Page 253 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

232 PART III Therapeutic Modalities for the Cancer Patient

Tcells
VetBooks.ir iDCS Cysteine Treg

deprivation
arginase
iNos arginase
ROS TGF-β
IL-10

MDSC TGF-β
TGF-β
NK TGF-β R
IDO
CSF1 IL-10
CCL2 IL-8
DC

decr IL-12
PD1 PDL1 Tumor
Tcells
TAM
hypoxia

decr IL-12

TNFα IL-10 TGF-β
• Fig. 14.1 Mechanisms of tumor cell evasion via hijacking the immune system. DC, Dendritic cell; iDC,
immature dendritic cell; MDSC, myeloid-derived suppressor cell; TAM, tumor-associated macrophage;
Treg, regulatory T-cell.

Failure of Tumor Cells to Activate the Immune System We also demonstrated that PD-L1 is regulated by T cell cytokines
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One of the most exciting achievements in human cancer therapy in dogs. Several new monoclonal antibody therapeutics targeting
and immunotherapy has been development of monoclonal anti- checkpoint molecules have been approved, including Yervoy (Ipi-
bodies (mAbs) that either block or activate signaling through limumab) targeting CTLA-4 and Keytruda (pembrolizumab) and
so-called checkpoint molecules. 11–14 Checkpoint molecules are Opdivo (nivolumab) targeting PD-1, for treatment of four differ-
expressed primarily by T cells, and are divided into two classes, ent cancers (melanoma, head and neck cancer, bladder cancer, and
including those that negatively regulate T cells (coinhibitory check- Hodgkin lymphoma). In addition, pembrolizumab has recently
point molecules) and those that stimulate T cells (costimulatory received expanded approval for treatment of any cancer with high
checkpoint molecules). At present, there are at least 16 identified levels of microsatellite instability, which is associated with genera-
checkpoint molecules, which include eight coinhibitory receptors tion of neoantigens recognized by tumor-infiltrating T cells. An
(PD-1, CTLA-4, TIM-3, VISTA, BTLA, B7-H3, B7-H4, and antibody therapeutic targeting PD-L1 (Tecentriq, atezolizumab)
LAG3) and eight costimulatory receptors (CD28, OX40, GITR, was also recently approved in humans. Responses in patients with
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ICOS, CD137, CD27, CD40L, and CD122). All of these mol- advanced, heavily pretreated tumors to checkpoint targeted thera-
ecules are potential targets for tumor immunotherapy using anti- pies are reported in approximately 20% of patients, and many of
bodies that either activate (costimulatory checkpoint molecules) or these responses are durable and in some cases complete. 25
inhibit (coinhibitory molecules) signaling. These checkpoint mol- Currently, similar therapies are not yet available for veterinary
ecules have been evaluated as targets for tumor immunotherapy in patients. Due to target–antigen specificity, the Food and Drug
rodent models, and most have also been evaluated in human clini- Administration (FDA)-approved antibodies do not cross-react
cal trials. 1–5 At present, PD-1 (and its ligand PD-L1) and CTLA-4 with canine antigens and the constant domain portion of the anti-
antibodies have been approved for treatment of cancer in humans. bodies is specific for humans (aka humanized antibodies). How-
Of the costimulatory checkpoint molecule targeted therapeutics, ever, there is growing interest in developing similar antibodies in
antibodies targeting OX40 and GITR are the most promising and a canonized form for use in veterinary medicine. For example, we
furthest advanced in human trials. 16–18 reported recently the target specificity and functional properties of
In particular, the PD-1/PD-L1 axis has been targeted to reverse canine specific PD-1 targeted antibodies. In addition, a clinical
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immunosuppression in cancer. 11,12,19,20 PD-1 and CTLA-4 are trial evaluating a canine version of this antibody is currently in
expressed primarily on T cells and NK cells, whereas PD-L1 is progress in dogs with cancer. Results of the first trial of a canine
expressed by myeloid cells (monocytes, macrophages, and den- chimeric antibody targeting canine PD-L1 were also reported
dritic cells) and by certain tumor cells. 21–23 We and others have recently. Development of checkpoint molecule targeted thera-
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reported recently that some tumors in dogs express PD-L1, and pies for dogs is likely to continue rapidly and to eventually exert a
we have also shown that macrophages in dogs express PD-L1. tremendous effect on veterinary oncology.
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