Pathogens and glioma: a history of unexpected discoveries ushering in novel therapy

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  • 1 Departments of Neurological Surgery,
  • | 2 Cell Biology, and
  • | 3 Pathology, University of Miami Miller School of Medicine, Miami, Florida
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In the late 19th century, Dr. William B. Coley introduced the theory that infections may aid in the treatment of malignancy. With the creation of Coley’s toxin, reports of remission during viral illnesses for systemic malignancies soon emerged. A few decades after this initial discovery, Austrian physicians performed intravascular injections of Clostridium to induce oncolysis in patients with glioblastoma. Since then, suggestions between improved survival and infectious processes have been reported in several patients with glioma, which ultimately marshaled the infamous use of intracerebral Enterobacter. These early observations of tumor regression and concomitant infection piloted a burgeoning field focusing on the use of pathogens in molecular oncology.

In the late 19th century, Dr. William B. Coley introduced the theory that infections may aid in the treatment of malignancy. With the creation of Coley’s toxin, reports of remission during viral illnesses for systemic malignancies soon emerged. A few decades after this initial discovery, Austrian physicians performed intravascular injections of Clostridium to induce oncolysis in patients with glioblastoma. Since then, suggestions between improved survival and infectious processes have been reported in several patients with glioma, which ultimately marshaled the infamous use of intracerebral Enterobacter. These early observations of tumor regression and concomitant infection piloted a burgeoning field focusing on the use of pathogens in molecular oncology.

Since the late 19th century, the notion that pathogens may assist in the treatment of cancer has been established. This theory was first conceptualized in 1891 when William B. Coley (a prominent New York surgeon) noticed the disappearance of malignant recurrent sarcoma in a young child who was suffering from a superficial streptococcal infection (erysipelas).10,11,63,68 Upon investigation of the medical literature at that time, Coley discovered that many cases of cancer regression were noted during infections; the most noticeable was the relationship between erysipelas and sarcoma. Coley’s literature search was initially fruitful, discovering 38 cases of carcinomas and sarcomas that improved during concomitant erysipelas infections (Fig. 1).48 Soon afterward, in 1891, Coley began to treat patients with sarcoma using inoculations of Streptococcus with varying degrees of success. Initial patients experienced septic episodes, in which the patient almost died, and the tumor would caseate. Nevertheless, survival was improved up to 8 years by repeatedly treating recurrent tumors with this “toxin therapy.”12 However, this treatment’s safety and efficacy proved to be variable, necessitating a change in its formulation.3,11,67 His methods continued well into the middle to late 20th century as the molecular discovery of related cytokines (tumor necrosis factor, interleukins) facilitated more directed therapies.4,68 Although Coley later adopted the use of heat-killed bacterial exotoxins into his treatment instead of live bacterial inoculations, his discovery inspired more investigators and scientists to become aware of the oncolytic effects of foreign infection. As a result of his discovery and methods, Dr. Coley would soon be regarded as the father of immunotherapy.

Fig. 1.
Fig. 1.

Initial results of William Coley using bacterial toxins (Streptococcus erysipelas and the Bacillus prodigiosus) for sarcoma.11 A: Round-celled sarcoma of the neck successfully treated 7 years after initial diagnosis. B: Inoperable spindle-celled sarcoma of the scapula/chest-wall. C: Full recovery of the patient in panel B, 12 years after treatment.

The Beginnings of Virology and Cancer Treatment

In 1904, a link between viral infection and cancer was made when Dock noticed that a 42-year-old woman with leukemia spontaneously went into remission after a suspected influenza outbreak (which was decades prior to the classification of influenza as a virus).19 Subsequently, in 1912, De Pace witnessed the regression of cervical carcinoma after Pasteur’s vaccination for rabies, suggesting a link between viral inoculation and cancer response.18,29 Over the ensuing decades, more investigators noticed the same trend for hematological malignancies during viral infections; however, the results were not entirely satisfactory as “the majority of cases did not produce remissions in physical signs or in the blood.”4,69 Nevertheless, these initial successes for hematological malignancies were translated for cancer therapy using a variety of systemic viruses (feline panleukopenia virus, varicella, measles, mumps, and Newcastle disease virus).1,6,29,49,52,64,67 From these studies, the one published in 1956 by the National Cancer Institute using wild adenovirus as treatment for cervical cancer showed that more than 50% of treated patients had tumor regression, but its duration was limited.29 These initial discouraging results led to the abandonment of this research. Years later, however, with new molecular biology techniques, the viruses could be modified to increase their infectiveness and selectivity to destroy the tumoral cells.

These early observations ushered in a new burgeoning field of pathogen therapy for cancer, and would soon set the stage for many infamous cases in neurosurgical oncology history.

The Infamous Use of Clostridium

In the middle of the 20th century, Austrian physicians discovered that malignant tissue inoculated with spores of nonpathogenic Clostridium butyricum (M55) would undergo liquefactive necrosis. C. butyricum, later marketed as a probiotic, would transform into mature bacteria in the malignant tissue and induce oncolysis.44 The hypoxic, rapidly proliferative substrate of malignant tumors provided an ideal environment for the bacteria. As a result, 49 patients with suspected glioblastoma were given intracarotid injections of M55 spores to induce oncolysis and abscess formation that would necessitate resection (Fig. 2).27 The results were dismal, with 19 of 49 patients dying due to abscess formation/encephalitis, and the remainder of the patients dying after surgery/recurrence. Nevertheless, this discovery propelled the field of oncolysis for glioblastoma.27 Nearly 30 years later, the use of Clostridium continues to be studied for its oncolytic properties in glioblastoma, yet malignant edema, increased intracranial pressure, and abscess formation remain barriers to propagating this type of therapy.42,60

Fig. 2.
Fig. 2.

A: C. butryicum M55 in brain abscess. B: Liquefaction of glioblastoma following carotid injection of M55 (arrows indicate abscess cavity). From Heppner F, Möse JR: The liquefaction (oncolysis) of malignant gliomas by a nonpathogenic Clostridium. Acta Neurochir (Wien) 42(1–2):123–125, 1978. With permission of Springer. Figure is available in color online only.

The Use of Enterobacter and Glioblastoma

Over the last two decades, the association between pathogenic infections and increased survival in patients with malignant glioma was further substantiated by various case reports of spontaneous regression and improved survival during infections.34 In 1999, Bowles and Perkins reported both oncolytic and adjuvant immune responses in 3 patients co-infected with Enterobacter aerogenes after surgery.8 In 2009, Bohman et al. reported a similar trend toward increased survival in 18 patients who developed postoperative infections. More recently, Italian researchers retrospectively noticed a drastic improvement in median survival in patients with glioblastoma who developed pathogenic infections after surgery.7,17

As a result of these studies, researchers and neurosurgeons in California sought to investigate the clinical utility of introducing E. aerogenes into the surgical site of patients suffering from glioblastoma. Although consent was obtained from patients to use this treatment modality, no specific IRB or FDA approval was obtained. This led to widespread media coverage on the biomedical ethics of unregulated clinical research, and ultimately to sanctions on the research privileges of 2 neurosurgeons. Although all 3 patients died, it is unclear whether the treatment modality helped extend survival.2

Viral Oncology and Glioblastoma

Virotherapy for glioblastoma burgeoned in the late 20th century as scientists learned to rationally modify viral genomes and neutralize viral toxicity.70 In 1991, Martuza et al. used these techniques to develop the first artificially engineered oncolytic herpes simplex virus.43 In 2000, the use of herpes virus for treatment of malignant gliomas in humans was published.41 Since then, these same laboratory techniques have been extended to include many additional viruses that have been primarily focused on glioblastoma.70 Gliomas were the ideal target for viral-based therapies due to their highly replicative nature, lack of distant metastasis, and confinement by postmitotic cells (thereby limiting spread of the virus to nonneoplastic tissues).70 Oncolytic viral therapy utilizes tumor cells for viral replications and subsequent lysis and dissemination; the unique ability of oncolytic viruses to preferentially target cancer cells is largely due to the tumor’s reliance on oncogenic signaling pathways and their tendency to proliferate. Currently, over a dozen viral families have been manipulated for oncolytic viral therapy for glioblastoma including adenovirus, Newcastle disease virus, vaccinia, poliovirus, and measles. Most, if not all, of these viral-based therapies are now undergoing early Phase I/II clinical trials (Tables 13).22,31,37,41 Many of these clinical trials use intraparenchymal convection-enhanced delivery methods to introduce these virotherapeutics into the tumor/surgical cavity (Fig. 3).

TABLE 1.

Published clinical trials using viruses in glioma

Authors & YearNo. of Patients (N = 429)VirusTumor TypeMedian PFS (mos)Median OS (mos)Trial PhaseCitations on Web of Science on 1/31/2016
Markert et al., 200021HSV G207Recurrent GBMMean 3.5Mean 12.8I578
Trask et al., 200013AdHSV-TK/GCVRecurrent GBM310I183
Rampling et al., 20009HSV 1716Recurrent MGRange 2–24I380
Papanastassiou et al., 200212HSV 1716Primary & recurrent GBM7I184
Lang et al., 200315Adenovirus ONYX-015Recurrent GBM310I235
Germano et al., 200311HSV-TK/GCVRecurrent GBM26I85
Smitt et al., 200314HSV-TK/GCVRecurrent GBM2.34II63
Immonen et al., 200436HSV-TK/GCVPrimary & recurrent GBM14I230
Chiocca et al., 200424Adenovirus ONYX-015Recurrent HGG1.56I203
Harrow et al., 200412HSV 1716Primary & recurrent GBMRange 3–22NA169
Freeman et al., 200614HDV-HUJRecurrent GBM7I143
Chiocca et al., 200811Ad.hIFN-βRecurrent MG24I48
Forsyth et al., 200812ReovirusRecurrent GBM15I103
Markert et al., 20096HSV G207Recurrent GBM36.6 (posttreatment), 23 (postdiagnosis)Ib137
Chiocca et al., 201112AdV-TK/valacyclovirPrimary HGG912Ib32
Stragliotto et al., 201322CMV/valacyclovirPrimary GBM5.518I/II34
Westphal et al., 2013119Sitimagene ceradenovec/ganciclovirPrimary GBM16III33
Kicielinski et al., 201415ReovirusRecurrent HGG24.5I13
Lang et al., 201437Delta-24-RGD adenovirus or DNX-2401Recurrent HGG11I0
Ji et al., 201653HSV-TK/GCVRecurrent HGG710IINA

GBM = glioblastoma; HGG = high-grade glioma; MG = malignant gliomas; NA = not available; OS = overall survival; PFS = progression-free survival.

For virus details see Table 3.

TABLE 2.

Ongoing clinical trials using viruses in glioma

TitleNCT No.Start Date (Mo-Yr)No. of PatientsVirusTumor TypeTrial Phase
Safety and efficacy study of Reolysin® in the treatment of recurrent malignant gliomas00528684Jul-0618ReolysinMG1
Viral therapy in treating patients with recurrent glioblastoma multiforme00390299Oct-0640Carcinoembryonic antigen-expressing measles virusMG1
Phase 2a study of AdV-tk with standard radiation therapy for malignant glioma (BrTK02)00589875Mar-0752AdV-tk/valacyclovirMG2
Safety study of replication-competent adenovirus (Delta-24-RGD) in patients with recurrent glioblastoma01582516Jun-1020Delta-24-RGD adenovirusRecurring GBM1 & 2
CMV-specific cytotoxic T lymphocytes expressing CAR targeting HER2 in patients with GBM01109095Oct-1016HER.CAR CMV-specific CTLsGBM1
Virus DNX2401 and temozolomide in recurrent glioblastoma01956734Sep-1331DNX2401 & temozolomideRecurring GBM1
Combined cytotoxic and immune-stimulatory therapy for glioma (dose escalation of Ad-hCMV-TK and Ad-hCMV-Flt3L)01811992Dec-1318Ad-hCMV-TK & Ad-hCMV-Flt3LMG & GBM1
Oncolytic HSV 1716 in treating younger patients with refractory or recurrent high grade glioma that can be removed by surgery02031965Dec-1324HSV 1716/dexamethasonePediatric refractory or recurrent HGG1
DNX-2401 with interferon gamma (IFN-γ) for recurrent glioblastoma or gliosarcoma brain tumors02197169Aug-1436DNX-2401/interferon-gammaGBM or gliosarcoma1
Genetically engineered HSV-1 phase 1 study02062827Sep-1436M032 (NSC 733972)High-grade recurrent or refractory gliomas1
A study of Ad-RTS-hIL-12 with veledimex in subjects with glioblastoma or malignant glioma02026271Jun-1548INXN-2001/veledimexMG & GBM1
Wild-type reovirus in combination with sargramostim in treating younger patients with high-grade recurrent or refractory brain tumors02444546Jun-1521Sargramostim/wild-type reovirusPediatric high-grade recurrent or refractory glioma1
P2/3 randomized study of Toca 511 and Toca FC versus SOC in subjects undergoing surgery for recurrent GBM/AA02414165Nov-15170Toca 511/Toca FC/lomustine/temozolomide/bevacizumabMG & GBM2 & 3
HSV G207 alone or with a single radiation dose in children with progressive or recurrent supratentorial brain tumors02457845Jan-1618G207MG1
PVSRIPO for recurrent glioblastoma (GBM)01491893Jan-1665PVSRIPOMG & GBM1
A study of the safety of Toca 511, a retroviral replicating vector, combined with Toca FC in subjects with newly diagnosed high grade glioma receiving standard of care02598011Mar-1618Toca 511/Toca FCNewly diagnosed HGG1

For virus details see Table 3.

TABLE 3.

Antitumor mechanism of the viruses used in the clinical trials

VirusMechanism
HSV 1716First-generation oncolytic virus based on herpes simplex virus 1. It has a deletion of the gene ICP34.5. This gene enables the virus to replicate in differentiated cells such as neurons. The ICP34.5 deletion promotes selective tumor infection & replication in rapidly dividing cells w/o neurovirulence.25,51,55
HSV G207First-generation oncolytic virus based on herpes simplex virus 1. It has the ICP34.5 gene deleted & the ICP6 gene inactivated by insertion of the E. coli LacZ gene. It lacks ribonucleotide reductase, rendering it unable to replicate in normal cells.40,41
HSV-TK/GCVThese herpes simplex viruses are “armed” with the thymidine kinase gene. This gene phosphorylates gancyclovir (GCV) which is a nucleoside analog converting it into a nucleotide-like precursor, resulting in block of the replication of DNA & thereby killing the replicating cell by apoptosis.30,45,58,64
M032 HSV-1Second-generation oncolytic virus based on herpes simplex virus 1 that, in addition to selectively killing the replicating tumor cells w/o neurovirulence, is “armed” w/ the IL-12 gene, inducing immune response against surviving tumor cells.57
Ad-RTS-hIL-12 (INXN-2001)/veledimexAdenovirus vector engineered to express hIL-12, a protein that improves the body’s natural response to disease by enhancing the ability of the immune system to kill tumor cells & may interfere w/ blood flow to the tumor.57
Ad-hCMV-TK/valacyclovirFirst-generation adenoviral vector human serotype 5 deleted in E1a & E3 viral encoding regions, engineered to express its respective therapeutic transgene HSV1-TK under the control of the human cytomegalovirus promoter (hCMV) followed by an antiherpetic prodrug, valacyclovir.13
Ad-hCMV-Flt3L/valacyclovirFirst-generation adenoviral vector human serotype 5 deleted in E1a & E3 viral encoding regions. The vector expresses its transgene Flt3L under the control of the human cytomegalovirus promoter (hCMV). Flt3L causes maturation & proliferation of dendritic cells & natural killer cells, inducing immune response against tumor cells that survived against V1-TK/valacyclovir produced by the Ad-hCMV-TK.36,71
Ad.hIFN-β (BG00001)First-generation adenoviral vector human serotype 5 deleted in E1a & E3 viral encoding regions. The vector is a recombinant adenovirus expressing the interferon-β gene, which has direct antiproliferative, antiangiogenic, & immunostimulatory antitumoral effects.16
Delta-24-RGD adenovirus or DNX-2401Adenovirus that harbors a 24–base pair deletion in the E1A region (responsible for binding Rb protein & possessing enhanced infectivity because of the addition of RGD-4C). This virus targets the abnormal p16INK4/Rb pathway.32,33,38
ONYX-015Adenovirus w/ deletion of a gene encoding a p53-inhibitory protein, E1B-55kD. This deletion provides selective infection to replicate in & kill cells that harbor a mutation of p53. The adenovirus lacks the E1B gene, prohibiting replication in normal cells.5,14,26,581,6,15,27
MV-CEAMeasles virus expressing carcinoembryonic antigen.46,54
HDV-HUJNewcastle disease virus (single-strand RNA virus) attenuated strain (lentogenic) w/ a selective cytotoxic potential for cancer cells.21,56
PVSRIPOPoliovirus:rhinovirus chimera, genetically recombinant, nonpathogenic, w/ a tumor-specific conditional replication phenotype. It consists of the genome of the live attenuated poliovirus serotype 1 (SABIN) vaccine (PV1S) w/ its cognate internal ribosomal entry site (IRES) element replaced w/ that of human rhinovirus type 2 (HRV2).24
ReovirusReoviruses are double-stranded RNA viruses that are trophic to mammalian cells. In glioblastoma cells, upregulated renin-angiotensin system signaling promotes viral replication in tumor cells.20,35,61
Toca 511Toca 511 consists of a purified retroviral replicating vector encoding a modified yeast cytosine deaminase gene, which converts the antifungal 5-flurocytosine (5FC) to the anticancer drug 5-FU in cells that have been infected by the Toca 511 vector. Other names are vocimagene amiretrorepvec, RRV, retroviral replicating viral.53
Fig. 3.
Fig. 3.

Viral and bacterial intraparenchymal delivery into tumor via convection-enhanced delivery: herpes virus (left), replicating retrovirus (center), and gram-negative bacilli, such as Escherichia coli and Enterobacter (right). Illustration by Roberto Suazo. Copyright Ashish H. Shah. Published with permission.

Along with these strides in oncolytic viral therapy, viral vectors were also being used to introduce gene therapy for gliomas. These therapies were initially geared at restoring tumor suppressive mechanisms by reintroducing normal wild-type genes such as p53 or the cyclin-dependent kinase pathway through adenoviral vectors.9,28,39,50 However, initial clinical results did not demonstrate a significantly longer overall survival (10 months).37 Nevertheless, such discoveries pioneered more tailored gene therapies for suppression of angiogenesis, elimination of drug resistance, and activation of antitumor immune responses. A whole host of these viral-based gene therapies are being used to alter glioblastoma molecular biology. Lastly, viral-based vectors are now being used to introduce “suicide genes” into glioma cells. By using viral vectors, suicide genes such as thymidine kinase and cytosine deaminase can be incorporated into the tumor cellular genome, and converted into toxic metabolites by prodrugs (ganciclovir and 5-fluorocytosine, respectively).47,53 This type of suicide gene therapy is now being employed by a variety of centers across the US for recurrent glioblastoma.

Conclusions

Early observations of tumor regression and concomitant infection have ushered in a burgeoning field focusing on the use of pathogens in molecular oncology. Over the last several decades, research into oncolysis and immune activation secondary to foreign molecular exposure has identified potential therapeutic alternatives to current mainstay glioma therapy. Current glioma treatment such as immunosuppressive chemotherapy and steroids may curtail the oncolytic capacity of pathogens. Although the long-term safety of virotherapy has yet to be demonstrated, there is promise that such therapies may effectively improve survival for treatment-refractory gliomas.

Disclosures

Dr. Ivan has served as a consultant to Medtronic. Dr. Kasahara has served as a consultant to Tocagen Inc.

Author Contributions

Conception and design: Shah, Kasahara. Acquisition of data: Shah, Jusué-Torres. Analysis and interpretation of data: Shah, Jusué-Torres, Kasahara. Drafting the article: Shah, Jusué-Torres. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Shah.

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    Markert JM, Liechty PG, Wang W, Gaston S, Braz E, Karrasch M, et al.: Phase Ib trial of mutant herpes simplex virus G207 inoculated pre-and post-tumor resection for recurrent GBM. Mol Ther 17:199207, 2009

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    Markert JM, Medlock MD, Rabkin SD, Gillespie GY, Todo T, Hunter WD, et al.: Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Ther 7:867874, 2000

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    Marth E, Ascher WP, Pavelka R, Möse JR: Tumor lysis of a glioblastoma by Clostridium oncolyticum. J Chemother 1 (4 Suppl):11771178, 1989

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    Moese JR, Moese G: Oncolysis by Clostridia. I. Activity of Clostridium butyricum (M-55) and other nonpathogenic Clostridia against the Ehrlich carcinoma. Cancer Res 24:212216, 1964

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    Moolten FL, Wells JM: Curability of tumors bearing herpes thymidine kinase genes transferred by retroviral vectors. J Natl Cancer Inst 82:297300, 1990

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    Myers R, Harvey M, Kaufmann TJ, Greiner SM, Krempski JW, Raffel C, et al.: Toxicology study of repeat intracerebral administration of a measles virus derivative producing carcinoembryonic antigen in rhesus macaques in support of a phase I/II clinical trial for patients with recurrent gliomas. Hum Gene Ther 19:690698, 2008

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    Nanda D, Vogels R, Havenga M, Avezaat CJ, Bout A, Smitt PS: Treatment of malignant gliomas with a replicating adenoviral vector expressing herpes simplex virus-thymidine kinase. Cancer Res 61:87438750, 2001

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    Nauts HC, Swift WE, Coley BL: The treatment of malignant tumors by bacterial toxins as developed by the late William B. Coley, M.D., reviewed in the light of modern research. Cancer Res 6:205216, 1946

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    Okuno Y, Asada T, Yamanishi K, Otsuka T, Takahashi M, Tanioka T, et al.: Studies on the use of mumps virus for treatment of human cancer. Biken J 21:3749, 1978

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  • 50

    Pan D, Wei X, Liu M, Feng S, Tian X, Feng X, et al.: Adenovirus mediated transfer of p53, GM-CSF and B7-1 suppresses growth and enhances immunogenicity of glioma cells. Neurol Res 32:502509, 2010

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  • 51

    Papanastassiou V, Rampling R, Fraser M, Petty R, Hadley D, Nicoll J, et al.: The potential for efficacy of the modified (ICP 34.5) herpes simplex virus HSV1716 following intratumoural injection into human malignant glioma: a proof of principle study. Gene Ther 9:398406, 2002

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  • 52

    Parker JN, Bauer DF, Cody JJ, Markert JM: Oncolytic viral therapy of malignant glioma. Neurotherapeutics 6:558569, 2009

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    Perez OD, Logg CR, Hiraoka K, Diago O, Burnett R, Inagaki A, et al.: Design and selection of Toca 511 for clinical use: modified retroviral replicating vector with improved stability and gene expression. Mol Ther 20:16891698, 2012

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    Phuong LK, Allen C, Peng KW, Giannini C, Greiner S, TenEyck CJ, et al.: Use of a vaccine strain of measles virus genetically engineered to produce carcinoembryonic antigen as a novel therapeutic agent against glioblastoma multiforme. Cancer Res 63:24622469, 2003

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    Rampling R, Cruickshank G, Papanastassiou V, Nicoll J, Hadley D, Brennan D, et al.: Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma. Gene Ther 7:859866, 2000

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    Reichard KW, Lorence RM, Cascino CJ, Peeples ME, Walter RJ, Fernando MB, et al.: Newcastle disease virus selectively kills human tumor cells. J Surg Res 52:448453, 1992

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    Roth JC, Cassady KA, Cody JJ, Parker JN, Price KH, Coleman JM, et al.: Evaluation of the safety and biodistribution of M032, an attenuated herpes simplex virus type 1 expressing hIL-12, after intracerebral administration to Aotus nonhuman primates. Hum Gene Ther Clin Dev 25:1627, 2014

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    Shah AC, Benos D, Gillespie GY, Markert JM: Oncolytic viruses: clinical applications as vectors for the treatment of malignant gliomas. J Neurooncol 65:203226, 2003

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    Smitt PS, Driesse M, Wolbers J, Kros M, Avezaat C: Treatment of relapsed malignant glioma with an adenoviral vector containing the herpes simplex thymidine kinase gene followed by ganciclovir. Mol Ther 7:851858, 2003

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    Staedtke V, Bai RY, Sun W, Huang J, Kibler KK, Tyler BM, et al.: Clostridium novyi-NT can cause regression of orthotopically implanted glioblastomas in rats. Oncotarget 6:55365546, 2015

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  • View in gallery

    Initial results of William Coley using bacterial toxins (Streptococcus erysipelas and the Bacillus prodigiosus) for sarcoma.11 A: Round-celled sarcoma of the neck successfully treated 7 years after initial diagnosis. B: Inoperable spindle-celled sarcoma of the scapula/chest-wall. C: Full recovery of the patient in panel B, 12 years after treatment.

  • View in gallery

    A: C. butryicum M55 in brain abscess. B: Liquefaction of glioblastoma following carotid injection of M55 (arrows indicate abscess cavity). From Heppner F, Möse JR: The liquefaction (oncolysis) of malignant gliomas by a nonpathogenic Clostridium. Acta Neurochir (Wien) 42(1–2):123–125, 1978. With permission of Springer. Figure is available in color online only.

  • View in gallery

    Viral and bacterial intraparenchymal delivery into tumor via convection-enhanced delivery: herpes virus (left), replicating retrovirus (center), and gram-negative bacilli, such as Escherichia coli and Enterobacter (right). Illustration by Roberto Suazo. Copyright Ashish H. Shah. Published with permission.

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  • 41

    Markert JM, Medlock MD, Rabkin SD, Gillespie GY, Todo T, Hunter WD, et al.: Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Ther 7:867874, 2000

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  • 42

    Marth E, Ascher WP, Pavelka R, Möse JR: Tumor lysis of a glioblastoma by Clostridium oncolyticum. J Chemother 1 (4 Suppl):11771178, 1989

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    • Crossref
    • PubMed
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    • Export Citation
  • 44

    Moese JR, Moese G: Oncolysis by Clostridia. I. Activity of Clostridium butyricum (M-55) and other nonpathogenic Clostridia against the Ehrlich carcinoma. Cancer Res 24:212216, 1964

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    Moolten FL, Wells JM: Curability of tumors bearing herpes thymidine kinase genes transferred by retroviral vectors. J Natl Cancer Inst 82:297300, 1990

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    Myers R, Harvey M, Kaufmann TJ, Greiner SM, Krempski JW, Raffel C, et al.: Toxicology study of repeat intracerebral administration of a measles virus derivative producing carcinoembryonic antigen in rhesus macaques in support of a phase I/II clinical trial for patients with recurrent gliomas. Hum Gene Ther 19:690698, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47

    Nanda D, Vogels R, Havenga M, Avezaat CJ, Bout A, Smitt PS: Treatment of malignant gliomas with a replicating adenoviral vector expressing herpes simplex virus-thymidine kinase. Cancer Res 61:87438750, 2001

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Nauts HC, Swift WE, Coley BL: The treatment of malignant tumors by bacterial toxins as developed by the late William B. Coley, M.D., reviewed in the light of modern research. Cancer Res 6:205216, 1946

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    • Export Citation
  • 49

    Okuno Y, Asada T, Yamanishi K, Otsuka T, Takahashi M, Tanioka T, et al.: Studies on the use of mumps virus for treatment of human cancer. Biken J 21:3749, 1978

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50

    Pan D, Wei X, Liu M, Feng S, Tian X, Feng X, et al.: Adenovirus mediated transfer of p53, GM-CSF and B7-1 suppresses growth and enhances immunogenicity of glioma cells. Neurol Res 32:502509, 2010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51

    Papanastassiou V, Rampling R, Fraser M, Petty R, Hadley D, Nicoll J, et al.: The potential for efficacy of the modified (ICP 34.5) herpes simplex virus HSV1716 following intratumoural injection into human malignant glioma: a proof of principle study. Gene Ther 9:398406, 2002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52

    Parker JN, Bauer DF, Cody JJ, Markert JM: Oncolytic viral therapy of malignant glioma. Neurotherapeutics 6:558569, 2009

  • 53

    Perez OD, Logg CR, Hiraoka K, Diago O, Burnett R, Inagaki A, et al.: Design and selection of Toca 511 for clinical use: modified retroviral replicating vector with improved stability and gene expression. Mol Ther 20:16891698, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54

    Phuong LK, Allen C, Peng KW, Giannini C, Greiner S, TenEyck CJ, et al.: Use of a vaccine strain of measles virus genetically engineered to produce carcinoembryonic antigen as a novel therapeutic agent against glioblastoma multiforme. Cancer Res 63:24622469, 2003

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 55

    Rampling R, Cruickshank G, Papanastassiou V, Nicoll J, Hadley D, Brennan D, et al.: Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma. Gene Ther 7:859866, 2000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56

    Reichard KW, Lorence RM, Cascino CJ, Peeples ME, Walter RJ, Fernando MB, et al.: Newcastle disease virus selectively kills human tumor cells. J Surg Res 52:448453, 1992

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 57

    Roth JC, Cassady KA, Cody JJ, Parker JN, Price KH, Coleman JM, et al.: Evaluation of the safety and biodistribution of M032, an attenuated herpes simplex virus type 1 expressing hIL-12, after intracerebral administration to Aotus nonhuman primates. Hum Gene Ther Clin Dev 25:1627, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58

    Shah AC, Benos D, Gillespie GY, Markert JM: Oncolytic viruses: clinical applications as vectors for the treatment of malignant gliomas. J Neurooncol 65:203226, 2003

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59

    Smitt PS, Driesse M, Wolbers J, Kros M, Avezaat C: Treatment of relapsed malignant glioma with an adenoviral vector containing the herpes simplex thymidine kinase gene followed by ganciclovir. Mol Ther 7:851858, 2003

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60

    Staedtke V, Bai RY, Sun W, Huang J, Kibler KK, Tyler BM, et al.: Clostridium novyi-NT can cause regression of orthotopically implanted glioblastomas in rats. Oncotarget 6:55365546, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 61

    Stragliotto G, Rahbar A, Solberg NW, Lilja A, Taher C, Orrego A, et al.: Effects of valganciclovir as an add-on therapy in patients with cytomegalovirus-positive glioblastoma: a randomized, double-blind, hypothesis-generating study. Int J Cancer 133:12041213, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 62

    Strong JE, Tang D, Lee PWK: Evidence that the epidermal growth factor receptor on host cells confers reovirus infection efficiency. Virology 197:405411, 1993

  • 63

    Swain J: The treatment of malignant tumours by the toxins of the Streptococcus erysipelatis and Bacillus prodigiosus. BMJ 2:14151416, 1895

  • 64

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