5.2: Immunotherapy limitations: anti-PD1 and study models

Class of HMB422 2020; Dr. William Ju

56 5.2: Immunotherapy limitations: anti-PD1 and study models

Linking PD1 and LIF

Tumours with high levels of LIF are typically also associated with the infiltration of tumour-associated macrophages (TAMs) (Pascual-García et al.). LIF blockades remove the epigenetic silencing of CXCL9 within TAMs to allow for the attraction of cytotoxic T cells within the tumour microenvironment (Pascual-García et al.). Now that there is the allowance of CD8+ T cells, an antitumor immune response can be coordinated. Complimentary to this, the addition of PD1 blockades works in tandem to LIF blockades to promote immunological memory and increased survival rates through inducing increased tumour cell death and decreasing pro-tumoral TAMs (Pascual-García et al.). With this being said, there are limitations to using these blockades in cancer therapy. We will address these limitations below.

PD1 blockade limitations

Patients utilizing anti-PD-1/PD-L1 therapy may not always come out with beneficial results as an outcome of acquiring resistance to this treatment (Song et al. 157-172). There are 3 main proposed mechanisms used to explain this resistance:

1) T cell exhaustion. A threshold for PD-1 expression has been identified within resistant tumours that are also anti-PD-1 sensitive. PD-1 expression above the threshold within T cells can lead to extreme T cell exhaustion not able to be saved by anti-PD-1 therapy.
2) An insufficient amount of pre-existing T cells or not enough T cell recruitment towards the tumour.
3) Within the tumour microenvironment, other accumulated suppressive factors may have prevented the full efficacy of anti-PD-1. These can include Tregs, TAMs, cytokines, immature dendritic cells, and vascular endothelial growth factor-A. Additionally, tumor intrinsic factors reduced the potential of anti-PD-1/PD-L1. These included the upregulation of tumour-suppressive metabolites, tumour immunogenicity, and PD-L1 and MHC-1 expression.

Study model limitations when incorporating LIF blockades

The introduction of LIF blockades have effectively shown to regulate CD8+ T cell recruitment and aid as a novel therapeutic cancer target. Pascual-García et al. conducted a study treating NOD SCID gamma (NSG) mice (an immunodeficient animal model) with neutralizing LIF antibodies following a tumour fragment and peripheral blood mononuclear cell (PBMC) inoculation from patients with high LIF expression. This study was conducted within an in vivo mouse model and therefore only a short-term assessment of T cell infiltration was able to be made without resulting in graft-versus-host disease.

Definition

Graft-versus-host disease (GvHD): A disease in which the graft from a donor (the T cells) views the host’s cells as foreign and proceeds to attack the tissue. This disease can be life-threatening and even fatal.

- Acute GvHD (aGvHD) is defined to occur within 100 days following the transplant.
- Chronic GvHD (cGvHD) is defined as occurring after the first 100-day period.

More about GvHD: Its importance and what it looks like in patients

NSG humanized mice are highly standardized and characterized for allowing successful PBMC transplantations to study cancer and associated aspects of health and disease (Schroeder and DiPersio 318-333). In just 20 days the onset of aGvHD can occur within these mice preventing long-term survival analyses to be done.

GvHD prevention

By taking approaches to prevent GvHD, the implications of LIF treatments in immunotherapy can be enhanced. Three main targets for the prevention of GvHD are IL-17A (a pro-inflammatory cytokine), CSF-1 (a colony-stimulating factor), and JAKs (cytoplasmic tyrosine kinases) (MacDonald et al. 19-26). The factor that has shown promising effects within NSG mice is the use of JAK2 in synergistic combination with Aurora kinase A (Betts et al.). To prevent GvHD and preserve the anti-tumour response of T cells, a specific mechanism of action must occur. This includes the inhibition of both JAK2 and Aurora kinase A, followed by the attenuation of CD28 co-stimulation and subsequent attenuation of Il-6 mediated signal transduction (Betts et al.). This strategy may be used within future studies to prevent the rapid onset of GvHD within in vivo mouse models for long term testing purposes.

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