Page 286 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 15 Molecular/Targeted Therapy of Cancer 265

myeloma. 244 Thalidomide has been evaluated in veterinary oncol- occurs during treatment with metronomic cyclophosphamide and
ogy for treatment of canine hemangiosarcoma (HSA) and other possibly other chemotherapy agents. 253,254 The resulting angio-
genic suppression may be complemented by decreased tumor
tumors as a single agent and in combination with chemotherapy,
VetBooks.ir including metronomic chemotherapy protocols. 245,246 Targeting cell production of proangiogenic growth factors such as VEGF,
through reduced tumor cell mass.
angiogenesis in combination with chemotherapy has been con-
sidered a useful strategy, 204 particularly as drug delivery may be Other components of angiogenesis may also be targeted by
enhanced through a “normalized” vasculature. 210 Many reported metronomic delivery of chemotherapy. Mechanistically, tumor
early clinical trials utilize a cocktail of multiple drugs, such as angiogenesis involves recruitment of CEPs. 195 These CEP cells
COX inhibitor, kinase inhibitor, thalidomide, and/or chemother- may be most influential in rebuilding tumor vessels during the
apy agent(s). Multiple drug trial design may increase the chances break period after the acute damage of MTD chemotherapy expo-
of documenting anticancer activity, but is challenging to decipher sure. 255 Preclinical models have demonstrated that CEPs acutely
the relative contributions of a particular agent to the outcome of decrease with MTD treatment, only to rapidly rebound during
the treatment protocol. the break period (similar to other bone marrow-derived cells),
when they may contribute to EC repopulation. 256 In contrast,
Metronomic Chemotherapy metronomic chemotherapy delivery does not appear to be associ-
ated with a CEP surge, leading instead to a sustained antiangio-
Ideal anticancer therapies would be highly efficacious, widely genic effect. 256–258
available at low cost, and associated with a low risk of causing
adverse events. Keeping this in mind, along with the statement Immunomodulatory Effects
of Fidler and Ellis that “Cancer is a chronic disease and should The ability of tumors to grow undetected by the host immune
be treated like other chronic diseases,” one path taken toward the system is a well-recognized feature of malignancy. Through the
identification of optimal therapies has been the exploration of dynamic process of immunoediting the phenotype of neoplastic
metronomic drug delivery. 247 Characterized by chronic adminis- cells evolves to escape immune detection. Two major immune
tration of chemotherapeutic agents at low doses, metronomic che- cells, regulatory T lymphocytes (Treg), and myeloid-derived sup-
motherapy (or low-dose continuous chemotherapy) is being used pressor cells (MDSCs), are key players in this process. Although
with increasing understanding and frequency in the treatment of they limit pathologic inflammation under normal condi-
humans and companion animals with cancer. tions, Treg and MDSC efficiently suppress antitumor immune
The term metronomic chemotherapy (MC) was originally responses in cancer patients. 259–261 Treg are particularly adept at
introduced by Hanahan and colleagues in 2000 to describe the inhibiting effector (cytotoxic) T cells through direct cell-to cell
concept that the continuous administration of certain cytotoxic contact and secretion of immunosuppressive cytokines such as
drugs targeted tumor ECs, impairing their ability to repair and TGF-β and IL-10. MDSC and other immune cells such as poorly
recover as long as no extended drug-free gaps were allowed. 248 functional dendritic cells and inhibitory macrophages also help
Although a number of cytotoxic chemotherapy agents achieve establish tumor tolerance and an immunosuppressive tumor
at least a portion of their therapeutic efficacy through inhibi- microenvironment.
tion of tumor angiogenesis, their delivery at the MTD in con- Although it may seem counterintuitive, a number of che-
ventional chemotherapy protocols necessitates a break period to motherapeutic agents display both immunostimulatory and
permit recovery of normal cell populations. 249,250 When many immunosuppressive effects, a difference that sometimes depends
of the same drugs are instead delivered in a metronomic fashion, only on the dose and schedule of drug administration. One of
the therapeutic target shifts from the rapidly dividing tumor cell the best examples of this concept is illustrated by the alkylating
population to the more slowly proliferating tumor endothelium. agent cyclophosphamide (CYC). Whereas high doses have long
Although this approach was initially designed to overcome the been used as a myeloablative preconditioning therapy for proce-
development of chemotherapeutic drug resistance via inhibition dures such as bone marrow transplantation, metronomic delivery
of tumor angiogenesis, additional mechanisms of action have of CYC is associated with multiple immunostimulatory effects
since been uncovered. These include activation of antitumor including decreases in the number and function of Treg, den-
immunity, induction of tumor dormancy, and inhibition of can- dritic cell activation, and stimulation of tumor-specific cytotoxic
cer stem cells. Compared with typical MTD treatment regimens, T cells. 262
the low toxicity profile, ease of administration for orally deliv- The clinical effect of metronomic CYC chemotherapy on
ered drugs, and decreased cost make MC protocols particularly the host immune system was first demonstrated in a key study
appealing in veterinary oncology. However, mechanistic and by Ghiringhelli in which human patients with advanced can-
clinical evaluation in veterinary patients is still at a relatively early cer experienced a selective decrease in circulating Treg numbers
stage. with marked restoration of T effector cell proliferation and NK
cell function. 263 Numerous additional studies have since uncov-
Mechanisms of Action ered direct and specific inhibitory effects of low-dose CYC on
Treg function, often with corresponding increases in effector
Tumor Angiogenesis T-cell function and decreased expression of immunosuppressive
When different types of cells in culture were exposed to continu- cytokines. 262,264 Worth noting, however, are results of studies in
ous ultralow doses of chemotherapy, proliferating EC populations mouse tumor models and in human cancer patients documenting
displayed an exquisite sensitivity compared with other cell types, stimulation of MDSC recruitment and rebounding tumor growth
including tumor cells in many instances. 251,252 Although the rea- during administration of metronomic CYC. 265–267
sons for EC selectivity are not entirely clear, the explanation likely Immunomodulatory effects of CYC have also been reported
goes beyond mere targeting of rapidly dividing cells. Experimen- in dogs with spontaneous cancer. Metronomic administration
tal evidence has suggested that upregulation of thrombospondin-1 of CYC, for example, appears to be immunostimulatory based