cells while minimizing collateral damage to neighboring eloquent cerebral cortex. The rationale for using the immune system to target brain tumors is based on the premise that the inherent specificity of immunologic reactivity could meet the clear need for more specific and precise therapy. The success of this modality is dependent on our ability to understand the mechanisms of immune regulation within the central nervous system (CNS), as well as counter the broad defects in host cell-mediated immunity that malignant gliomas are known to elicit. Recent advances in our understanding of tumor-induced and host-mediated immunosuppressive mechanisms, the development of effective strategies to combat these suppressive effects, and a better understanding of how to deliver immunologic effector molecules more efficiently to CNS tumors have all facilitated significant progress toward the realization of true clinical benefit from immunotherapeutic treatment of malignant gliomas. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme remains refractory to conventional therapy, and novel therapeutic modalities are desperately needed. TP-38 is a recombinant chimeric protein containing a genetically engineered form of the cytotoxic Pseudomonas exotoxin fused to transforming growth factor (TGF)-α. TGF-α binds with high affinity to the epidermal growth factor receptor, which is uniformly overexpressed in malignant gliomas, often because of gene amplification. Prior to therapy with TP-38, the patient described here was completely refractory to multiple other therapies, with radiographic and pathologic evidence of tumor progression. After therapy, she improved clinically, was weaned off steroids and anti-convulsants, and experienced a progressive decrease in enhancing tumor volume. Despite multiple prior recurrences, she has not progressed for >43 months after TP-38 therapy. Small remaining areas of enhancement demonstrate no evidence of tumor histologically and are hypometabolic on positron emission tomography. This report describes a dramatic and sustained clinical and radiographic response in a patient with a bifrontal glioblastoma multiforme treated with intratumoral infusion of a novel targeted toxin, TP-38. [ABSTRACT FROM AUTHOR]

Cell adhesion molecules of the immunoglobulin superfamily are aberrantly expressed in malignant glioma. Amongst these, the human poliovirus receptor CD155 provides a molecular target for therapeutic intervention with oncolytic poliovirus recombinants. Poliovirus has been genetically modified through insertion of regulatory sequences derived from human rhinovirus type 2 to selectively replicate within and destroy can-cerous cells. Efficacious oncolysis mediated by poliovirus derivatives depends on the presence of CD155 in targeted tumors. To prepare oncolytic polioviruses for clinical application, we have developed a series of assays in high-grade malignant glioma (HGL) to characterize CD155 expression levels and susceptibility to oncolytic poliovirus recombinants. Analysis of 6 HGL cases indicates that CD155 is expres-sed in these tumors and in primary cell lines derived from these tumors. Upregulation of the molecular target CD155 rendered explant cultures of all studied tumors highly susceptible to a prototype oncolytic poliovirus recombinant. Our observations support the clinical application of such agents against HGL. [ABSTRACT FROM AUTHOR]

In preclinical studies, BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea, plus CPT-11 (irinotecan) exhibits scheduledependent, synergistic activity against malignant glioma (MG). We previously established the maximum tolerated dose of CPT-11 when administered for 4 consecutive weeks in combination with BCNU administered on the first day of each 6-week cycle. We now report a phase 2 trial of BCNU plus CPT-11 for patients with MG. In the current study, BCNU (100 mg/m²) was administered on day 1 of each 6-week cycle. CPT-11 was administered on days 1, 8, 15, and 22 at 225 mg/m² for patients receiving CYP3A1- or CYP3A4-inducing anticonvulsants and at 125 mg/m² for those not on these medications. Newly diagnosed patients received up to 3 cycles before radiotherapy, while recurrent patients received up to 8 cycles. The primary end point of this study was radiographic response, while time to progression and overall survival were also assessed. Seventy-six patients were treated, including 37 with newly diagnosed tumors and 39 with recurrent disease. Fifty-six had glioblastoma multiforme, 18 had anaplastic astrocytoma, and 2 had anaplastic oligodendroglioma. Toxicities (grade ⩾3) included infections (13%), thromboses (12%), diarrhea (10%), and neutropenia (7%). Interstitial pneumonitis developed in 4 patients. Five newly diagnosed patients (14%; 95% CI, 5%–29%) achieved a radiographic response (1 complete response and 4 partial responses). Five patients with recurrent MG also achieved a response (1 complete response and 4 partial responses; 13%; 95% CI, 4%–27%). More than 40% of both newly diagnosed and recurrent patients achieved stable disease. Median time to progression was 11.3 weeks for recurrent glioblastoma multiforme patientsand 16.9 weeks for recurrent anaplastic astrocytoma/ anaplastic oligodendroglioma patients. We conclude that the activity of BCNU plus CPT-11 for patients with MG appears comparable to that of CPT-11 alone and may be more toxic. [ABSTRACT FROM AUTHOR]

Despite remarkable advancements in imaging modalities and treatment options available to patients diagnosed with malignant brain tumors, the prognosis for those with high-grade lesions remains poor. Adoptive T-cell therapy is an attempt to harness and amplify the tumor-eradicating capacity of a patients' own T cells and then return these effectors to the patient in such a state that they effectively eliminate residual tumor. The immunologic treatment of high-grade malignant brain tumors stands apart from other malignant diseases with regard to its central nervous system immune privilege and concerns of autoimmunity and therefore represents a unique challenge in tumor immunotherapy. Animal studies of several experimental tumors have demonstrated that the adoptive transfer of T cells from tumor-bearing mice were consistently less effective than the transfer of T cells from non-tumor-bearing mice that had been vaccinated against tumor antigens.

The use of anti-idiotype (anti-id) vaccines for immunotherapy of human cancers is attractive, as immunization with true anti-id reagents (Ab2β) has been shown to induce both cellular and humoral immunity, frequently when the original antigen does not, or when a state of anergy to the self-expressed tumor-associated antigen exists. The aim of this study was to investigate the potential of an anti-id vaccine approach to the glioma-associated antigen epidermal growth factor receptor variant III (EGFRvIII) for human clinical trials. By using conventional methodology, seven rat mAbs specific for the binding site of the murine anti-EGFRvIII-specific mAb Y10, as defined by the ability to inhibit the binding of mAb Y10 to EGFRvIII expressed on cells or as purified protein, were generated, and a subset (3/7) was found to be true Ab2β, as defined by the ability to induce the formation of antibody directed against EGFRvIII in two species (mouse and rabbit) when used as immunogen. The ability of these three Ab2β to elicit a protective anti-tumor response when used as a vaccine in the syngeneic, subcutaneous C57Bl/6-B16mseEGFRvIII tumor model was investigated. Following vaccination with one Ab2β mAb (2C7), 6/20 mice failed to develop tumor upon challenge, and 3/20 mice with outgrowing tumors exhibited dramatic regression of incipient tumors. Vaccination with a second mAb (5G8) resulted in one tumor-free survivor and one tumor regressor; vaccination with the third Ab2β mAb (7D3) did not confer protection, but did significantly increase the latency period until tumor outgrowth in all vaccinated recipients. The ability of Ab2β mAb 2C7 to induce an anti-EGFRvIII response in non-human primates was investigated by using the saponin adjuvant approved for human clinical trial, QS-21. Three of three macaques produced anti-EGFRvIII titers, as detected on EGFRvIII-expressing cells by both ELISA and fluorescence-activated cytometric analysis, following six immunizations with Ab2β mAb 2C7 and QS-21. The results obtained confirm that an anti-id response in the EGFRvIII antigen system can be induced in rodents, rabbits, and non-human primates, and it may prove a useful adjunct to immunotherapeutic approaches to EGFRvIII-positive gliomas, breast carcinomas, and non-small-cell lung tumors. [ABSTRACT FROM AUTHOR]

Purpose: Patients with recurrent malignant gliomas treated with stereotactic radiosurgery (SRS) and multiagent systemic therapies were reviewed to determine the effects of patient- and treatment-related factors on survival and toxicity. Methods and Materials: A retrospective analysis was performed on patients with recurrent malignant gliomas treated with salvage SRS from September 2002 to March 2010. All patients had experienced progression after treatment with temozolomide and radiotherapy. Salvage SRS was typically administered only after multiple postchemoradiation salvage systemic therapies had failed. Results: 63 patients were treated with SRS for recurrent high-grade glioma; 49 patients had World Health Organization (WHO) Grade 4 disease. Median follow-up was 31 months from primary diagnosis and 7 months from SRS. Median overall survival from primary diagnosis was 41 months for all patients. Median progression-free survival (PFS) and overall survival from SRS (OS-SRS) were 6 and 10 months for all patients, respectively. The 1-year OS-SRS for patients with Grade 4 glioma who received adjuvant (concurrent with or after SRS) bevacizumab was 50% vs. 22% for patients not receiving adjuvant bevacizumab (p = 0.005). Median PFS for patients with a WHO Grade 4 glioma who received adjuvant bevacizumab was 5.2 months vs. 2.1 months for patients who did not receive adjuvant bevacizumab (p = 0.014). Karnofsky performance status (KPS) and age were not significantly different between treatment groups. Treatment-related Grade 3/4 toxicity for patients receiving and not receiving adjuvant BVZ was 10% and 14%, respectively (p = 0.58).On multivariate analysis, the relative risk of death and progression with adjuvant bevacizumab was 0.37 (confidence interval [CI] 0.17–0.82) and 0.45 (CI 0.21–0.97). KPS >70 and age <50 years were significantly associated with improved survival. Conclusions: The combination of salvage radiosurgery and bevacizumab to treat recurrent malignant gliomas is well tolerated and seems to be associated with improved outcomes. Prospective multiinstitutional studies are required to determine efficacy and long-term toxicity with this approach. [ABSTRACT FROM AUTHOR]

Background: The prognosis of patients with recurrent World Health Organization (WHO) grade IV malignant glioma is dismal, and there is currently no effective therapy. We conducted a dose-finding and toxicity study in this population of patients, evaluating convection-enhanced, intratumoral delivery of the recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO). PVSRIPO recognizes the poliovirus receptor CD155, which is widely expressed in neoplastic cells of solid tumors and in major components of the tumor microenvironment.Methods: We enrolled consecutive adult patients who had recurrent supratentorial WHO grade IV malignant glioma, confirmed on histopathological testing, with measurable disease (contrast-enhancing tumor of ≥1 cm and ≤5.5 cm in the greatest dimension). The study evaluated seven doses, ranging between 107 and 1010 50% tissue-culture infectious doses (TCID50), first in a dose-escalation phase and then in a dose-expansion phase.Results: From May 2012 through May 2017, a total of 61 patients were enrolled and received a dose of PVSRIPO. Dose level -1 (5.0×107 TCID50) was identified as the phase 2 dose. One dose-limiting toxic effect was observed; a patient in whom dose level 5 (1010 TCID50) was administered had a grade 4 intracranial hemorrhage immediately after the catheter was removed. To mitigate locoregional inflammation of the infused tumor with prolonged glucocorticoid use, dose level 5 was deescalated to reach the phase 2 dose. In the dose-expansion phase, 19% of the patients had a PVSRIPO-related adverse event of grade 3 or higher. Overall survival among the patients who received PVSRIPO reached a plateau of 21% (95% confidence interval, 11 to 33) at 24 months that was sustained at 36 months.Conclusions: Intratumoral infusion of PVSRIPO in patients with recurrent WHO grade IV malignant glioma confirmed the absence of neurovirulent potential. The survival rate among patients who received PVSRIPO immunotherapy was higher at 24 and 36 months than the rate among historical controls. (Funded by the Brain Tumor Research Charity and others; ClinicalTrials.gov number, NCT01491893 .). [ABSTRACT FROM AUTHOR]

Astrocytic and oligodendroglial gliomas are intrinsic brain tumours characterized by infiltrative growth and resistance to classic cancer therapies, which renders them inevitably lethal. Glioblastoma, the most common type of glioma, also exhibits neoangiogenesis and profound immunosuppressive properties. Accordingly, strategies to revert glioma-associated immunosuppression and promote tumour-directed immune responses have been extensively explored in rodent models and in large clinical trials of tumour immunotherapy. This Review describes vaccination approaches investigated for the treatment of glioma. Several strategies have reached phase III clinical trials, including vaccines targeting epidermal growth factor receptor variant III, and the use of either immunogenic peptides or tumour lysates to stimulate autologous dendritic cells. Other approaches in early phases of clinical development employ multipeptide vaccines such as IMA-950, cytomegalovirus-derived peptides, or tumour-derived peptides such as heat shock protein-96 peptide complexes and the Arg132His mutant form of isocitrate dehydrogenase. However, some preclinical trial data suggest that addition of immunomodulatory reagents such as immune checkpoint inhibitors, transforming growth factor-β inhibitors, signal transducer and activator of transcription 3 inhibitors, or modifiers of tryptophan metabolism could augment the therapeutic activity of vaccination and overcome glioma-associated immunosuppression. [ABSTRACT FROM AUTHOR]

Abstract: For the study of malignant glioma, we have previously characterized a highly tumorigenic murine astrocytoma, SMA-560, which arose spontaneously in an inbred, immunocompetent VM/Dk mouse. Using this cell line as a model of murine glioma, we performed DNA microarray analysis of autologous normal murine astroctyes (NMA) and SMA-560 tumor cells grown in monolayer culture or intracranially in syngeneic immunocompetent or immunocompromised hosts in order to determine whether tumors grown in vitro recreate the complex genetic regulation that occurs in vivo. Our findings support our hypothesis that glioma phenotype in vitro may be quite different in vivo and significantly altered by in situ growth factors and other invading cell populations. [Copyright &y& Elsevier]