Laboratory/Animal/Preclinical Studies
Effects of Newcastle Disease Virus on Human Cancer Cells
NDV and Cancer Immunotherapy
Effects of Newcastle Disease Virus on Human Cancer Cells
The ability of Newcastle disease virus (NDV) to replicate efficiently in human cancer cells has been
demonstrated in both laboratory studies and animal
studies.[1-12] Reviewed in [13,14] Several of these studies
have provided much of the evidence that lytic strains of NDV are also
oncolytic.[3-6,8-10,12] Reviewed in [13]
Strain 73-T, which is lytic, has been shown to kill the following types of
human cancer cells in vitro : fibrosarcoma, osteosarcoma, neuroblastoma, bladder carcinoma, cervical carcinoma, melanoma, Wilms tumor, and myeloid leukemia;[3,6,8,9] however,
this strain did not kill human B-cell lymphoma (i.e., Burkitt lymphoma) cells in
vitro.[8] In addition, strain 73-T did not kill normal, proliferating human white blood cells or normal human skin fibroblasts in vitro,[3,6,8] but it
killed normal human lung fibroblasts in vitro at the same rate that it killed
cancer cells.[8]
Lytic strain Roakin has been reported to kill human B-cell lymphoma and
human T-cell lymphoma (i.e., Hodgkin lymphoma) cells in
vitro four to five times faster than it kills normal, resting human white blood cells.[4,5]
This strain, however, has also been reported to kill normal, proliferating
human white blood cells in vitro, though at a lower rate than it kills cancer cells.[4]
Lytic strain Italien (or Italian) has been shown to kill human squamous cell lung carcinoma,
melanoma, breast carcinoma, and larynx carcinoma, but not cervical carcinoma, cells in vitro.[12] The replication
efficiency of this strain in normal human cells was not tested.
Overall, these results show that there are some types of human cancer cells
in which individual lytic strains of NDV do not replicate very well and that
there are some types of normal human cells in which they replicate very
efficiently. Nonetheless, these data and the absence of serious illness in
individuals infected with NDV Reviewed in [1-3,10,13,15-21] are consistent with
the view that NDV replicates much more efficiently in human cancer cells than
it does in most types of normal human cells.
NDV strain Ulster, which is nonlytic, has also been shown to replicate
efficiently in human cancer cells in vitro, including cells of the following
types of human tumors: colorectal carcinoma, gastric carcinoma, pancreatic carcinoma, bladder carcinoma,
breast carcinoma, ovarian carcinoma, renal cell carcinoma, lung
carcinoma, larynx carcinoma, cervical carcinoma, glioblastoma, melanoma, B-cell
lymphoma, and T-cell lymphoma.[7] This strain does not replicate very
efficiently in resting or proliferating normal human white blood cells in
vitro.[7] Other experiments have shown that NDV Ulster can kill infected
cells,[22] Reviewed in [14] and it can replicate in human cancer cells
whether they are actively proliferating or not.[7] Reviewed in [20]
The ability of lytic strains of NDV to kill human cancer cells in vivo has also been examined. In xenograft studies, human cancer cells
were injected either subcutaneously or intradermally into athymic, nude mice (i.e., mice
that do not reject tumor cells from other animals because they have a
defective immune system), and tumors were allowed to form. NDV was
injected directly into the tumors, and tumor growth and animal survival were
monitored.
Intratumoral injection of strain 73-T was associated with complete tumor regression in 75% to 100% of mice bearing human fibrosarcoma, neuroblastoma,
or cervical carcinoma tumors.[1-3,10] Intratumoral injection of 73-T was
also associated with more than 80% tumor regression in 66% of mice bearing
human synovial sarcoma tumors.[2] In addition, intratumoral injection of 73-T was associated with
68% to 96% inhibition of tumor growth in mice bearing human epidermoid, colon, lung,
breast, or prostate carcinoma tumors.[10]
Intratumoral injection of strain Italien was associated with complete tumor
regression in 100% of mice bearing human melanoma tumors. The growth of metastatic tumors in these animals,
however, was not affected, suggesting that the virus was unable to disseminate
widely throughout the body.[11] Reviewed in [14,20]
Replication of strain 73-T in the above-mentioned neuroblastoma xenografts
was demonstrated by showing an increase in the amount of virus that could be
recovered from tumor samples over time.[1] When this strain was
injected into the thigh muscle of athymic, nude mice, the amount of virus that
could be recovered decreased with time,[1] a finding consistent with the
proposal that NDV replicates much more efficiently in cancer cells than in
most normal cells.
In one study, mice bearing human neuroblastoma xenografts were given single
intraperitoneal injections of strain 73-T, and 9 (75%) of 12 treated mice
exhibited complete, durable tumor regressions.[10]
It is important to note that athymic, nude mice still make small numbers of T cells, and they produce interferons, natural killer cells, and macrophages. Reviewed in [11,23,24] The
possibility that these residual components of the immune system, which may be
activated by the presence of NDV, contributed to the antitumor effects
observed in the xenograft studies cannot be ruled out.
NDV and Cancer Immunotherapy
Other laboratory and animal studies have shown that NDV and NDV-infected
cancer cells can stimulate a variety of immune system responses that are
essential to the successful immunotherapy of
cancer.[6,8,22,25-37] Reviewed in
[11,20,38-42] A few of these studies used human cells,[6,8,26,27,35]
Reviewed in [20,39,42] but most used animal cells and animal
tumor models.[6,8,22,25,27-34,36] Reviewed in
[11,20,38-41]
Data from a 2004 pilot clinical trial of an NDV-modified autologous tumor vaccine in 20 patients with stage III or IV head and neck squamous cell carcinomas suggest that the vaccine strategy can stimulate human antitumor immune responses in a manner similar to those found in animal models and may significantly prolong 5-year survival rates in this patient population. The study demonstrated the feasibility and safety of the vaccine regimen: no major side effects were observed in any of the patients.[43]
Two in vitro studies have shown that infection of human immune system cells
with NDV causes the cells to produce and release the cytokines interferon-alpha and tumor necrosis factor (TNF)-alpha.[6,8] In one of these studies,[6] it was
shown further that infection of human cancer cells with NDV makes the cells
more sensitive to the cytotoxic effects of TNF-alpha.
Additional in vitro studies have shown that NDV-infected human cancer cells
are better at activating human cytotoxic T cells, helper T cells, and natural killer
cells than uninfected cancer cells.[8,26,27] The NDV protein hemagglutinin-neuraminidase, which is present in the plasma membrane of
virus-infected cells, appears to play a role in the enhancement of
T cell activation. There is evidence that this protein makes infected cells
more adhesive, thereby promoting the interaction between
virus-infected cells and immune system cells.[27] Reviewed in [20]
Other laboratory studies have shown that the interaction between
NDV-infected cancer cells and T cells can be improved if monoclonal antibodies that
bind the hemagglutinin-neuraminidase protein on the cancer cells and either
the CD3 protein or the CD28 protein on T cells (i.e., bispecific monoclonal
antibodies) are also used.[26,35] Reviewed in [20,39,42] It has been
reported that this improved interaction leads to better T cell
activation.[26,35] Reviewed in [20,39,42] T cells exposed to
NDV-infected human colon cancer cells and bispecific monoclonal antibodies
showed not only an increased ability to kill the virus-infected cells but also
an ability to inhibit the proliferation of uninfected colon cancer
cells.[26,35] Reviewed in [20] On the basis of these and other in vitro
findings, it has been proposed that vaccines consisting of NDV-infected cancer
cells and bispecific monoclonal antibodies be tested in
humans.[20,26,35,39,42]
As noted above, animal cells and animal tumor models have also been used to
explore the immunotherapy potential of NDV. ESb, a mouse model of metastatic
T-cell lymphoma has been employed in most of this
work;[22,25,28,32-34,36,37] Reviewed in [11,20,38-42] however,
additional experiments have utilized one or more of the following
tumor models: mouse B16 melanoma,[30] mouse Lewis lung carcinoma,[29,32] mouse
P815 mastocytoma,[32] mouse Ca
761-P93 mammary carcinoma,[32] and
guinea pig L10
hepatocellular carcinoma.[31]
In one study,[32] it was shown that anticancer activity could be induced in
mouse macrophages both in vitro and in vivo by infection with NDV strain
Ulster. Similar activation of mouse macrophages in vitro was observed after
infection with the NDV lytic strain Lasota. In this study, the activated
macrophages showed cytotoxic activity toward ESb, P815 mastocytoma, and Ca
761-P93 mammary carcinoma cells in vitro. Other experiments demonstrated
that much of the observed anticancer activity could be attributed to the
production and release of TNF-alpha by the infected macrophages. In addition,
the infected, activated macrophages showed anticancer activity in vivo when
they were injected into mice bearing Ca 761-P93 mammary carcinoma or Lewis
lung carcinoma tumors.[32]
In another study, Reviewed in [11] intratumoral injection of NDV strain
Ulster into growing ESb tumors in immunocompetent mice led to a
cessation of tumor growth and an absence of metastases in 42% of treated animals. In
the remaining mice, tumor growth and metastatic spread continued at the same
rate as in control animals. Reviewed in [11]
Additional results from this study indicated that the anticancer effect in the
responding animals was due primarily to the activation of T cells directed
against a tumor-specific antigen on ESb cells rather than a virus
antigen. Reviewed in [11]
Other studies with NDV Ulster and the ESb tumor model support the idea that
virus proteins inserted in the plasma membrane of NDV-infected cancer cells
may help the immune system recognize tumor-specific antigens better,
potentially leading to an increased ability to kill uninfected cancer cells and virus-infected cells.[22,25,28,33,34,36] Reviewed in [11,20,38,40,41]
At least four studies [22,25,34,36] Reviewed in [40,41] have shown that T cells
isolated from mice that have growing ESb tumors can be activated in vitro by co-culture with NDV-infected ESb
cells and that the resulting activated T cells possess an enhanced ability to
kill uninfected ESb cells in vitro. In addition, two in vivo studies [28]
Reviewed in [11] have shown that mice injected with NDV-infected, irradiated ESb cells are 30 to 250 times
more resistant to later injection with proliferating ESb cells than mice that
are initially injected with uninfected, irradiated ESb cells. Furthermore, at
least two in vivo studies have demonstrated that vaccination of mice with NDV-infected,
irradiated ESb cells after surgery to remove a growing ESb primary tumor can prevent the growth
of metastatic tumors in approximately 50% of treated animals.[28,33] Reviewed
in [11,38,40,41] When the surviving mice were subsequently injected with
proliferating ESb cells, they all remained free of cancer, indicating that the
NDV/tumor cell vaccine had conferred anticancer immunity.[28,33] Reviewed in
[11,40,41] Similar results were obtained from in vivo studies that employed the
mouse B16 melanoma model,[30] the mouse Lewis lung carcinoma model,[29] or the
guinea pig L10 hepatocellular carcinoma model.[31]
One factor that may influence the effectiveness of NDV/tumor cell vaccines
is overall tumor burden. Results
obtained with the B16 mouse melanoma model suggest that these vaccines are
less effective in individuals with advanced metastatic disease.[30]
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