Page 257 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

236 PART III Therapeutic Modalities for the Cancer Patient

Nonspecific Immune Activation to Generate mouse melanoma model, treatment with VNP20009, an attenu-
Antitumor Activity Using Biological Response ated Salmonella typhimurium, was able to slow tumor growth
and specifically target primary tumor and metastatic lesions.
133
VetBooks.ir Modifiers Although this study showed that the effects were independent of B
and T cells, possible indirect effects of the Salmonella include pro-
In the 1900s, William Coley observed that cancer patients who
developed bacterial infections survived longer than those who did duction of inflammatory cytokines, such as TNF-α. 134 Recently,
not (reviewed 119 ). Building on these observations, Coley devel- another proposed mechanism involves the ability of Salmonella
oped “Coley’s toxins” consisting of killed cultures of Streptococ- to induce melanoma cells to express gap junctions that can inter-
cus pyogenes and Serratia marcescens that he gave to patients with act with DCs and cause bits of tumor cell proteins to be loaded
inoperable sarcomas. Although with this “vaccine” Coley saw cure and expressed on the surface of these DCs for presentation to T
rates of approximately 15%, his therapy was discontinued because cells. 135 Unfortunately, in human trials, the bacteria failed to colo-
of its significant failure rate and intolerable side effects. However, nize some patients and did not provide any antitumor activity. 136
this seminal work laid the foundation for further studies aimed at Administration of VNP20009 in dogs resulted in a more
nonspecific, pan immune activation to treat cancer through the positive outcome than in humans. In a Phase I clinical trial,
use of biological response modifiers (BRMs). VNP20009 was administered to dogs with a variety of malignant
tumors. 137 In this study, 41 dogs received intravenous infusions
Bacillus of Calmette and Guerin and Corynebacterium of VNP20009 either weekly or biweekly at escalating doses. Fever
parvum and vomiting were reported as dose-limiting toxicities. Bacterial
One of the most well-known and clinically used BRM is bacil- colonization was seen in approximately 40% of dogs and signifi-
lus of Calmette and Guerin (BCG), a live, attenuated strain of cant clinical responses observed in 15% of patients, with an over-
Mycobacterium bovis. Currently, in human medicine, BCG is all rate of 37% of dogs experiencing either a transient response or
intravesically instilled into the bladder, where it is considered to stable disease. Thus the use of VNP20009 in specific dog tumors
be effective as a means to treat and prevent relapse of noninva- should be further investigated, perhaps in combination with mod-
sive transitional cell carcinoma. 120,121 One proposed mechanism ified Salmonella engineered to deliver tumor cytotoxic agents.
for its antitumor effects relates to the recruitment of neutrophils
and their ability to promote urothelial cell turnover. 122 This Liposome-Encapsulated Muramyl Tripeptide
recruitment most likely relates to the ability of BCG to elicit Th1 Bacterial cell components, such as peptides derived from mycobac-
inflammatory cytokines, 123,124 a cytokine profile associated with terial cell walls, were evaluated for potential immunogenicity. One
inducing cytolytic cells to kill the target tumor cells (compared such product is muramyl tripeptide-phosphatidylethanolamine
with a Th2-cytokine response, which is typically associated with (MTP-PE), an NOD2 receptor agonist, that when encapsulated
antiinflammatory immune responses). in a liposome (L-MTP-PE) can efficiently activate monocytes
BCG immunotherapy has been evaluated in dogs with can- and macrophages to produce proinflammatory cytokines, such as
cer, 125 but its clinical use as an immunotherapy in dogs is limited. IL-1α and -β, IL-6, IL-7, IL-8, IL-12 and TNF-α. 138 L-MTP-PE
Although BCG can be safely instilled into canine bladders, 126 the has been assessed in Phase I and II trials of people with osteosar-
rate of true superficial (as opposed to infiltrative) bladder can- coma (OSA), renal carcinoma, and metastatic melanoma. 138–140
cers is extremely low in dogs compared with humans. 127 Recent Moreover, this drug has been approved for use in treating pediatric
uses of BCG in dogs includes treatment of CTVT in conjunc- osteosarcoma in Europe under the name Mepact (mifamurtide). 141
tion with vincristine, 128 or in combination with human chorionic L-MTP-PE has been evaluated in veterinary medicine in a vari-
gonadotropin (LDI-100), to treat dogs with mast cell tumors. 129 ety of studies. 142–146 The survival benefit of L-MTP-PE therapy
In this study, response rates for grade I and II MCTs were com- has been most clearly demonstrated in dogs with appendicular
parable to those for single-agent vinblastine, but without the OSA. 147 In this study, dogs receiving L-MTP-PE after limb ampu-
myelosuppression. tation had a median survival time (MST) of 222 days whereas
Another BRM studied in human and veterinary medicine is dogs that received placebo had a MST of 77 days. However, as
Corynebacterium parvum. In human and dog melanoma stud- most of the dogs in both groups developed metastatic disease, fur-
ies, C. parvum displayed antitumor activity as an adjunct to ther studies evaluated the efficacy of L-MTP-PE in conjunction
surgery. 130,131 However, the efficacy of C. parvum as an immuno- with chemotherapy. 142 In this study, dogs receiving L-MTP-PE
therapy in other canine cancers has been disappointing. 132 after treatment with cisplatin had a MST of 14.4 months ver-
sus 9.8 months in dogs that received cisplatin only. Interestingly,
Immunotherapy with Live Attenuated Salmonella only 73% of dogs receiving L-MTP-PE developed metastatic dis-
As a tumor grows, the core may become necrotic as the initial ease compared with 93% in the cisplatin-only group. However,
tumor cells are deprived of nutrients. Layered upon the necrotic in a second trial, these investigators saw no significant survival
core are tumor cells that exist in an area of hypoxia—they are out advantage in dogs with OSA that received L-MTP-PE concur-
of reach of blood vessels that can supply them with oxygen. These rently with cisplatin.The authors postulated that cisplatin attenu-
cells remain viable and pose a challenge to most immunotherapies, ated antimetastatic potential of L-MTP-PE because of impaired
chemotherapies, and even small-molecule drugs because of their immune effectors. L-MTP-PE was also evaluated for efficacy in
restricted location. Recently researchers have begun to genetically canine hemangiosarcoma (HSA). 144 Dogs that received L-MTP-
modify facultative anaerobic bacteria that can penetrate and sur- PE with chemotherapy after splenectomy had a MST of 9 months
vive in these regions. In fact, it has been shown that several strains versus 5.7 months seen with dogs receiving chemotherapy alone.
of Salmonella, including S. typhimurium and S. choleraesuius, tar- In another study only dogs with stage I oral melanoma that
get tumors after systemic administration. These bacteria penetrate received L-MTP-PE had an increased survival over placebo-
the necrotic core and feed on the dead cells while also emitting treated dogs. 145 No differences were observed in dogs with more
natural toxins that will destroy surrounding, viable cells. Using a advanced disease.