General Information
Information presented in this section about the use of Newcastle disease virus (NDV) in the treatment
of human cancer is summarized in a table located at the end of the
section.
NDV is a paramyxovirus that
causes Newcastle disease in a wide variety of birds (most notably, in
chickens). Reviewed in [1-4] This often fatal disease is characterized by inflammation of respiratory tract and of either
the brain or the gastrointestinal tract. Reviewed in [1-3,5,6] NDV can also infect humans, but, in humans, it is generally not very virulent, causing only mild flu-like
symptoms or conjunctivitis and/or laryngitis. Reviewed in [1,3,7-15] The
perception that NDV can replicate up to 10,000 times better in human cancer cells than in most normal human cells [13,16-20] Reviewed in [2,7-11,14,21-24]
has prompted much interest in this virus as a potential anticancer agent. NDV
has been labeled as a complementary and alternative medicine treatment because it is widely believed to be nontoxic; Reviewed in [15] however, this virus has been studied extensively by
the conventional medical community.
The genetic material of NDV is RNA rather
than DNA. Reviewed in [1,4,14,19,24-28] As
with other types of viruses, essentially all of NDV’s replication cycle takes place
inside infected cells, which are also known as host cells. Reviewed in [14,19,27,29]
During a replication cycle, new virus proteins and copies of the NDV genetic
material (i.e., genome) are made in the
host cell’s cytoplasm. NDV is also an enveloped virus, which means
that progeny virus particles are
released from infected cells by budding off from them. Reviewed in [19,27,30]
In this process, single copies of the NDV genome become wrapped in an outer
coat (i.e., an envelope) that is made from a small piece of the host cell’s plasma membrane. Generally, the NDV outer coat contains only virus proteins
that have been specifically inserted into the host cell's plasma
membrane; Reviewed in [19,25,29,30] however, some host cell proteins may be
included as well. Reviewed in [31,32] Two specific virus proteins, hemagglutinin-neuraminidase and the fusion protein, are the main NDV
proteins found in the outer coat of isolated virus particles. Reviewed in
[4,19,25,27]
There are many different strains of NDV, and they have been classified as
either lytic or nonlytic for human cells. Lytic strains and nonlytic strains
both appear to replicate much more efficiently in human cancer cells than they
do in most normal human cells,[13,16-21] Reviewed in [14,33] and viruses of
both strain types have been investigated as potential anticancer agents. One
major difference between lytic strains and nonlytic strains is that lytic
strains are able to make infectious progeny virus particles in human cells,
whereas nonlytic strains are not. Reviewed in [14,19,25-27,34] This difference
is due to the ability of lytic strains to produce activated
hemagglutinin-neuraminidase and fusion protein molecules in the outer coat of progeny
viruses in human cells. The progeny virus particles made by nonlytic strains
contain inactive versions of these molecules. Activated
hemagglutinin-neuraminidase and fusion protein molecules are required for NDV
to enter a cell to replicate. Initial binding of NDV to a host cell takes
place through the interaction of hemagglutinin-neuraminidase molecules in the
virus coat with sialic-acid –containing molecules (i.e., gangliosides) on the surface of the
cell. It is important to note, however, that nonlytic strains of NDV can make
infectious progeny viruses in some types of nonhuman cells (e.g., chicken embryo cells), Reviewed in
[14,19,25,26,33] thereby allowing these strains to be maintained.
Another major difference between lytic strains and nonlytic strains is
that, although they both have the potential to kill infected cells, the
mechanisms by which they accomplish this result are different. The production
of infectious progeny virus particles by lytic strains gives them the ability
to kill host cells fairly quickly. The budding of progeny viruses that
contain activated hemagglutinin-neuraminidase and fusion protein molecules in
their outer coats causes the plasma membrane of NDV-infected cells to fuse
with the plasma membrane of adjacent cells, leading to the production of
large, inviable fused cells known as syncytia.[13] Reviewed in [14,19,27] The
more efficiently a lytic strain can replicate inside a host cell, the more
quickly it can kill that cell. The preferential killing of cancer cells by a
lytic virus is known as oncolysis;
thus, lytic strains of NDV are also called oncolytic strains. In contrast, nonlytic
strains of NDV kill infected cells more slowly, with death apparently the
result of viral disruption of normal host
cell metabolism.[35] Reviewed in [33]
As indicated previously, both lytic strains and nonlytic strains have been
investigated for their anticancer potential. In fact, the major differences
between the 2 strain types have been exploited to develop 3 different
approaches to cancer therapy:
- The infection of cancer patients with a lytic strain of NDV.
- The use of oncolysates, i.e., preparations
containing plasma membrane fragments from NDV-infected cancer calls, as
anticancer vaccines.
- The use of intact cancer cells infected with a nonlytic strain of NDV as whole cell vaccines.
One proposed advantage of the first approach is that virus replication may
allow the spread of cytotoxic viruses
to every cancer cell in the body; Reviewed in [9,31] however, the production of virus-neutralizing
antibodies by the immune system might limit this possibility. Reviewed in
[7,9,14,27] The rationale for the second and third approaches is that tumor-specific antigens (i.e., proteins or other molecules that are generally located in the plasma
membrane of cancer cells and that are either unique to cancer cells or much
more abundant in them) may be better recognized by the immune system if they
are associated with virus antigens (i.e., virus proteins that have been inserted into the plasma membrane of host
cells). Reviewed in [9,13,14,25,29,31,36-42] If this enhanced recognition takes
place, then it may increase the chance that cancer cells, whether they are
virus infected or not, will be recognized as foreign by the immune system
and be destroyed. Reviewed in [9,13,25,41,42]
The principal developers of the third approach have stated that whole cell
vaccines can stimulate the immune system better than oncolysates, Reviewed in
[19,25,26,34,35,37,40,43-45] and that cells infected with a nonlytic strain of
NDV will remain intact in the body long enough to generate these more
effective immune responses.[35] Reviewed in [33] It should be noted that the
cancer cells used in the third approach are treated with enough gamma radiation to prevent
further cell division, but not enough to cause cell death, either before or
after they are infected with the nonlytic virus.[43,44,46-52] Reviewed in [14]
This precaution ensures that patients are not given a vaccine that contains
actively proliferating cancer
cells.
Either a patient’s own cancer cells (i.e., autologous cells) or cells from another
patient with the same type of cancer (i.e., allogeneic cells) can be used to make
oncolysates and whole cell vaccines. It is important to note that immune
system responses similar to those obtained with oncolysates and whole cell
vaccines may occur in patients infected with a lytic strain of NDV and that
these responses would be expected to
contribute to any observed anticancer effect.
To conduct human studies with viruses, vaccines, or other biological materials in the United States, researchers must file an Investigational New
Drug (IND) application with the U.S. Food and Drug Administration (FDA).
Biological materials and drugs have been held to similar safety and
effectiveness standards since 1972. In an IND application, researchers must
provide safety and toxicity data from laboratory and animal studies to justify
the dose, the route, and the schedule of administration to be used in the
proposed clinical studies. Among the safety issues to be addressed,
researchers must demonstrate an absence of harmful contaminants. Most human
studies of NDV as an anticancer agent have taken place outside the United
States; therefore, they have not required an IND. At present, at least 1 group of U.S. investigators has filed an IND application to study NDV as an anticancer treatment.[53] It should be noted that the FDA has not approved the use of NDV to treat any medical condition.
The NDV strains that have been evaluated most widely for the treatment of
cancer are 73-T, MTH-68, and Ulster.[1,7,12,36,39,43,44,46-52,54-67] Reviewed in
[23,45,68] Strain 73-T is lytic, and Ulster is nonlytic. Strain MTH-68 has not
been classified, but it is assumed to be lytic.[1,7,60] Reviewed in [23,69,70]
All 3 strains have shown little or no evidence of neurotropism (i.e., an ability to
replicate efficiently in normal nerve cells or normal neural tissue).
In animal studies, NDV infection has been accomplished by intratumoral,[10,11,13,24,25] Reviewed
in [33] intraperitoneal,[24,25,71] Reviewed
in [33] intravenous,[33] intramuscular,[37] or subcutaneous [37] injection.
NDV-infected, whole cell vaccines have been given to animals by
intraperitoneal,[40] intradermal,[41] Reviewed in [33] or
subcutaneous injection, Reviewed in [33] or by a combination of subcutaneous
and intramuscular injection.[37,72]
In human studies, NDV oncolysates have been administered by subcutaneous
[12,36,39,54,57,59,61-64] or intradermal [56,58] injection. NDV-infected,
whole cell vaccines have been administered by intradermal injection
only.[43,44,46-52,65-67] In cases where patients have been infected with a
lytic strain of NDV, intratumoral,[21] intravenous,[1,53,60,73] or
intramuscular [55] injection has been used, as well as inhalation [1,7] and direct injection
into the colon (i.e., via a colostomy opening).[1] In some instances, cytokine treatment has been combined with
NDV therapy.[39,46,47,50,56,58,59,64]
Table 1. Strains of NDV Tested in
Human/Clinical Cancer Studiesa
NDV Strain
|
Strain Type
|
Formulation
|
Suggested Mechanism(s) of
Action
|
Reference
Citation(s)
|
73-T |
Lytic |
Infectious virus |
Cancer cells killed by virus; stimulation of immune system |
[21] |
73-T |
Lytic |
Oncolysate vaccineb |
Stimulation of immune system |
[12,36,39,54,57,59,61-64] |
Ulster |
Nonlytic |
Infected tumor-cell vaccine |
Stimulation of immune system |
[43,44,46-52,65-67] |
MTH-68 |
Lytic |
Infectious virus |
Cancer cells killed by virus; stimulation of immune
system |
[1,7,55,60] |
Italien |
Lytic |
Oncolysate vaccine/infectious virus |
Stimulation of immune system; cancer cells killed by
virus |
[56,58] |
Hickman |
Lytic |
Infectious virus |
Cancer cells killed by virus; stimulation of immune
system |
[73] |
PV701 |
Lytic |
Infectious virus |
Cancer cells killed by virus; stimulation of immune
system |
[53] |
aSee text for more details.
|
bOncolysates are prepared from virus-infected cancer cells; they consist
primarily of cell membrane fragments and contain virus proteins and cancer
cell proteins.
|
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