Progress in Adaptive Immunotherapy for Cancer in Companion Animals: Success on the Path to a Cure

Abstract

Harnessing the ability of the immune system to eradicate cancer has been a long-held goal of oncology. Work from the last two decades has finally brought immunotherapy into the forefront for cancer treatment, with demonstrable clinical success for aggressive tumors where other therapies had failed. In this review, we will discuss a range of therapies that are in different stages of clinical or preclinical development for companion animals with cancer, and which share the common objective of eliciting adaptive, anti-tumor immune responses. Even though challenges remain, manipulating the immune system holds significant promise to create durable responses and improve outcomes in companion animals with cancer. Furthermore, what we learn from this process will inform and accelerate development of comparable therapies for human cancer patients.

Keywords: Fas ligand; T-lymphocytes; adaptive immunity; antibodies; immunization; virotherapy.

Figure 1

Mechanisms of targeting tumors using monoclonal antibodies (A) The first class of mAbs binds directly to tumor cells and induces apoptosis or antagonizes oncogenic pathways. The Fc region of the mAb may also induce antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) or phagocytosis of the tumor cell. (B) The second class of mAbs blocks growth promoting pathways in the stroma. In the example shown here, an anti-VEGF mAb acts to prevent angiogenesis. (C) The third class of mAbs, immune checkpoint inhibitors, blocks the interaction of inhibitory receptors expressed on activated T cells (CTLA-4, PD-1) with ligands on antigen presenting cells (B7, PD-L1) or tumor cells (PD-L1 or PD-L2). This therapy prevents the attenuation of the T cell response and allows activated T cells to kill tumor cells.

Figure 2

AdFasL induces an anti-tumor inflammatory response in the tumor microenvironment. Interaction with FasL+ tumor cells causes macrophages to undergo apoptosis and release inflammatory cytokines and neutrophil chemoattractants. The infiltrating neutrophils are responsible for localized tumor cell destruction and the release of tumor associated antigens (TAA). These antigens are cross-presented to cytolytic CD8 T cells, which locate and destroy tumor cells at distant metastatic sites and provide protection from further challenge via immunologic memory. In addition, cytokines released by macrophages drive the differentiation of pro-inflammatory Th17 T cells [50] and induce apoptosis of anti-inflammatory T regulatory cells.

Figure 3

Vaccination strategies and challenges. Vaccines utilize a variety of strategies to activate the immune system against tumor associated antigens (TAAs), including tumor cell lysates or peptide antigens, dendritic cells (DCs) activated with TAAs, and DNA plasmids designed to produce TAAs. The TAAs must then be presented by functional antigen presenting cells to T cells capable of recognizing the TAA. Once activated, T cells must traffic to the tumor and induce tumor cell death. T cell tolerance to TAAs, dysfunctional antigen presentation, T-cell exhaustion induced by checkpoint inhibitors (such as PD-1), and immunosuppressive cells in the tumor microenvironment may all result in suppression of the immune response and variable patient responses to vaccination.

Figure 4

Approaches to adoptive T cell therapy. In the top scheme, a resected tumor sample is digested into a single cell suspension and cultured in the presence of IL-2 to select for naturally occurring tumor-infiltrating lymphocytes (TILs). The TILs are then expanded, tested for anti-tumor activity, and reinfused into the patient. In the bottom scheme, autologous T cells are harvested from the blood and either a transgenic T cell receptor (TCR) or a chimeric antigen receptor (CAR) is introduced by viral or non-viral transduction. TCRs are capable of recognizing a specific tumor antigen presented in the context of an MHC molecule. CARs are MHC-independent and capable of directly recognizing an antigen on the tumor cell surface. Following transduction, the transgenic T cells are expanded and reinfused.