Publications by authors named "John H Sampson"

255 Publications

A conjoined universal helper epitope can unveil antitumor effects of a neoantigen vaccine targeting an MHC class I-restricted neoepitope.

NPJ Vaccines 2021 Jan 18;6(1):12. Epub 2021 Jan 18.

Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA.

Personalized cancer vaccines targeting neoantigens arising from somatic missense mutations are currently being evaluated for the treatment of various cancers due to their potential to elicit a multivalent, tumor-specific immune response. Several cancers express a low number of neoantigens; in these cases, ensuring the immunotherapeutic potential of each neoantigen-derived epitope (neoepitope) is crucial. In this study, we discovered that therapeutic vaccines targeting immunodominant major histocompatibility complex (MHC) I-restricted neoepitopes require a conjoined helper epitope in order to induce a cytotoxic, neoepitope-specific CD8+ T-cell response. Furthermore, we show that the universally immunogenic helper epitope P30 can fulfill this requisite helper function. Remarkably, conjoined P30 was able to unveil immune and antitumor responses to subdominant MHC I-restricted neoepitopes that were, otherwise, poorly immunogenic. Together, these data provide key insights into effective neoantigen vaccine design and demonstrate a translatable strategy using a universal helper epitope that can improve therapeutic responses to MHC I-restricted neoepitopes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41541-020-00273-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814002PMC
January 2021

Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy.

Nat Commun 2021 01 13;12(1):352. Epub 2021 Jan 13.

Department of Neurosurgery, Duke University Medical Center, Durham, NC, 27710, USA.

Several immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits in 10-20% of patients. Here we perform genomic analysis of tumor tissue from recurrent WHO grade IV glioblastoma patients acquired prior to immunotherapy intervention. We report that very low tumor mutation burden is associated with longer survival after recombinant polio virotherapy or after immune checkpoint blockade in recurrent glioblastoma patients. A relationship between tumor mutation burden and survival is not observed in cohorts of immunotherapy naïve newly diagnosed or recurrent glioblastoma patients. Transcriptomic analyses reveal an inverse relationship between tumor mutation burden and enrichment of inflammatory gene signatures in cohorts of recurrent, but not newly diagnosed glioblastoma tumors, implying that a relationship between tumor mutation burden and tumor-intrinsic inflammation evolves upon recurrence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-20469-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806846PMC
January 2021

Checkpoint inhibitor immunotherapy for glioblastoma: current progress, challenges and future outlook.

Expert Rev Clin Pharmacol 2020 Oct 11;13(10):1147-1158. Epub 2020 Sep 11.

Department of Neurosurgery, Duke University Medical Center , Durham, NC, USA.

Introduction: 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.

Areas Covered: 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.

Expert Opinion: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17512433.2020.1817737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658017PMC
October 2020

Temozolomide treatment outcomes and immunotherapy efficacy in brain tumor.

J Neurooncol 2021 Jan 19;151(1):55-62. Epub 2020 Aug 19.

Duke University, Durham, NC, USA.

Introduction: Glioblastoma (GBM) has a survival rate of around 2 years with aggressive current standard of care. While other tumors have responded favorably to trials combining immunotherapy and chemotherapy, GBM remains uniformly deadly with minimal increases in overall survival. GBM differ from others due to being isolated behind the blood brain barrier, increased heterogeneity and mutational burden, and immunosuppression from the brain environment and tumor itself.

Methods: We have reviewed clinical and preclinical studies investigating how different doses (dose intense (DI) and metronomic) and timing of immunotherapy following TMZ treatment can eradicate tumor cells, alter tumor mutational burden, and change immune cells.

Results: Recent clinical trials with standard of care (SoC), DI and metronomic TMZ regimes are no able to completely eradicate GBM. Elevated TMZ levels in DI treatment can overcome MGMT resistance but may result in hypermutation of surviving tumor cells. Higher levels of TMZ will also generate a higher degree of lymphopenia compared to SoC and metronomic regimes in preclinical studies.

Conclusion: The different levels of lymphopenia and tumor eradication discussed in this review suggest possible beneficial pairings between immunotherapy and TMZ treatment. Treatments resulting in profound lymphopenia will allow for expansion of vaccine specific T cells or of CAT T cells. Clinical and preclinical studies are currently comparing different combinations of TMZ and immunotherapy timing to treat GBM through a balance between tumor killing and immune cell expansion. More frequent immune monitoring time points in ongoing clinical trials are crucial for further development of these combinations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11060-020-03598-2DOI Listing
January 2021

GLP toxicology study of a fully-human T cell redirecting CD3:EGFRvIII binding immunotherapeutic bispecific antibody.

PLoS One 2020 31;15(7):e0236374. Epub 2020 Jul 31.

Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC, United States of America.

We recently reported the development of a fully-human, CD3-binding bispecific antibody for immunotherapy of malignant glioma. To translate this therapeutic (hEGFRvIII-CD3- bi-scFv) to clinical trials and to help further the translation of other similar CD3-binding therapeutics, some of which are associated with neurologic toxicities, we performed a good laboratory practice (GLP) toxicity study to assess for potential behavioral, chemical, hematologic, and pathologic toxicities including evaluation for experimental autoimmune encephalomyelitis (EAE). To perform this study, male and female C57/BL6 mice heterozygous for the human CD3 transgene (20/sex) were allocated to one of four designated groups. All animals were administered one dose level of hEGFRvIII-CD3 bi-scFv or vehicle control. Test groups were monitored for feed consumption, changes in body weight, and behavioral disturbances including signs of EAE. Urinalysis, hematologic, and clinical chemistry analysis were also performed. Vehicle and test chemical-treated groups were humanely euthanized 48 hours or 14 days following dose administration. Complete gross necropsy of all tissues was performed, and selected tissues plus all observed gross lesions were collected and evaluated for microscopic changes. This included hematoxylin-eosin histopathological evaluation and Fe-ECR staining for myelin sheath enumeration. There were no abnormal clinical observations or signs of EAE noted during the study. There were no statistical changes in food consumption, body weight gain, or final body weight among groups exposed to hEGFRvIII-CD3 bi-scFv compared to the control groups for the 2- and 14-day timepoints. There were statistical differences in some clinical chemistry, hematologic and urinalysis endpoints, primarily in the females at the 14-day timepoint (hematocrit, calcium, phosphorous, and total protein). No pathological findings related to hEGFRvIII-CD3 bi-scFv administration were observed. A number of gross and microscopic observations were noted but all were considered to be incidental background findings. The results of this study allow for further translation of this and other important CD3 modulating bispecific antibodies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236374PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394377PMC
September 2020

Once, Twice, Three Times a Finding: Reproducibility of Dendritic Cell Vaccine Trials Targeting Cytomegalovirus in Glioblastoma.

Clin Cancer Res 2020 Oct 27;26(20):5297-5303. Epub 2020 Jul 27.

The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.

Despite standard of care for glioblastoma, including gross total resection, high-dose radiation, and dose-limited chemotherapy, this tumor remains one of the most aggressive and therapeutically challenging. The relatively small number of patients with this diagnosis compared with more common solid tumors in clinical trials commits new glioblastoma therapies to testing in small, underpowered, nonrandomized settings. Among approximately 200 registered glioblastoma trials identified between 2005 and 2015, nearly half were single-arm studies with sample sizes not exceeding 50 patients. These constraints have made demonstrating efficacy for novel therapies difficult in glioblastoma and other rare and aggressive cancers. Novel immunotherapies for glioblastoma such as vaccination with dendritic cells (DC) have yielded mixed results in clinical trials. To address limited numbers, we sequentially conducted three separate clinical trials utilizing cytomegalovirus (CMV)-specific DC vaccines in patients with newly diagnosed glioblastoma whereby each follow-up study had nearly doubled in sample size. Follow-up data from the first blinded, randomized phase II clinical trial (NCT00639639) revealed that nearly one third of this cohort is without tumor recurrence at 5 years from diagnosis. A second clinical trial (NCT00639639) resulted in a 36% survival rate at 5 years from diagnosis. Results of the first two-arm trial (NCT00639639) showed increased migration of the DC vaccine to draining lymph nodes, and this increased migration has been recapitulated in our larger confirmatory clinical study (NCT02366728). We have now observed that nearly one third of the glioblastoma study patient population receiving CMV-specific DC vaccines results in exceptional long-term survivors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-1082DOI Listing
October 2020

PD-1 Inhibitors: Do they have a Future in the Treatment of Glioblastoma?

Clin Cancer Res 2020 Oct 11;26(20):5287-5296. Epub 2020 Jun 11.

Preston Robert Tisch Brain Tumor Center at Duke, Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.

Glioblastoma (WHO grade IV glioma) is the most common malignant primary brain tumor in adults. Survival has remained largely static for decades, despite significant efforts to develop new effective therapies. Immunotherapy and especially immune checkpoint inhibitors and programmed cell death (PD)-1/PD-L1 inhibitors have transformed the landscape of cancer treatment and improved patient survival in a number of different cancer types. With the exception of few select cases (e.g., patients with Lynch syndrome) the neuro-oncology community is still awaiting evidence that PD-1 blockade can lead to meaningful clinical benefit in glioblastoma. This lack of progress in the field is likely to be due to multiple reasons, including inherent challenges in brain tumor drug development, the blood-brain barrier, the unique immune environment in the brain, the impact of corticosteroids, as well as inter- and intratumoral heterogeneity. Here we critically review the clinical literature, address the unique aspects of glioma immunobiology and potential immunobiological barriers to progress, and contextualize new approaches to increase the efficacy of PD-1/PD-L1 inhibitors in glioblastoma that may identify gaps and testable relevant hypotheses for future basic and clinical research and to provide a novel perspective to further stimulate preclinical and clinical research to ultimately help patients with glioma, including glioblastoma, which is arguably one of the greatest areas of unmet need in cancer. Moving forward, we need to build on our existing knowledge by conducting further fundamental glioma immunobiology research in parallel with innovative and methodologically sound clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-1135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682636PMC
October 2020

Comparative study of α-helical and β-sheet self-assembled peptide nanofiber vaccine platforms: influence of integrated T-cell epitopes.

Biomater Sci 2020 Jun 26;8(12):3522-3535. Epub 2020 May 26.

Biomedical Engineering Department, Duke University, Durham, NC 27708, USA.

Several different self-assembling peptide systems that form nanofibers have been investigated as vaccine platforms, but design principles for adjusting the character of the immune responses they raise have yet to be well articulated. Here we compared the immune responses raised by two structurally dissimilar peptide nanofibers, one a β-sheet fibrillar system (Q11), and one an α-helical nanofiber system (Coil29), hypothesizing that integrated T-cell epitopes within the latter would promote T follicular helper (Tfh) cell engagement and lead to improved antibody titers and quality. Despite significantly different internal structures, nanofibers of the two peptides exhibited surprisingly similar nanoscale morphologies, and both were capable of raising strong antibody responses to conjugated peptide epitopes in mice without adjuvant. Both were minimally inflammatory, but as hypothesized Coil29 nanofibers elicited antibody responses with higher titers and avidities against a conjugated model epitope (OVA) and a candidate peptide epitope for vaccination against S. aureus. Subsequent investigation indicated that Coil29 nanofibers possessed internal CD4+ T cell epitopes: whereas Q11 nanofibers required co-assembly of additional CD4+ T cell epitopes to be immunogenic, Coil29 nanofibers did not. Coil29 nanofibers also raised stronger germinal center B cell responses and follicular helper T cell (Tfh) responses relative to Q11 nanofibers, likely facilitating the improvement of the antibody response. These findings illustrate design strategies for improving humoral responses raised by self-assembled peptide nanofibers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0bm00521eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665831PMC
June 2020

First in human dose calculation of a single-chain bispecific antibody targeting glioma using the MABEL approach.

J Immunother Cancer 2020 04;8(1)

Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina, United States

Background: First-in-human (FIH) clinical trials require careful selection of a safe yet biologically relevant starting dose. Typically, such starting doses are selected based on toxicity studies in a pharmacologically relevant animal model. However, with the advent of target-specific and highly active immunotherapeutics, both the Food and Drug Administration and the European Medicines Agency have provided guidance that recommend determining a safe starting dose based on a minimum anticipated biological effect level (MABEL) approach.

Methods: We recently developed a T cell activating bispecific antibody that effectively treats orthotopic patient-derived malignant glioma and syngeneic glioblastoma in mice (hEGFRvIII:CD3 bi-scFv). hEGFRvIII:CD3 bi-scFv is comprized of two single chain antibody fragments (bi-scFvs) that bind mutant epidermal growth factor receptor variant III (EGFRvIII), a mutation frequently seen in malignant glioma, and human CD3ε on T cells, respectively. In order to establish a FIH dose, we used a MABEL approach to select a safe starting dose for hEGFRvIII:CD3 bi-scFv, based on a combination of in vitro data, in vivo animal studies, and theoretical human receptor occupancy modeling.

Results: Using the most conservative approach to the MABEL assessment, a dose of 57.4 ng hEGFRvIII:CD3 bi-scFv/kg body weight was selected as a safe starting dose for a FIH clinical study.

Conclusions: The comparison of our MABEL-based starting dose to our in vivo efficacious dose and the theoretical human receptor occupancy strongly supports that our human starting dose of 57.4 ng hEGFRvIII:CD3 bi-scFv/patient kg will be safe.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2019-000213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254109PMC
April 2020

Rindopepimut with Bevacizumab for Patients with Relapsed EGFRvIII-Expressing Glioblastoma (ReACT): Results of a Double-Blind Randomized Phase II Trial.

Clin Cancer Res 2020 04 7;26(7):1586-1594. Epub 2020 Feb 7.

Celldex Therapeutics, Inc., Hampton, New Jersey.

Purpose: Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma.

Patients And Methods: In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naïve patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut or a control injection of keyhole limpet hemocyanin, each concurrent with bevacizumab. The primary endpoint was 6-month progression-free survival (PFS6) by central review with a one-sided significance of 0.2.

Results: Between May 2012 and 2014, 73 patients were randomized (36 rindopepimut, 37 control). Rindopepimut toxicity included transient, low-grade local reactions. As primary endpoint, PFS6 was 28% (10/36) for rindopepimut compared with 16% (6/37) for control ( = 0.12, one-sided). Secondary and exploratory endpoints also favored the rindopepimut group including a statistically significant survival advantage [HR, 0.53; 95% confidence interval (CI), 0.32-0.88; two-sided log-rank = 0.01], a higher ORR [30% (9/30) vs. 18% (6/34; = 0.38)], median duration of response [7.8 months (95% CI, 3.5-22.2) vs. 5.6 (95% CI, 3.7-7.4)], and ability to discontinue steroids for ≥6 months [33% (6/18) vs. 0% (0/19)]. Eighty percent of rindopepimut-treated patients achieved robust anti-EGFRvIII titers (≥1:12,800), which were associated with prolonged survival (HR = 0.17; 95% CI, 0.07-0.45; < 0.0001).

Conclusions: Our randomized trial supports the potential for targeted immunotherapy among patients with GBM, but the therapeutic benefit requires validation due to the small sample size and potential heterogeneity of bevacizumab response among recurrent patients with GBM..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-18-1140DOI Listing
April 2020

CAR T cells and checkpoint inhibition for the treatment of glioblastoma.

Expert Opin Biol Ther 2020 06 17;20(6):579-591. Epub 2020 Feb 17.

Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA.

: Glioblastoma (GBM) is a highly aggressive brain tumor and is one of the most lethal human cancers. Chimeric antigen receptor (CAR) T cell therapy has markedly improved survival in previously incurable disease; however, this vanguard treatment still faces challenges in GBM. Likewise, checkpoint blockade therapies have not enjoyed the same victories against GBM. As it becomes increasingly evident that a mono-therapeutic approach is unlikely to provide anti-tumor efficacy, there evolves a critical need for combined treatment strategies.: This review highlights the clinical successes observed with CAR T cell therapy as well the current efforts to overcome its perceived limitations. The review also explores employed combinations of CAR T cell approaches with immune checkpoint blockade strategies, which aim to potentiate immunotherapeutic benefits while restricting the impact of tumor heterogeneity and T cell exhaustion.: Barriers such as tumor heterogeneity and T cell exhaustion have exposed the weaknesses of various mono-immunotherapeutic approaches to GBM, including CAR T cell and checkpoint blockade strategies. Combining these potentially complementary strategies, however, may proffer a rational means of mitigating these barriers and advancing therapeutic successes against GBM and other solid tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14712598.2020.1727436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202971PMC
June 2020

Current multidisciplinary management of brain metastases.

Cancer 2020 04 23;126(7):1390-1406. Epub 2020 Jan 23.

Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.

Brain metastasis (BM), the most common adult brain tumor, develops in 20% to 40% of patients with late-stage cancer and traditionally are associated with a poor prognosis. The management of patients with BM has become increasingly complex because of new and emerging systemic therapies and advancements in radiation oncology and neurosurgery. Current therapies include stereotactic radiosurgery, whole-brain radiation therapy, surgical resection, laser-interstitial thermal therapy, systemic cytotoxic chemotherapy, targeted agents, and immune-checkpoint inhibitors. Determining the optimal treatment for a specific patient has become increasingly individualized, emphasizing the need for multidisciplinary discussions of patients with BM. Recognizing and addressing the sequelae of BMs and their treatment while maintaining quality of life and neurocognition is especially important because survival for patients with BMs has improved. The authors present current and emerging treatment options for patients with BM and suggest approaches for managing sequelae and disease recurrence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.32714DOI Listing
April 2020

Brain immunology and immunotherapy in brain tumours.

Nat Rev Cancer 2020 01 5;20(1):12-25. Epub 2019 Dec 5.

The Preston Robert Tisch Brain Tumor Center at Duke, Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA.

Gliomas, the most common malignant primary brain tumours, remain universally lethal. Yet, seminal discoveries in the past 5 years have clarified the anatomy, genetics and function of the immune system within the central nervous system (CNS) and altered the paradigm for successful immunotherapy. The impact of standard therapies on the response to immunotherapy is now better understood, as well. This new knowledge has implications for a broad range of tumours that develop within the CNS. Nevertheless, the requirements for successful therapy remain effective delivery and target specificity, while the dramatic heterogeneity of malignant gliomas at the genetic and immunological levels remains a profound challenge.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41568-019-0224-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327710PMC
January 2020

Antigen-loaded monocyte administration induces potent therapeutic antitumor T cell responses.

J Clin Invest 2020 02;130(2):774-788

Department of Immunology.

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+ 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+ 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI128267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994156PMC
February 2020

The current state of immunotherapy for gliomas: an eye toward the future.

J Neurosurg 2019 09;131(3):657-666

1Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, and.

The last decade has seen a crescendo of FDA approvals for immunotherapies against solid tumors, yet glioblastoma remains a prominent holdout. Despite more than 4 decades of work with a wide range of immunotherapeutic modalities targeting glioblastoma, efficacy has been challenging to obtain. Earlier forms of immune-based platforms have now given way to more current approaches, including chimeric antigen receptor T-cells, personalized neoantigen vaccines, oncolytic viruses, and checkpoint blockade. The recent experiences with each, as well as the latest developments and anticipated challenges, are reviewed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3171/2019.5.JNS181762DOI Listing
September 2019

Pharmacokinetic Analysis of a Novel Human EGFRvIII:CD3 Bispecific Antibody in Plasma and Whole Blood Using a High-Resolution Targeted Mass Spectrometry Approach.

J Proteome Res 2019 08 19;18(8):3032-3041. Epub 2019 Jul 19.

Preston Robert Tisch Brain Tumor Center , Duke University Medical Center , Durham , North Carolina , United States.

Bispecific single chain antibody fragments (bi-scFv) represent an emerging class of biotherapeutics. We recently developed a fully human bi-scFv (EGFRvIII:CD3 bi-scFv) with the goal of redirecting CD3-expressing T cells to recognize and destroy malignant, EGFRvIII-expressing glioma. In mice, we showed that EGFRvIII:CD3 bi-scFv effectively treats orthotopic patient-derived malignant glioma and syngeneic glioblastoma. Here, we developed a targeted assay for pharmacokinetic (PK) analysis of EGFRvIII:CD3 bi-scFv, a necessary step in the drug development process. Using microflow liquid chromatography coupled to a high resolution parallel reaction monitoring mass spectrometry, and data analysis in Skyline, we developed a bottom-up proteomic assay for quantification of EGFRvIII:CD3 bi-scFv in both plasma and whole blood. Importantly, a protein calibrator, along with stable isotope-labeled EGFRvIII:CD3 bi-scFv protein, were used for absolute quantification. A PK analysis in a CD3 humanized mouse revealed that EGFRvIII:CD3 bi-scFv in plasma and whole blood has an initial half-life of ∼8 min and a terminal half-life of ∼2.5 h. Our results establish a sensitive, high-throughput assay for direct quantification of EGFRvIII:CD3 bi-scFv without the need for immunoaffinity enrichment. Moreover, these pharmacokinetic parameters will guide drug optimization and dosing regimens in future IND-enabling and phase I studies of EGFRvIII:CD3 bi-scFv.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jproteome.9b00145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325320PMC
August 2019

The Evolving Modern Management of Brain Metastasis.

Clin Cancer Res 2019 11 18;25(22):6570-6580. Epub 2019 Jun 18.

Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.

The incidence of brain metastases is increasing as cancer therapies improve and patients live longer, providing new challenges to the multidisciplinary teams that care for these patients. Brain metastatic cancer cells possess unique characteristics that allow them to penetrate the blood-brain barrier, colonize the brain parenchyma, and persist in the intracranial environment. In addition, brain metastases subvert the innate and adaptive immune system, permitting evasion of the antitumor immune response. Better understanding of the above mechanisms will allow for development and delivery of more effective therapies for brain metastases. In this review, we outline the molecular mechanisms underlying development, survival, and immunosuppression of brain metastases. We also discuss current and emerging treatment strategies, including surgery, radiation, disease-specific and mutation-targeted systemic therapy, and immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-18-1624DOI Listing
November 2019

Single-institution retrospective review of patients with recurrent glioblastoma treated with bevacizumab in clinical practice.

Health Sci Rep 2019 Apr 13;2(4):e114. Epub 2019 Feb 13.

The Preston Robert Tisch Brain Tumor Center Duke University Medical Center Durham North Carolina.

Background And Aims: This retrospective review of patients with recurrent glioblastoma treated at the Preston Robert Tisch Brain Tumor Center investigated treatment patterns, survival, and safety with bevacizumab in a real-world setting.

Methods: Adult patients with glioblastoma who initiated bevacizumab at disease progression between January 1, 2009, and May 14, 2012, were included. A Kaplan-Meier estimator was used to describe overall survival (OS), progression-free survival (PFS), and time to greater than or equal to 20% reduction in Karnofsky Performance Status (KPS). The effect of baseline demographic and clinical factors on survival was examined using a Cox proportional hazards model. Adverse event (AE) data were collected.

Results: Seventy-four patients, with a median age of 59 years, were included in this cohort. Between bevacizumab initiation and first failure, defined as the first disease progression after bevacizumab initiation, biweekly bevacizumab and bevacizumab/irinotecan were the most frequently prescribed regimens. Median duration of bevacizumab treatment until failure was 6.4 months (range, 0.5-58.7). Median OS and PFS from bevacizumab initiation were 11.1 months (95% confidence interval [CI], 7.3-13.4) and 6.4 months (95% CI, 3.9-8.5), respectively. Median time to greater than or equal to 20% reduction in KPS was 29.3 months (95% CI, 13.8-∞). Lack of corticosteroid usage at the start of bevacizumab therapy was associated with both longer OS and PFS, with a median OS of 13.2 months (95% CI, 8.6-16.6) in patients who did not initially require corticosteroids versus 7.2 months (95% CI, 4.8-12.5) in those who did ( = 0.0382, log-rank), while median PFS values were 8.6 months (95% CI, 4.6-9.7) and 3.7 months (95% CI, 2.7-6.6), respectively ( = 0.0243, log-rank). Treatment failure occurred in 70 patients; 47 of whom received salvage therapy, and most frequently bevacizumab/carboplatin (7/47; 14.9%). Thirteen patients (18%) experienced a grade 3 AE of special interest for bevacizumab.

Conclusions: Treatment patterns and outcomes for patients with recurrent glioblastoma receiving bevacizumab in a real-world setting were comparable with those reported in prospective clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hsr2.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482327PMC
April 2019

MTAP Loss Promotes Stemness in Glioblastoma and Confers Unique Susceptibility to Purine Starvation.

Cancer Res 2019 07 30;79(13):3383-3394. Epub 2019 Apr 30.

The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.

Homozygous deletion of methylthioadenosine phosphorylase () is one of the most frequent genetic alterations in glioblastoma (GBM), but its pathologic consequences remain unclear. In this study, we report that loss of MTAP results in profound epigenetic reprogramming characterized by hypomethylation of /CD133-associated stem cell regulatory pathways. MTAP deficiency promotes glioma stem-like cell (GSC) formation with increased expression of /CD133 and enhanced tumorigenicity of GBM cells and is associated with poor prognosis in patients with GBM. As a combined consequence of purine production deficiency in -null GBM and the critical dependence of GSCs on purines, the enriched subset of CD133 cells in -null GBM can be effectively depleted by inhibition of purine synthesis. These findings suggest that MTAP loss promotes the pathogenesis of GBM by shaping the epigenetic landscape and stemness of GBM cells while simultaneously providing a unique opportunity for GBM therapeutics. SIGNIFICANCE: This study links the frequently mutated metabolic enzyme MTAP to dysregulated epigenetics and cancer cell stemness and establishes MTAP status as a factor for consideration in characterizing GBM and developing therapeutic strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-18-1010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810595PMC
July 2019

Brain Tumor Microenvironment and Host State: Implications for Immunotherapy.

Clin Cancer Res 2019 07 25;25(14):4202-4210. Epub 2019 Feb 25.

Duke University Department of Immunology, Duke University Medical Center, Durham, North Carolina.

Glioblastoma (GBM) is a highly lethal brain tumor with poor responses to immunotherapies that have been successful in more immunogenic cancers with less immunosuppressive tumor microenvironments (TME). The GBM TME is uniquely challenging to treat due to tumor cell-extrinsic components that are native to the brain, as well as tumor-intrinsic mechanisms that aid in immune evasion. Lowering the barrier of immunosuppression by targeting the genetically stable tumor stroma presents opportunities to treat the tumor in a way that circumvents the complications of targeting a constantly mutating tumor with tumor antigen-directed therapies. Tumor-associated monocytes, macrophages, and microglia are a stromal element of particular interest. Macrophages and monocytes compose the bulk of infiltrating immune cells and are considered to have protumor and immunosuppressive effects. Targeting these cells or other stromal elements is expected to convert what is considered the "cold" TME of GBM to a more "hot" TME phenotype. This conversion could increase the effectiveness of what have become conventional frontline immunotherapies in GBM-creating opportunities for better treatment through combination therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-18-1627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635001PMC
July 2019

Challenges to curing primary brain tumours.

Nat Rev Clin Oncol 2019 08;16(8):509-520

CRUK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.

Despite decades of research, brain tumours remain among the deadliest of all forms of cancer. The ability of these tumours to resist almost all conventional and novel treatments relates, in part, to the unique cell-intrinsic and microenvironmental properties of neural tissues. In an attempt to encourage progress in our understanding and ability to successfully treat patients with brain tumours, Cancer Research UK convened an international panel of clinicians and laboratory-based scientists to identify challenges that must be overcome if we are to cure all patients with a brain tumour. The seven key challenges summarized in this Position Paper are intended to serve as foci for future research and investment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41571-019-0177-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650350PMC
August 2019

Author Correction: Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors.

Nat Med 2019 Mar;25(3):529

Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA.

In the version of this article originally published, the figure callout in this sentence was incorrect: "Furthermore, in S1P1-KI mice themselves, whereas PD-1 blockade was ineffectual as monotherapy, the effects of 4-1BB agonism and checkpoint blockade proved additive, with the combination prolonging median survival and producing a 50% long-term survival rate (Fig. 6f)." The callout should have been to Supplementary Fig. 6b. The error has been corrected in the PDF and HTML versions of the article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-019-0355-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825406PMC
March 2019

Effective effectors: How T cells access and infiltrate the central nervous system.

Pharmacol Ther 2019 05 14;197:52-60. Epub 2018 Dec 14.

Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, United States; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, United States; Department of Neurosurgery, Duke University School of Medicine, Durham, NC 27710, United States; Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27710, United States; Department of Pathology, Duke University School of Medicine, Durham, NC 27710, United States. Electronic address:

Several Phase II and III clinical trials have demonstrated that immunotherapy can induce objective responses in otherwise refractory malignancies in tumors outside the central nervous system. In large part, effector T cells mediate much of the antitumor efficacy in these trials, and potent antitumor T cells can be generated through vaccination, immune checkpoint blockade, adoptive transfer, and genetic manipulation. However, activated T cells must still traffic to, infiltrate, and persist within tumor in order to mediate tumor lysis. These requirements for efficacy pose unique challenges for brain tumor immunotherapy, due to specific anatomical barriers and populations of specialized immune cells within the central nervous system that function to constrain immunity. Both autoimmune and infectious diseases of the central nervous system provide a wealth of information on how T cells can successfully migrate to the central nervous system and then engender sustained immune responses. In this review, we will examine the commonalities in the efferent arm of immunity to the brain for autoimmunity, infection, and tumor immunotherapy to identify key factors underlying potent immune responses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pharmthera.2018.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164682PMC
May 2019

CD27 stimulation unveils the efficacy of linked class I/II peptide vaccines in poorly immunogenic tumors by orchestrating a coordinated CD4/CD8 T cell response.

Oncoimmunology 2018;7(12):e1502904. Epub 2018 Sep 5.

Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2018.1502904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279317PMC
September 2018

Immunotherapy for Glioblastoma: Adoptive T-cell Strategies.

Clin Cancer Res 2019 04 16;25(7):2042-2048. Epub 2018 Nov 16.

Duke Brain Tumor Immunotherapy Program, Duke University Medical Center and Duke University, Durham, North Carolina.

Glioblastoma (GBM) is a devastating disease with an extremely poor prognosis. Immunotherapy via adoptive cell transfer (ACT), especially with T cells engineered to express chimeric antigen receptors (CAR), represents a particularly promising approach. Despite the recent success of CAR T cells for blood cancers, the question remains whether this powerful anticancer therapy will ultimately work for brain tumors, and whether the primary immunologic challenges in this disease, which include antigenic heterogeneity, immune suppression, and T-cell exhaustion, can be adequately addressed. Here, we contextualize these concepts by reviewing recent developments in ACT for GBM, with a special focus on pioneering clinical trials of CAR T-cell therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-18-1625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445734PMC
April 2019

Preventing Lck Activation in CAR T Cells Confers Treg Resistance but Requires 4-1BB Signaling for Them to Persist and Treat Solid Tumors in Nonlymphodepleted Hosts.

Clin Cancer Res 2019 01 13;25(1):358-368. Epub 2018 Nov 13.

Department of Neurosurgery, Duke Brain Tumor Immunotherapy Program, Duke University Medical Center, Durham, North Carolina.

Purpose: Chimeric antigen receptor (CAR) T cells have shown promise against solid tumors, but their efficacy has been limited, due in part, to immunosuppression by CD4FoxP3 regulatory T cells (Tregs). Although lymphodepletion is commonly used to deplete Tregs, these regimens are nonspecific, toxic, and provide only a narrow window before Tregs repopulate hosts. Importantly, CARs have also been shown to inadvertently potentiate Tregs by providing a source of IL2 for Treg consumption. We explored whether disruption of the IL2 axis would confer efficacy against solid tumors without the need for lymphodepletion.

Experimental Design: We developed second- (CD28z) and third- (CD28-4-1BBz) generation CARs targeting EGFRvIII. To eliminate secretion of IL2, 2 amino acid substitutions were introduced in the PYAP Lck-binding motif of the CD28 domain (ΔCD28). We evaluated CARs against B16 melanomas expressing EGFRvIII.

Results: CD28z CARs failed to engraft . Although 4-1BB addition improved expansion, CD28-4-1BBz CARs required lymphodepletion to treat solid tumors. CARs deficient in Lck signaling, however, significantly retarded tumor growth without a need for lymphodepletion and this was dependent on inclusion of 4-1BB. To evaluate CAR vulnerability to Tregs, we lymphodepleted mice and transferred CARs alone or with purified Tregs. Cotransfer with Tregs abrogated the efficacy of CD28-4-1BBz CARs, whereas the efficacy of ΔCD28-4-1BBz CARs remained unperturbed.

Conclusions: In the absence of lymphodepletion, CARs targeting solid tumors are hindered by Treg immunosuppression and poor persistence. Here, CARs were modified to circumvent Treg suppression and to simultaneously improve engraftment. Modified CARs treated solid tumors without a need for lymphodepletion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-18-1211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390292PMC
January 2019

Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors.

Nat Med 2018 09 13;24(9):1459-1468. Epub 2018 Aug 13.

Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA.

T cell dysfunction contributes to tumor immune escape in patients with cancer and is particularly severe amidst glioblastoma (GBM). Among other defects, T cell lymphopenia is characteristic, yet often attributed to treatment. We reveal that even treatment-naïve subjects and mice with GBM can harbor AIDS-level CD4 counts, as well as contracted, T cell-deficient lymphoid organs. Missing naïve T cells are instead found sequestered in large numbers in the bone marrow. This phenomenon characterizes not only GBM but a variety of other cancers, although only when tumors are introduced into the intracranial compartment. T cell sequestration is accompanied by tumor-imposed loss of S1P1 from the T cell surface and is reversible upon precluding S1P1 internalization. In murine models of GBM, hindering S1P1 internalization and reversing sequestration licenses T cell-activating therapies that were previously ineffective. Sequestration of T cells in bone marrow is therefore a tumor-adaptive mode of T cell dysfunction, whose reversal may constitute a promising immunotherapeutic adjunct.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-018-0135-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129206PMC
September 2018

Hyaluronic acid based low viscosity hydrogel as a novel carrier for Convection Enhanced Delivery of CAR T cells.

J Clin Neurosci 2018 Oct 21;56:163-168. Epub 2018 Jul 21.

Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, United States; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, United States; Department of Pathology, Duke University Medical Center, Durham, NC 27710, United States. Electronic address:

Convection Enhanced Delivery (CED) infuses therapeutic agents directly into the intracranial area continuously under pressure. The convection improves the distribution of therapeutics such as those aimed at brain tumors. Although CED successfully delivers small therapeutic agents, this technique fails to effectively deliver cells largely due to cell sedimentation during delivery. To overcome this limitation, we have developed a low viscosity hydrogel (LVHydrogel), which is capable of retaining cells in suspension. In this study, we evaluated whether LVHydrogel can effectively act as a carrier for the CED of tumor-specific chimeric antigen receptor (CAR) T cells. CAR T cells were resuspended in saline or LVHydrogel carriers, loaded into syringes, and passed through the CED system for 5 h. CAR T cells submitted to CED were counted and the efficiency of delivery was determined. In addition to delivery, the ability of CAR T cells to migrate and induce cytotoxicity was evaluated. Our studies demonstrate that LVHydrogel is a superior carrier for CED in comparison to saline. The efficiency of cell delivery in saline carrier was only ∼3-5% of the total cells whereas delivery by the LVHydrogel carrier was much higher, reaching ∼45-75%. Migration and Cytotoxicity was similar in both carriers in non-infused samples but we found superior cytotoxicity in LVHydrogel group post-infusion. We demonstrate that LVHydrogel, a biodegradable biomaterial which does not cause acute toxicity on preclinical animal models, prevents cellular sedimentation during CED and presents itself as a superior carrier to the current carrier, saline, for the CED of CAR T cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jocn.2018.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6185757PMC
October 2018

Recurrent Glioblastoma Treated with Recombinant Poliovirus.

N Engl J Med 2018 07 26;379(2):150-161. Epub 2018 Jun 26.

From the Departments of Neurosurgery (A.D., M.G., A.H.F., H.S.F., K.B.P., D.R., J.H.S., G.V., D.A., D.D.B.), Biostatistics (J.E.H., F.M.), Surgery (D.P.B., S.N.), and Pathology (W.T.H., R.E.M.) and the Preston Robert Tisch Brain Tumor Center (A.D., M.G., J.E.H., D.P.B., A.H.F., H.S.F., F.M., S.N., K.B.P., D.R., J.H.S., G.V., W.T.H., R.E.M., D.A., D.D.B.), Duke University Medical Center, and Istari Oncology (D.P.B.) - all in Durham, NC; Tempus Labs, Chicago (N.B.); and the School of Medicine, Deakin University, Geelong, VIC, Australia (A.M.M.).

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 10 and 10 50% tissue-culture infectious doses (TCID), 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 (5.0×10 TCID) was identified as the phase 2 dose. One dose-limiting toxic effect was observed; a patient in whom dose level 5 (10 TCID) 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 .).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1716435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065102PMC
July 2018