Page 252 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

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Cancer Immunotherapy

STEVEN DOW AND AMANDA GUTH

The main role of the immune system is recognition of “foreign” chapter will first discuss the role of the immune system in regu-
proteins. In the case of cancer, this role includes immune rec- lating tumor development, then the various classes of immuno-
ognition of mutated or altered forms of self-proteins that arise therapies both currently in use and those under investigation. The
during tumorigenesis (commonly referred to as “tumor antigens” biological basis for the therapies, their use in human and compan-
[TAs]). However, it is now apparent that powerful regulatory cells ion animals, and their successes and limitations will be discussed.
and expression of certain molecules whose main functions are to
prevent rampant, uncontrolled immune responses can also serve
to block natural development of effective antitumor immune Immune System Control of Tumor
response. Therefore immunotherapy approaches in treatment of
various cancers must take into account the ability to overcome Development and Growth
these negative regulators of tumor immunity to be successful. Immune Surveillance of Cancer
Under appropriate conditions, the immune system is capable
of controlling cancer. For example, it is well established that the Forty years ago, Thomas and Burnet, while studying how lym-
incidence of virally induced cancers is increased in immunosup- phocytes could respond to newly formed antigens on trans-
pressed individuals. Further, cancer incidence increases in aged formed cells, put forth the concept that the immune system could
individuals and correlates with the progression of immunese- actively respond to and eliminate neoplastic cells, an idea known
6
nescence (aging and exhaustion of the immune response) that is as immune surveillance. In contrast, later studies showed that
thought to reduce immunosurveillance of cancer, a topic discussed genetically manipulated immunodeficient (athymic) mice did not
in the text that follows. Moreover, in some cases, spontaneous demonstrate an increased incidence of spontaneously or carcinogen-
remission of tumors is observed without any therapeutic interven- induced cancer. Such observations led to the immune surveil-
7,8
tion, most likely attributed to a successful immune response. Bio- lance concept falling out of favor.
logically, tumor-specific T cells are observed in the tumor tissue Since the development of more sensitive and sophisticated
and tumor-draining lymph nodes, providing evidence that these technologies, many of the ideas behind the concept of the immune
cells have encountered and recognized the tumor cells as foreign. surveillance hypothesis are now again accepted, and currently, this
Finally, in some cases, paraneoplastic autoimmunity develops, modification of the original hypothesis is referred to as the immu-
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suggesting that the antitumor immune response has somehow noediting hypothesis, which consists of three phases: (1) “elimina-
gone unchecked by regulatory cells. tion”—removal of the immunogenic tumor cells by the immune
Recently the field of immunotherapy took an exciting twist system; however, less immunogenic cells can survive; (2) “equilib-
with the development in human medicine of therapeutic anti- rium”—tumor growth and immune destruction are equal; and (3)
bodies designed to target immune suppressive molecules (check- “escape”—tumor growth ensues due to decreased immunogenic-
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point molecules) and/or their ligands expressed on T cells and ity, immune suppression, and rapid tumor cell growth. However,
antigen-presenting cells, such as programmed death molecule-1 despite recent data, a controversy still remains around the immune
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(PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4). By surveillance hypothesis, discussed in a review by Schreiber et al.
using antibodies to block negative signaling by certain checkpoint
molecules such as PD-1 and CTLA-4, remarkable, and durable, Mechanisms of Immune Evasion by Tumors
antitumor responses have been observed in a significant, but
minority, subset of patients with advanced tumors such as mela- Given the fact that cancer can develop in immunocompetent indi-
noma, renal cell carcinoma, and non–small cell lung cancer. 1–5 viduals, clearly tumor cells are able to avoid recognition by the
The development of checkpoint targeted immunotherapies has immune system. This is accomplished by various mechanisms
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reignited the field of immunotherapy for cancer, and similar anti- discussed in the text that follows, which involve both changes in
bodies for treatment of cancer in dogs are under development by the tumor cells themselves and ways in which the tumor and the
several different groups, including ours. tumor stromal environment can manipulate the immune system
Improving knowledge of the immune system and how it is reg- and prevent antitumor immunity. These mechanisms of immune
ulated will increase our ability to design better immunotherapies. evasion pose a significant challenge to the development of effec-
In addition, immunotherapy has the potential to work in con- tive immunotherapies. Fig. 14.1 demonstrates some of these key
junction with chemotherapies, radiation therapy, and surgery. This mechanisms.

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