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Journal ArticleDOI

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

09 Jun 2017-Journal of Neurosurgery (American Association of Neurological Surgeons)-Vol. 128, Iss: 4, pp 1139-1146
TL;DR: In the late 19th century, Dr. William B. Coley introduced the theory that infections may aid in the treatment of malignancy and piloted a burgeoning field focusing on the use of pathogens in molecular oncology.
Abstract: 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.

Summary (1 min read)

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 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 For virus details see Table 3 . on oncogenic signaling pathways and their tendency to proliferate.
  • 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.
  • Initial clinical results did not demonstrate a significantly longer overall survival (10 months).

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.
  • There is promise that such therapies may effectively improve survival for treatment-refractory gliomas.

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UC San Francisco Previously Published Works
Title
Pathogens and glioma: a history of unexpected discoveries ushering in novel therapy.
Permalink
https://escholarship.org/uc/item/7ps2b7v5
Journal
Journal of neurosurgery, 128(4)
ISSN
0022-3085
Authors
Shah, Ashish H
Jusué-Torres, Ignacio
Ivan, Michael E
et al.
Publication Date
2018-04-01
DOI
10.3171/2016.12.jns162123
Peer reviewed
eScholarship.org Powered by the California Digital Library
University of California

HISTORICAL VIGNETTE
J Neurosurg 128:1139–1146, 2018
S
ince the late 19th century, the notion that pathogens
may assist in the treatment of cancer has been estab-
lished. This theory was rst conceptualized in 1891
when William B. Coley (a prominent New York surgeon)
noticed the disappearance of malignant recurrent sarco-
ma in a young child who was suffering from a supercial
streptococcal infection (erysipelas).
10,11,63,68
Upon inves-
tigation of the medical literature at that time, Coley dis-
covered that many cases of cancer regression were noted
during infections; the most noticeable was the relationship
between erysipelas and sarcoma. Coleys literature search
was initially fruitful, discovering 38 cases of carcinomas
and sarcomas that improved during concomitant erysip-
elas 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 treat-
ing recurrent tumors with this “toxin therapy.
12
However,
this treatments safety and efcacy 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 bacte-
rial exotoxins into his treatment instead of live bacterial
inoculations, his discovery inspired more investigators and
scientists to become aware of the oncolytic effects of for-
eign infection. As a result of his discovery and methods,
Dr. Coley would soon be regarded as the father of immu-
notherapy.
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 sus-
pected inuenza 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.
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, PhD
2,3
Departments of
1
Neurological Surgery,
2
Cell Biology, and
3
Pathology, 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 eld 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
J Neurosurg Volume 128 • April 2018 1139©AANS 2018, except where prohibited by US copyright law

A. H. Shah et al.
J Neurosurg Volume 128 • April 20181140
classication of inuenza as a virus).
19
Subsequently, in
1912, De Pace witnessed the regression of cervical car-
cinoma 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 satisfac-
tory 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 pa-
FIG. 1. Initial results of William Coley using bacterial toxins (Streptococcus erysipelas and the Bacillus prodigiosus) for sar-
coma.
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.
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.

Use of pathogens in treatment of glioma
J Neurosurg Volume 128 • April 2018 1141
tients 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 molecu-
lar biology techniques, the viruses could be modied to
increase their infectiveness and selectivity to destroy the
tumoral cells.
These early observations ushered in a new burgeoning
eld of pathogen therapy for cancer, and would soon set
the stage for many infamous cases in neurosurgical oncol-
ogy 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 un-
dergo liquefactive necrosis. C. butyricum, later marketed
as a probiotic, would transform into mature bacteria in the
malignant tissue and induce oncolysis.
44
The hypoxic, rap-
idly proliferative substrate of malignant tumors provided
an ideal environment for the bacteria. As a result, 49 pa-
tients 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 eld of oncolysis for glioblasto-
ma.
27
Nearly 30 years later, the use of Clostridium contin-
ues to be studied for its oncolytic properties in glioblasto-
ma, yet malignant edema, increased intracranial pressure,
and abscess formation remain barriers to propagating this
type of therapy.
42,60
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 vari-
ous 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 research-
ers retrospectively noticed a drastic improvement in me-
dian survival in patients with glioblastoma who developed
pathogenic infections after surgery.
7,17
As a result of these studies, researchers and neurosur-
geons in California sought to investigate the clinical util-
ity of introducing E. aerogenes into the surgical site of
patients suffering from glioblastoma. Although consent
was obtained from patients to use this treatment modality,
TABLE 1. Published clinical trials using viruses in glioma
Authors & Year
No. of
Patients
(N = 429) Virus Tumor Type
Median
PFS
(mos)
Median OS
(mos)
Trial
Phase
Citations on
Web of Science
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),
23 (postdiagnosis)
Ib 137
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-
ovec/ganciclovir
Primary GBM 16 III 33
Kicielinski et al., 2014 15 Reovirus Recurrent HGG 2 4.5 I 13
Lang et al., 2014 37 Delta-24-RGD adeno-
virus or DNX-2401
Recurrent HGG 11 I 0
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.

A. H. Shah et al.
J Neurosurg Volume 128 • April 20181142
no specic 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 mo-
dality helped extend survival.
2
Viral Oncology and Glioblastoma
Virotherapy for glioblastoma burgeoned in the late 20th
century as scientists learned to rationally modify viral ge-
nomes and neutralize viral toxicity.
70
In 1991, Martuza et
al. used these techniques to develop the rst articially
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 labora-
tory techniques have been extended to include many ad-
ditional viruses that have been primarily focused on glio-
blastoma.
70
Gliomas were the ideal target for viral-based
therapies due to their highly replicative nature, lack of
distant metastasis, and connement by postmitotic cells
(thereby limiting spread of the virus to nonneoplastic tis-
sues).
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 tumors reliance
TABLE 2. Ongoing clinical trials using viruses in glioma
Title
NCT
No.
Start
Date
(Mo-Yr)
No.
of
Patients Virus Tumor Type
Trial
Phase
Safety and efcacy study of Reolysin
®
in the treatment of
recurrent malignant gliomas
00528684 Jul-06 18 Reolysin MG 1
Viral therapy in treating patients with recurrent glioblas-
toma multiforme
00390299 Oct-06 40 Carcinoembryonic
antigen-expressing
measles virus
MG 1
Phase 2a study of AdV-tk with standard radiation therapy
for malignant glioma (BrTK02)
00589875 Mar-07 52 AdV-tk/valacyclovir MG 2
Safety study of replication-competent adenovirus (Delta-
24-RGD) in patients with recurrent glioblastoma
01582516 Jun-10 20 Delta-24-RGD adeno-
virus
Recurring GBM 1 & 2
CMV-specic cytotoxic T lymphocytes expressing CAR
targeting HER2 in patients with GBM
01109095 Oct-10 16 HER.CAR CMV-
specic CTLs
GBM 1
Virus DNX2401 and temozolomide in recurrent glioblas-
toma
01956734 Sep-13 31 DNX2401 & temozolo-
mide
Recurring GBM 1
Combined cytotoxic and immune-stimulatory therapy for
glioma (dose escalation of Ad-hCMV-TK and Ad-hCMV-
Flt3L)
01811992 Dec-13 18 Ad-hCMV-TK & Ad-
hCMV-Flt3L
MG & GBM 1
Oncolytic HSV 1716 in treating younger patients with
refractory or recurrent high grade glioma that can be
removed by surgery
02031965 Dec-13 24 HSV 1716/dexametha-
sone
Pediatric refractory or
recurrent HGG
1
DNX-2401 with interferon gamma (IFN-γ) for recurrent
glioblastoma or gliosarcoma brain tumors
02197169 Aug-14 36 DNX-2401/interferon-
gamma
GBM or gliosarcoma 1
Genetically engineered HSV-1 phase 1 study 02062827 Sep-14 36 M032 (NSC 733972) High-grade recurrent
or refractory gliomas
1
A study of Ad-RTS-hIL-12 with veledimex in subjects with
glioblastoma or malignant glioma
02026271 Jun-15 48 INXN-2001/veledimex MG & GBM 1
Wild-type reovirus in combination with sargramostim in
treating younger patients with high-grade recurrent or
refractory brain tumors
02444546 Jun-15 21 Sargramostim/wild-
type reovirus
Pediatric high-grade
recurrent or refrac-
tory glioma
1
P2/3 randomized study of Toca 511 and Toca FC versus
SOC in subjects undergoing surgery for recurrent GBM/
AA
02414165 Nov-15 170 Toca 511/Toca FC/
lomustine/temozolo-
mide/bevacizumab
MG & GBM 2 & 3
HSV G207 alone or with a single radiation dose in children
with progressive or recurrent supratentorial brain tumors
02457845 Jan-16 18 G207 MG 1
PVSRIPO for recurrent glioblastoma (GBM) 01491893 Jan-16 65 PVSRIPO MG & GBM 1
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 care
02598011 Mar-16 18 Toca 511/Toca FC Newly diagnosed HGG 1
For virus details see Table 3.

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Book ChapterDOI
TL;DR: This review summarizes new developments on pathophysiological aspects of GBM and novel therapeutic strategies to enhance quality of life of patients using novel therapeutic advances in gliomas.
Abstract: Glioblastoma Multiforme (GBM) is one the most common intracranial tumors discovered by Burns (1800) and Abernethy (1804) based on gross morphology of the autopsied material and referred to as "medullary sarcoma" and later "fungus medullare" (Abernethy, 1804; Burns, 1800). Virchow in 1863 was the first German pathologist using histomorphological techniques discovered that GBM is a tumor of glial origin. Virchow (1863/65) also then used the term Glioma for the first time and classified as low-grade glioma and high-grade glioma very similar to that of today according to World health organization (WHO) classification (Jellinger, 1978; Virchow, 1863/65). After almost >50 years of this discovery, Baily and Cushing (1926) based on modern neuropathological tools provide the classification of gliomas that is still valid today (Baily & Cushing, 1926). Although, our knowledge about development of gliomas has advanced through development of modern cellular and molecular biological tools (Gately, McLachlan, Dowling, & Philip, 2017; Omuro & DeAngelis, 2013), therapeutic advancement of GBM still requires lot of efforts for the benefit of patients. This review summarizes new developments on pathophysiological aspects of GBM and novel therapeutic strategies to enhance quality of life of patients. These novel therapeutic approaches rely on enhanced penetration of drug therapy into the tumor tissues by use of nanomedicine for both the diagnostic and therapeutic purposes, referred to as "theranostic nanomedicine" (Alphandery, 2020; Zhao, van Straten, Broekman, Preat, & Schiffelers, 2020). Although, the blood-brain barrier (BBB) is fenestrated around the periphery of the tumor tissues, the BBB is still tight within the deeper tissues of the tumor. Thus, drug delivery is a challenge for gliomas and requires new therapeutic advances (Zhao et al., 2020). Associated edema development around tumor tissues is another factor hindering therapeutic effects (Liu, Mei, & Lin, 2013). These factors are discussed in details using novel therapeutic advances in gliomas.

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Cites background from "Pathogens and glioma: a history of ..."

  • ...This finding was the basis for the development of the “Coley’s toxin”, a mixture of heat-inactivated bacteria, which was found to increase the overall survival of sarcoma patients, in spite of the development of high fever and chill [7,8]....

    [...]

References
More filters
Journal ArticleDOI
18 Oct 1996-Science
TL;DR: Injection of the mutant virus into p53-deficient human cervical carcinomas grown in nude mice caused a significant reduction in tumor size and caused complete regression of 60 percent of the tumors, raising the possibility that mutant adenoviruses can be used to treat certain human tumors.
Abstract: The human adenovirus E1B gene encodes a 55-kilodalton protein that inactivates the cellular tumor suppressor protein p53. Here it is shown that a mutant adenovirus that does not express this viral protein can replicate in and lyse p53-deficient human tumor cells but not cells with functional p53. Ectopic expression of the 55-kilodalton EIB protein in the latter cells rendered them sensitive to infection with the mutant virus. Injection of the mutant virus into p53-deficient human cervical carcinomas grown in nude mice caused a significant reduction in tumor size and caused complete regression of 60 percent of the tumors. These data raise the possibility that mutant adenoviruses can be used to treat certain human tumors.

1,798 citations

Journal ArticleDOI
10 May 1991-Science
TL;DR: A thymidine kinase-negative mutant of herpes simplex virus-1 (dlsptk) that is attenuated for neurovirulence was tested as a possible treatment for gliomas and merit further evaluation as novel antineoplastic agents.
Abstract: Malignant gliomas are the most common malignant brain tumors and are almost always fatal. A thymidine kinase-negative mutant of herpes simplex virus-1 (dlsptk) that is attenuated for neurovirulence was tested as a possible treatment for gliomas. In cell culture, dlsptk killed two long-term human glioma lines and three short-term human glioma cell populations. In nude mice with implanted subcutaneous and subrenal U87 human gliomas, intraneoplastic inoculation of dlsptk caused growth inhibition. In nude mice with intracranial U87 gliomas, intraneoplastic inoculation of dlsptk prolonged survival. Genetically engineered viruses such as dlsptk merit further evaluation as novel antineoplastic agents.

969 citations

Journal ArticleDOI
TL;DR: It is reported that normal human cells were highly resistant to ONYX-015-mediated, replication-dependent cytolysis and a wide range of human tumor cells, including numerous carcinoma lines with either mutant or normal p53 gene sequences, were efficiently destroyed.
Abstract: The 55-kilodalton (kDa) protein from the E1B-region of adenovirus binds to and inactivates the p53 gene, which is mutated in half of human cancers. We have previously shown that the replication and cytopathogenicity of an E1B, 55-kDa gene-attenuated adenovirus, ONYX-015, is blocked by functional p53 in RKO and U20S carcinoma lines. We now report that normal human cells were highly resistant to ONYX-015-mediated, replication-dependent cytolysis. In contrast, a wide range of human tumor cells, including numerous carcinoma lines with either mutant or normal p53 gene sequences (exons 5-9), were efficiently destroyed. Antitumoral efficacy was documented following intratumoral or intravenous administration of ONYX-015 to nude mouse-human tumor xenografts; efficacy with ONYX-015 plus chemotherapy (cisplatin, 5-fluorouracil) was significantly greater than with either agent alone.

968 citations

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955 citations

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TL;DR: William Bradley Coley (Fig. I) stemmed from old New England stock and became an intern at the New York Hospital.
Abstract: William Bradley Coley (Fig. I) stemmed from old New England stock. After graduating from Yale in 1884. Coley spent two years in Portland, Oregon, teaching Latin and Greek before entering Harvard Medical School. After completing a competitive examination, he became an intern at the New York Hospital

816 citations