Pathogens and Glioma: a History of Unexpected Discoveries Ushering in Novel Therapy

HISTORICAL VIGNETTE J Neurosurg 128:1139–1146, 2018

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

Ashish H. Shah, MD,1 Ignacio Jusué-Torres, MD,1 Michael E. Ivan, MD, MBA,1 Ricardo J. Komotar, MD,1 and Noriyuki Kasahara, MD, PhD2,3

Departments of 1Neurological Surgery, 2Cell Biology, and 3Pathology, University of Miami Miller School of Medicine, Miami, Florida

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 Entero- bacter. These early observations of tumor regression and concomitant infection piloted a burgeoning field focusing on the use of pathogens in molecular oncology. https://thejns.org/doi/abs/10.3171/2016.12.JNS162123 KEY WORDS glioma; pathogens; virus; cancer; history; oncology

ince the late 19th century, the notion that pathogens this treatment’s safety and efficacy proved to be variable, may assist in the treatment of cancer has been estab- necessitating a change in its formulation.3,11,67 His methods lished. This theory was first conceptualized in 1891 continued well into the middle to late 20th century as the Swhen William B. Coley (a prominent New York surgeon) molecular discovery of related cytokines (tumor necrosis noticed the disappearance of malignant recurrent sarco- factor, interleukins) facilitated more directed therapies.4,68 ma in a young child who was suffering from a superficial Although Coley later adopted the use of heat-killed bacte- streptococcal infection (erysipelas).10,11,63,68 Upon inves- rial exotoxins into his treatment instead of live bacterial tigation of the medical literature at that time, Coley dis- inoculations, his discovery inspired more investigators and covered that many cases of cancer regression were noted scientists to become aware of the oncolytic effects of for- during infections; the most noticeable was the relationship eign infection. As a result of his discovery and methods, between erysipelas and sarcoma. Coley’s literature search Dr. Coley would soon be regarded as the father of immu- was initially fruitful, discovering 38 cases of carcinomas notherapy. and sarcomas that improved during concomitant erysipelas infections (Fig. 1).48 Soon afterward, in 1891, Coley The Beginnings of Virology and Cancer began to treat patients with sarcoma using inoculations of Streptococcus with varying degrees of success. Initial Treatment patients experienced septic episodes, in which the patient In 1904, a link between viral infection and cancer was almost died, and the tumor would caseate. Nevertheless, made when Dock noticed that a 42-year-old woman with survival was improved up to 8 years by repeatedly treat- leukemia spontaneously went into remission after a sus- ing recurrent tumors with this “toxin therapy.”12 However, pected influenza outbreak (which was decades prior to the

SUBMITTED August 15, 2016. ACCEPTED December 9, 2016. INCLUDE WHEN CITING Published online June 9, 2017; DOI: 10.3171/2016.12.JNS162123.

©AANS 2018, except where prohibited by US copyright law J Neurosurg Volume 128 • April 2018 1139

Unauthenticated | Downloaded 09/27/21 09:32 AM UTC A. H. Shah et al.

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. classification of influenza as a virus).19 Subsequently, in in physical signs or in the blood.”4,69 Nevertheless, these 1912, De Pace witnessed the regression of cervical car- initial successes for hematological malignancies were cinoma after Pasteur’s vaccination for rabies, suggesting translated for cancer therapy using a variety of systemic a link between viral inoculation and cancer response.18,29 viruses (feline panleukopenia virus, varicella, measles, Over the ensuing decades, more investigators noticed the mumps, and Newcastle disease virus).1,6,29,49,52,64,67 From same trend for hematological malignancies during viral these studies, the one published in 1956 by the National infections; however, the results were not entirely satisfac- Cancer Institute using wild adenovirus as treatment for tory as “the majority of cases did not produce remissions cervical cancer showed that more than 50% of treated pa-

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.

1140 J Neurosurg Volume 128 • April 2018

Unauthenticated | Downloaded 09/27/21 09:32 AM UTC Use of pathogens in treatment of glioma

TABLE 1. Published clinical trials using viruses in glioma No. of Median Citations on Patients PFS Median OS Trial Web of Science Authors & Year (N = 429) Virus Tumor Type (mos) (mos) Phase on 1/31/2016 Markert et al., 2000 21 HSV G207 Recurrent GBM Mean 3.5 Mean 12.8 I 578 Trask et al., 2000 13 AdHSV-TK/GCV Recurrent GBM 3 10 I 183 Rampling et al., 2000 9 HSV 1716 Recurrent MG Range 2–24 I 380 Papanastassiou et al., 2002 12 HSV 1716 Primary & recurrent GBM 7 I 184 Lang et al., 2003 15 Adenovirus ONYX-015 Recurrent GBM 3 10 I 235 Germano et al., 2003 11 HSV-TK/GCV Recurrent GBM 26 I 85 Smitt et al., 2003 14 HSV-TK/GCV Recurrent GBM 2.3 4 II 63 Immonen et al., 2004 36 HSV-TK/GCV Primary & recurrent GBM 14 I 230 Chiocca et al., 2004 24 Adenovirus ONYX-015 Recurrent HGG 1.5 6 I 203 Harrow et al., 2004 12 HSV 1716 Primary & recurrent GBM Range 3–22 NA 169 Freeman et al., 2006 14 HDV-HUJ Recurrent GBM 7 I 143 Chiocca et al., 2008 11 Ad.hIFN-β Recurrent MG 2 4 I 48 Forsyth et al., 2008 12 Reovirus Recurrent GBM 1 5 I 103 Markert et al., 2009 6 HSV G207 Recurrent GBM 3 6.6 (posttreatment), Ib 137 23 (postdiagnosis) Chiocca et al., 2011 12 AdV-TK/valacyclovir Primary HGG 9 12 Ib 32 Stragliotto et al., 2013 22 CMV/valacyclovir Primary GBM 5.5 18 I/II 34 Westphal et al., 2013 119 Sitimagene ceraden- Primary GBM 16 III 33 ovec/ganciclovir Kicielinski et al., 2014 15 Reovirus Recurrent HGG 2 4.5 I 13 Lang et al., 2014 37 Delta-24-RGD adeno- Recurrent HGG 11 I 0 virus or DNX-2401 Ji et al., 2016 53 HSV-TK/GCV Recurrent HGG 7 10 II NA 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. tients had tumor regression, but its duration was limited.29 discovery propelled the field of oncolysis for glioblasto- These initial discouraging results led to the abandonment ma.27 Nearly 30 years later, the use of Clostridium contin- of this research. Years later, however, with new molecu- ues to be studied for its oncolytic properties in glioblasto- lar biology techniques, the viruses could be modified to ma, yet malignant edema, increased intracranial pressure, increase their infectiveness and selectivity to destroy the and abscess formation remain barriers to propagating this tumoral cells. type of therapy.42,60 These early observations ushered in a new burgeoning field of pathogen therapy for cancer, and would soon set The Use of Enterobacter and Glioblastoma the stage for many infamous cases in neurosurgical oncology history. Over the last two decades, the association between pathogenic infections and increased survival in patients with malignant glioma was further substantiated by vari- The Infamous Use of Clostridium ous case reports of spontaneous regression and improved In the middle of the 20th century, Austrian physicians survival during infections.34 In 1999, Bowles and Perkins discovered that malignant tissue inoculated with spores of reported both oncolytic and adjuvant immune responses in nonpathogenic Clostridium butyricum (M55) would un- 3 patients co-infected with Enterobacter aerogenes after dergo liquefactive necrosis. C. butyricum, later marketed surgery.8 In 2009, Bohman et al. reported a similar trend as a probiotic, would transform into mature bacteria in the toward increased survival in 18 patients who developed malignant tissue and induce oncolysis.44 The hypoxic, rap- postoperative infections. More recently, Italian research- idly proliferative substrate of malignant tumors provided ers retrospectively noticed a drastic improvement in mean ideal environment for the bacteria. As a result, 49 pa- dian survival in patients with glioblastoma who developed tients with suspected glioblastoma were given intracarotid pathogenic infections after surgery.7,17 injections of M55 spores to induce oncolysis and abscess As a result of these studies, researchers and neurosur- formation that would necessitate resection (Fig. 2).27 The geons in California sought to investigate the clinical util- results were dismal, with 19 of 49 patients dying due to ity of introducing E. aerogenes into the surgical site of abscess formation/encephalitis, and the remainder of the patients suffering from glioblastoma. Although consent patients dying after surgery/recurrence. Nevertheless, this was obtained from patients to use this treatment modality,

J Neurosurg Volume 128 • April 2018 1141

Unauthenticated | Downloaded 09/27/21 09:32 AM UTC A. H. Shah et al.

TABLE 2. Ongoing clinical trials using viruses in glioma Start No. NCT Date of Trial Title No. (Mo-Yr) Patients Virus Tumor Type Phase Safety and efficacy study of Reolysin® in the treatment of 00528684 Jul-06 18 Reolysin MG 1 recurrent malignant gliomas Viral therapy in treating patients with recurrent glioblas- 00390299 Oct-06 40 Carcinoembryonic MG 1 toma multiforme antigen-expressing measles virus Phase 2a study of AdV-tk with standard radiation therapy 00589875 Mar-07 52 AdV-tk/valacyclovir MG 2 for malignant glioma (BrTK02) Safety study of replication-competent adenovirus (Delta- 01582516 Jun-10 20 Delta-24-RGD adeno- Recurring GBM 1 & 2 24-RGD) in patients with recurrent glioblastoma virus CMV-specific cytotoxic T lymphocytes expressing CAR 01109095 Oct-10 16 HER.CAR CMV- GBM 1 targeting HER2 in patients with GBM specific CTLs Virus DNX2401 and temozolomide in recurrent glioblas- 01956734 Sep-13 31 DNX2401 & temozolo- Recurring GBM 1 toma mide Combined cytotoxic and immune-stimulatory therapy for 01811992 Dec-13 18 Ad-hCMV-TK & Ad- MG & GBM 1 glioma (dose escalation of Ad-hCMV-TK and Ad-hCMV- hCMV-Flt3L Flt3L) Oncolytic HSV 1716 in treating younger patients with 02031965 Dec-13 24 HSV 1716/dexametha- Pediatric refractory or 1 refractory or recurrent high grade glioma that can be sone recurrent HGG removed by surgery DNX-2401 with interferon gamma (IFN-γ) for recurrent 02197169 Aug-14 36 DNX-2401/interferon- GBM or gliosarcoma 1 glioblastoma or gliosarcoma brain tumors gamma Genetically engineered HSV-1 phase 1 study 02062827 Sep-14 36 M032 (NSC 733972) High-grade recurrent 1 or refractory gliomas A study of Ad-RTS-hIL-12 with veledimex in subjects with 02026271 Jun-15 48 INXN-2001/veledimex MG & GBM 1 glioblastoma or malignant glioma Wild-type reovirus in combination with sargramostim in 02444546 Jun-15 21 Sargramostim/wild- Pediatric high-grade 1 treating younger patients with high-grade recurrent or type reovirus recurrent or refrac- refractory brain tumors tory glioma P2/3 randomized study of Toca 511 and Toca FC versus 02414165 Nov-15 170 Toca 511/Toca FC/ MG & GBM 2 & 3 SOC in subjects undergoing surgery for recurrent GBM/ lomustine/temozolo- AA mide/bevacizumab HSV G207 alone or with a single radiation dose in children 02457845 Jan-16 18 G207 MG 1 with progressive or recurrent supratentorial brain tumors PVSRIPO for recurrent glioblastoma (GBM) 01491893 Jan-16 65 PVSRIPO MG & GBM 1 A study of the safety of Toca 511, a retroviral replicating 02598011 Mar-16 18 Toca 511/Toca FC Newly diagnosed HGG 1 vector, combined with Toca FC in subjects with newly diagnosed high grade glioma receiving standard of care For virus details see Table 3. no specific IRB or FDA approval was obtained. This led engineered oncolytic herpes simplex virus.43 In 2000, the to widespread media coverage on the biomedical ethics of use of herpes virus for treatment of malignant gliomas in unregulated clinical research, and ultimately to sanctions humans was published.41 Since then, these same labora- on the research privileges of 2 neurosurgeons. Although tory techniques have been extended to include many ad- all 3 patients died, it is unclear whether the treatment mo- ditional viruses that have been primarily focused on glio- dality helped extend survival.2 blastoma.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 Viral Oncology and Glioblastoma (thereby limiting spread of the virus to nonneoplastic tis- Virotherapy for glioblastoma burgeoned in the late 20th sues).70 Oncolytic viral therapy utilizes tumor cells for century as scientists learned to rationally modify viral ge- viral replications and subsequent lysis and dissemination; nomes and neutralize viral toxicity.70 In 1991, Martuza et the unique ability of oncolytic viruses to preferentially al. used these techniques to develop the first artificially target cancer cells is largely due to the tumor’s reliance

1142 J Neurosurg Volume 128 • April 2018

Unauthenticated | Downloaded 09/27/21 09:32 AM UTC Use of pathogens in treatment of glioma

TABLE 3. Antitumor mechanism of the viruses used in the clinical trials Virus Mechanism HSV 1716 First-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 G207 First-generation oncolytic virus based on herpes simplex virus 1. It has the ICP34.5 gene deleted & the ICP6 gene inacti- vated by insertion of the E. coli LacZ gene. It lacks ribonucleotide reductase, rendering it unable to replicate in normal cells.40,41 HSV-TK/GCV These 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-1 Second-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- Adenovirus vector engineered to express hIL-12, a protein that improves the body’s natural response to disease by enhanc- 2001)/veledimex ing the ability of the immune system to kill tumor cells & may interfere w/ blood flow to the tumor.57 Ad-hCMV-TK/valacy- First-generation adenoviral vector human serotype 5 deleted in E1a & E3 viral encoding regions, engineered to express its clovir respective therapeutic transgene HSV1-TK under the control of the human cytomegalovirus promoter (hCMV) followed by an antiherpetic prodrug, valacyclovir.13 Ad-hCMV-Flt3L/vala- First-generation adenoviral vector human serotype 5 deleted in E1a & E3 viral encoding regions. The vector expresses its cyclovir transgene Flt3L under the control of the human cytomegalovirus promoter (hCMV). Flt3L causes maturation & prolifera- tion 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, & immunostimula- tory antitumoral effects.16 Delta-24-RGD adenovi- Adenovirus that harbors a 24–base pair deletion in the E1A region (responsible for binding Rb protein & possessing en- rus or DNX-2401 hanced infectivity because of the addition of RGD-4C). This virus targets the abnormal p16INK4/Rb pathway.32,33,38 ONYX-015 Adenovirus 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-CEA Measles virus expressing carcinoembryonic antigen.46,54 HDV-HUJ Newcastle disease virus (single-strand RNA virus) attenuated strain (lentogenic) w/ a selective cytotoxic potential for cancer cells.21,56 PVSRIPO Poliovirus:rhinovirus chimera, genetically recombinant, nonpathogenic, w/ a tumor-specific conditional replication phe- notype. 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 Reovirus Reoviruses 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 511 Toca 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

on oncogenic signaling pathways and their tendency to wild-type genes such as p53 or the cyclin-dependent ki- proliferate. Currently, over a dozen viral families have nase pathway through adenoviral vectors.9,28,39,50 However, been manipulated for oncolytic viral therapy for glioblas- initial clinical results did not demonstrate a significantly toma including adenovirus, Newcastle disease virus, vac- longer overall survival (10 months).37 Nevertheless, such cinia, poliovirus, and measles. Most, if not all, of these discoveries pioneered more tailored gene therapies for viral-based therapies are now undergoing early Phase I/II suppression of angiogenesis, elimination of drug resis- clinical trials (Tables 1–3).22,31,37,41 Many of these clinical tance, and activation of antitumor immune responses. A trials use intraparenchymal convection-enhanced delivery whole host of these viral-based gene therapies are being methods to introduce these virotherapeutics into the tu- used to alter glioblastoma molecular biology. Lastly, viral- mor/surgical cavity (Fig. 3). based vectors are now being used to introduce “suicide Along with these strides in oncolytic viral therapy, viral genes” into glioma cells. By using viral vectors, suicide vectors were also being used to introduce gene therapy for genes such as thymidine kinase and cytosine deaminase gliomas. These therapies were initially geared at restoring can be incorporated into the tumor cellular genome, and tumor suppressive mechanisms by reintroducing normal converted into toxic metabolites by prodrugs (ganciclovir

J Neurosurg Volume 128 • April 2018 1143

Unauthenticated | Downloaded 09/27/21 09:32 AM UTC A. H. Shah et al.

cus, varicella, and feline panleukopenia. Cancer 6:591–605, 1953 5. Bischoff JR, Kirn DH, Williams A, Heise C, Horn S, Muna M, et al: An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 274:373–376, 1996 6. Bluming AZ, Ziegler JL: Regression of Burkitt’s lymphoma in association with measles infection. Lancet 2:105–106, 1971 7. Bohman LE, Gallardo J, Hankinson TC, Waziri AE, Man- digo CE, McKhann GM II, et al: The survival impact of postoperative infection in patients with glioblastoma multiforme. Neurosurgery 64:828–835, 2009 8. Bowles AP Jr, Perkins E: Long-term remission of malignant brain tumors after intracranial infection: a report of four cases. Neurosurgery 44:636–643, 1999 9. Broaddus WC, Liu Y, Steele LL, Gillies GT, Lin PS, Loudon WG, et al: Enhanced radiosensitivity of malignant glioma cells after adenoviral p53 transduction. J Neurosurg 91:997– 1004, 1999 10. Coley WB: Contribution to the study of sarcoma of the fe- mur. Ann Surg 58:97–108, 1913 11. Coley WB: The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of the Streptococcus erysipelas and the Bacillus prodigiosus). Proc R Soc Med 3 (Surg Sect):1– 48, 1910 12. Coley WB: The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. FIG. 3. Viral and bacterial intraparenchymal delivery into tumor via 1893. Clin Orthop Relat Res (262):3–11, 1991 convection-enhanced delivery: herpes virus (left), replicating retrovirus 13. Chen SH, Shine HD, Goodman JC, Grossman RG, Woo SL: (center), and gram-negative bacilli, such as Escherichia coli and Entero- Gene therapy for brain tumors: regression of experimental bacter (right). Illustration by Roberto Suazo. Copyright Ashish H. Shah. gliomas by adenovirus-mediated gene transfer in vivo. Proc Published with permission. Natl Acad Sci U S A 91:3054–3057, 1994 14. Chiocca EA, Abbed KM, Tatter S, Louis DN, Hochberg FH, Barker F, et al: A phase I open-label, dose-escalation, 47,53 multi-institutional trial of injection with an E1B-attenuated and 5-fluorocytosine, respectively). This type of suicide adenovirus, ONYX-015, into the peritumoral region of recur- gene therapy is now being employed by a variety of centers rent malignant gliomas, in the adjuvant setting. Mol Ther across the US for recurrent glioblastoma. 10:958–966, 2004 15. Chiocca EA, Aguilar LK, Bell SD, Kaur B, Hardcastle J, Conclusions Cavaliere R, et al: Phase IB study of gene-mediated cytotoxic immunotherapy adjuvant to up-front surgery and inten- Early observations of tumor regression and concomi- sive timing radiation for malignant glioma. J Clin Oncol tant infection have ushered in a burgeoning field focus- 29:3611–3619, 2011 ing on the use of pathogens in molecular oncology. Over 16. Chiocca EA, Smith KM, McKinney B, Palmer CA, Rosen- the last several decades, research into oncolysis and im- feld S, Lillehei K, et al: A phase I trial of Ad.hIFN-beta gene mune activation secondary to foreign molecular exposure therapy for glioma. Mol Ther 16:618–626, 2008 17. De Bonis P, Albanese A, Lofrese G, de Waure C, Mangiola has identified potential therapeutic alternatives to current A, Pettorini BL, et al: Postoperative infection may influence mainstay glioma therapy. Current glioma treatment such survival in patients with glioblastoma: simply a myth? Neu- as immunosuppressive chemotherapy and steroids may rosurgery 69:864–869, 2011 curtail the oncolytic capacity of pathogens. Although the 18. De Pace N: Sulla scomparsa di un enorme cancro vegetante long-term safety of virotherapy has yet to be demonstrat- del callo dell’utero senza cura chirurgica. Ginecologia ed, there is promise that such therapies may effectively im- (France) 9:82–88, 1912 prove survival for treatment-refractory gliomas. 19. Dock G: The influence of complicating diseases upon leukemia. Am J Med Sci 127:563–592, 1904 20. Forsyth P, Roldán G, George D, Wallace C, Palmer CA, Mor- ris D, et al: A phase I trial of intratumoral administration of References reovirus in patients with histologically confirmed recurrent 1. Asada T: Treatment of human cancer with mumps virus. malignant gliomas. Mol Ther 16:627–632, 2008 Cancer 34:1907–1928, 1974 21. Freeman AI, Zakay-Rones Z, Gomori JM, Linetsky E, Ra- 2. Baker M: Can bacteria fight brain cancer? Nature News sooly L, Greenbaum E, et al: Phase I/II trial of intravenous Explainer. July 27, 2012. (http://www.nature.com/news/can- NDV-HUJ oncolytic virus in recurrent glioblastoma multi- bacteria-fight-brain-cancer-1.11080) [Accessed February 21, forme. Mol Ther 13:221–228, 2006 2017] 22. Geletneky K, Huesing J, Rommelaere J, Schlehofer JR, 3. Bickels J, Kollender Y, Merinsky O, Meller I: Coley’s toxin: Leuchs B, Dahm M, et al: Phase I/IIa study of intratumoral/ historical perspective. Isr Med Assoc J 4:471–472, 2002 intracerebral or intravenous/intracerebral administration 4. Bierman HR, Crile DM, Dod KS, Kelly KH, Petrakis NL, of Parvovirus H-1 (ParvOryx) in patients with progressive White LP, et al: Remissions in leukemia of childhood follow- primary or recurrent glioblastoma multiforme: ParvOryx01 ing acute infectious disease: staphylococcus and streptococ- protocol. BMC Cancer 12:99, 2012

1144 J Neurosurg Volume 128 • April 2018

Unauthenticated | Downloaded 09/27/21 09:32 AM UTC Use of pathogens in treatment of glioma

23. Germano IM, Fable J, Gultekin SH, Silvers A: Adenovirus/ virus G207 inoculated pre-and post-tumor resection for re- herpes simplex-thymidine kinase/ganciclovir complex: pre- current GBM. Mol Ther 17:199–207, 2009 liminary results of a phase I trial in patients with recurrent 41. Markert JM, Medlock MD, Rabkin SD, Gillespie GY, Todo malignant gliomas. J Neurooncol 65:279–289, 2003 T, Hunter WD, et al: Conditionally replicating herpes simplex 24. Goetz C, Dobrikova E, Shveygert M, Dobrikov M, Gromeier virus mutant, G207 for the treatment of malignant glioma: M: Oncolytic poliovirus against malignant glioma. Future results of a phase I trial. Gene Ther 7:867–874, 2000 Virol 6:1045–1058, 2011 42. Marth E, Ascher WP, Pavelka R, Möse JR: Tumor lysis of a 25. Harrow S, Papanastassiou V, Harland J, Mabbs R, Petty R, glioblastoma by Clostridium oncolyticum. J Chemother 1 (4 Fraser M, et al: HSV1716 injection into the brain adjacent to Suppl):1177–1178, 1989 tumour following surgical resection of high-grade glioma: 43. Martuza RL, Malick A, Markert JM, Ruffner KL, Coen safety data and long-term survival. Gene Ther 11:1648–1658, DM: Experimental therapy of human glioma by means of a 2004 genetically engineered virus mutant. Science 252:854–856, 26. Heise C, Sampson-Johannes A, Williams A, McCormick F, 1991 Von Hoff DD, Kirn DH: ONYX-015, an E1B gene-attenuated 44. Moese JR, Moese G: Oncolysis by Clostridia. I. Activity adenovirus, causes tumor-specific cytolysis and antitumoral of Clostridium butyricum (M-55) and other nonpathogenic efficacy that can be augmented by standard chemotherapeutic Clostridia against the Ehrlich carcinoma. Cancer Res agents. Nat Med 3:639–645, 1997 24:212–216, 1964 27. Heppner F, Möse JR: The liquefaction (oncolysis) of malig- 45. Moolten FL, Wells JM: Curability of tumors bearing herpes nant gliomas by a non pathogenic Clostridium. Acta Neuro- thymidine kinase genes transferred by retroviral vectors. J chir (Wien) 42:123–125, 1978 Natl Cancer Inst 82:297–300, 1990 28. Horowitz J: Adenovirus-mediated p53 gene therapy: over- 46. Myers R, Harvey M, Kaufmann TJ, Greiner SM, Krempski view of preclinical studies and potential clinical applications. JW, Raffel C, et al: Toxicology study of repeat intracerebral Curr Opin Mol Ther 1:500–509, 1999 administration of a measles virus derivative producing car- 29. Huebner RJ, Rowe WP, Schatten WE, Smith RR, Thomas cinoembryonic antigen in rhesus macaques in support of a LB: Studies on the use of viruses in the treatment of carci- phase I/II clinical trial for patients with recurrent gliomas. noma of the cervix. Cancer 9:1211–1218, 1956 Hum Gene Ther 19:690–698, 2008 30. Immonen A, Vapalahti M, Tyynelä K, Hurskainen H, Sand- 47. Nanda D, Vogels R, Havenga M, Avezaat CJ, Bout A, Smitt mair A, Vanninen R, et al: AdvHSV-tk gene therapy with PS: Treatment of malignant gliomas with a replicating ad- intravenous ganciclovir improves survival in human ma- enoviral vector expressing herpes simplex virus-thymidine lignant glioma: a randomised, controlled study. Mol Ther kinase. Cancer Res 61:8743–8750, 2001 10:967–972, 2004 48. Nauts HC, Swift WE, Coley BL: The treatment of malignant 31. Ji N, Weng D, Liu C, Gu Z, Chen S, Guo Y, et al: Adenovi- tumors by bacterial toxins as developed by the late William rus-mediated delivery of herpes simplex virus thymidine B. Coley, M.D., reviewed in the light of modern research. kinase administration improves outcome of recurrent high- Cancer Res 6:205–216, 1946 grade glioma. Oncotarget 7:4369–4378, 2016 49. Okuno Y, Asada T, Yamanishi K, Otsuka T, Takahashi M, 32. Jiang H, Clise-Dwyer K, Ruisaard KE, Fan X, Tian W, Tanioka T, et al: Studies on the use of mumps virus for treat- Gumin J, et al: Delta-24-RGD oncolytic adenovirus elicits ment of human cancer. Biken J 21:37–49, 1978 anti-glioma immunity in an immunocompetent mouse model. 50. Pan D, Wei X, Liu M, Feng S, Tian X, Feng X, et al: Adeno- PLoS One 9:e97407, 2014 virus mediated transfer of p53, GM-CSF and B7-1 suppresses 33. Jiang H, Gomez-Manzano C, Aoki H, Alonso MM, Kondo S, growth and enhances immunogenicity of glioma cells. Neu- McCormick F, et al: Examination of the therapeutic potential rol Res 32:502–509, 2010 of Delta-24-RGD in brain tumor stem cells: role of autopha- 51. Papanastassiou V, Rampling R, Fraser M, Petty R, Hadley gic cell death. J Natl Cancer Inst 99:1410–1414, 2007 D, Nicoll J, et al: The potential for efficacy of the modified 34. Kapp JP: Microorganisms as antineoplastic agents in CNS (ICP 34.5-) herpes simplex virus HSV1716 following intra- tumors. Arch Neurol 40:637–642, 1983 tumoural injection into human malignant glioma: a proof of 35. Kicielinski KP, Chiocca EA, Yu JS, Gill GM, Coffey M, principle study. Gene Ther 9:398–406, 2002 Markert JM: Phase 1 clinical trial of intratumoral reovirus 52. Parker JN, Bauer DF, Cody JJ, Markert JM: Oncolytic viral infusion for the treatment of recurrent malignant gliomas in therapy of malignant glioma. Neurotherapeutics 6:558–569, adults. Mol Ther 22:1056–1062, 2014 2009 36. King GD, Muhammad AK, Larocque D, Kelson KR, Xiong 53. Perez OD, Logg CR, Hiraoka K, Diago O, Burnett R, Inagaki W, Liu C, et al: Combined Flt3L/TK gene therapy induces A, et al: Design and selection of Toca 511 for clinical use: immunological surveillance which mediates an immune re- modified retroviral replicating vector with improved stability sponse against a surrogate brain tumor neoantigen. Mol Ther and gene expression. Mol Ther 20:1689–1698, 2012 19:1793–1801, 2011 54. Phuong LK, Allen C, Peng KW, Giannini C, Greiner S, 37. Lang FF, Bruner JM, Fuller GN, Aldape K, Prados MD, TenEyck CJ, et al: Use of a vaccine strain of measles virus Chang S, et al: Phase I trial of adenovirus-mediated p53 gene genetically engineered to produce carcinoembryonic antigen therapy for recurrent glioma: biological and clinical results. J as a novel therapeutic agent against glioblastoma multiforme. Clin Oncol 21:2508–2518, 2003 Cancer Res 63:2462–2469, 2003 38. Lang FF, Conrad C, Gomez-Manzano C, Tufaro F, Yung 55. Rampling R, Cruickshank G, Papanastassiou V, Nicoll J, WKA, Sawaya R, et al: First-in-human Phase I clinical trial Hadley D, Brennan D, et al: Toxicity evaluation of replica- of oncolytic Delta-24-Rgd (Dnx-2401) with biological end- tion-competent herpes simplex virus (ICP 34.5 null mutant points: implications for viro-immunotherapy. Neuro Oncol 1716) in patients with recurrent malignant glioma. Gene 16 (Suppl 3):iii39, 2014 (Abstract) Ther 7:859–866, 2000 39. Li H, Alonso-Vanegas M, Colicos MA, Jung SS, Lochmuller 56. Reichard KW, Lorence RM, Cascino CJ, Peeples ME, Walter H, Sadikot AF, et al: Intracerebral adenovirus-mediated RJ, Fernando MB, et al: Newcastle disease virus selectively p53 tumor suppressor gene therapy for experimental human kills human tumor cells. J Surg Res 52:448–453, 1992 glioma. Clin Cancer Res 5:637–642, 1999 57. Roth JC, Cassady KA, Cody JJ, Parker JN, Price KH, Cole- 40. Markert JM, Liechty PG, Wang W, Gaston S, Braz E, man JM, et al: Evaluation of the safety and biodistribution of Karrasch M, et al: Phase Ib trial of mutant herpes simplex M032, an attenuated herpes simplex virus type 1 expressing

J Neurosurg Volume 128 • April 2018 1145

Unauthenticated | Downloaded 09/27/21 09:32 AM UTC A. H. Shah et al.

hIL-12, after intracerebral administration to Aotus nonhu- 67. Wheelock EF, Dingle JH: Observations on the repeated ad- man primates. Hum Gene Ther Clin Dev 25:16 –27, 2014 ministration of viruses to a patient with acute leukemia. A 58. Shah AC, Benos D, Gillespie GY, Markert JM: Oncolytic preliminary report. N Engl J Med 271:645–651, 1964 viruses: clinical applications as vectors for the treatment of 68. Wiemann B, Starnes CO: Coley’s toxins, tumor necrosis fac- malignant gliomas. J Neurooncol 65:203–226, 2003 tor and cancer research: a historical perspective. Pharmacol 59. Smitt PS, Driesse M, Wolbers J, Kros M, Avezaat C: Treat- Ther 64:529–564, 1994 ment of relapsed malignant glioma with an adenoviral vector 69. Wintrobe M, Hasenbush L: Chronic leukemia: the early containing the herpes simplex thymidine kinase gene fol- phase of chronic leukemia, the results of treatment and the lowed by ganciclovir. Mol Ther 7:851–858, 2003 effects of complicating infections: a study of eighty-six 60. Staedtke V, Bai RY, Sun W, Huang J, Kibler KK, Tyler adults. Arch Intern Med 64:701–718, 1939 BM, et al: Clostridium novyi-NT can cause regression of 70. Wollmann G, Ozduman K, van den Pol AN: Oncolytic virus orthotopically implanted glioblastomas in rats. Oncotarget therapy for glioblastoma multiforme: concepts and candi- 6:5536–5546, 2015 dates. Cancer J 18:69–81, 2012 61. Stragliotto G, Rahbar A, Solberg NW, Lilja A, Taher C, Or- 71. Xiong W, Candolfi M, Liu C, Muhammad AK, Yagiz K, rego A, et al: Effects of valganciclovir as an add-on therapy Puntel M, et al: Human Flt3L generates dendritic cells from in patients with cytomegalovirus-positive glioblastoma: a canine peripheral blood precursors: implications for a dog randomized, double-blind, hypothesis-generating study. Int J glioma clinical trial. PLoS One 5:e11074, 2010 Cancer 133:1204–1213, 2013 62. Strong JE, Tang D, Lee PWK: Evidence that the epidermal growth factor receptor on host cells confers reovirus infection efficiency. Virology 197:405–411, 1993 63. Swain J: The treatment of malignant tumours by the toxins of Disclosures the Streptococcus erysipelatis and Bacillus prodigiosus. BMJ Dr. Ivan has served as a consultant to Medtronic. Dr. Kasahara 2:1415–1416, 1895 has served as a consultant to Tocagen Inc. 64. Taqi AM, Abdurrahman MB, Yakubu AM, Fleming AF: Re- gression of Hodgkin’s disease after measles. Lancet 1:1112, Author Contributions 1981 65. Trask TW, Trask RP, Aguilar-Cordova E, Shine HD, Wyde Conception and design: Shah, Kasahara. Acquisition of data: PR, Goodman JC, et al: Phase I study of adenoviral delivery Shah, Jusué-Torres. Analysis and interpretation of data: Shah, of the HSV-tk gene and ganciclovir administration in patients Jusué-Torres, Kasahara. Drafting the article: Shah, Jusué-Torres. with current malignant brain tumors. Mol Ther 1:195–203, Critically revising the article: all authors. Reviewed submitted 2000 version of manuscript: all authors. Approved the final version of 66. Westphal M, Ylä-Herttuala S, Martin J, Warnke P, Menei P, the manuscript on behalf of all authors: Shah. Eckland D, et al: Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir Correspondence for patients with operable high-grade glioma (ASPECT): a Ashish H. Shah, Department of Neurological Surgery, University randomised, open-label, phase 3 trial. Lancet Oncol 14:823– of Miami Miller School of Medicine, 1095 NW 14th Terrace, Rm. 833, 2013 2-06, Miami, FL 33136. email: [email protected].

1146 J Neurosurg Volume 128 • April 2018

Unauthenticated | Downloaded 09/27/21 09:32 AM UTC