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The use of checkpoint inhibitors (e.g. pembrolizumab and ipilimumab) has been hailed as a major breakthrough in the treatment of cancer. Discuss why checkpoint inhibitors enhance anti-tumour responses and how they might be improved to be more efficacious £7.49
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The use of checkpoint inhibitors (e.g. pembrolizumab and ipilimumab) has been hailed as a major breakthrough in the treatment of cancer. Discuss why checkpoint inhibitors enhance anti-tumour responses and how they might be improved to be more efficacious
Immune checkpoint therapy is a new area of research which is ranked with surgery, chemotherapy radiation to improve survival rates against cancer. The immune checkpoint drug treatments specifically target the regulatory pathways within T cells to enhance anti-tumour responses, a shift from traditio...
The use of checkpoint inhibitors (e.g.
pembrolizumab and ipilimumab) has been
hailed as a major breakthrough in the
treatment of cancer. Discuss why checkpoint
inhibitors enhance anti-tumour responses
and how they might be improved to be more
efficacious with fewer side effects?
Word count: 1871
1
, Introduction
Immune checkpoint therapy is a new area of research which is ranked with surgery, chemotherapy
radiation to improve survival rates against cancer. The immune checkpoint drug treatments
specifically target the regulatory pathways within T cells to enhance anti-tumour responses, a shift
from traditional therapies. Over the years there have been many drugs approved for treatments of
different cancers, the first being ipilimumab for CTLA-4 blockade and nivolumab and pembrolizumab
for PD-1 blockade (Cancer research UK, 2021). However, there have been varying clinical responses
among a wide range of patients that have created barriers for enhancing clinical efficacy. Despite this
there have been remarkable improvements in patients’ overall survival time. Moreover, more ways
in which this therapy has been developed is through a combination of drugs, targeting other
checkpoints and treatments which control the tumour microenvironment (TME). Overall, this essay
will discuss the mechanisms by which immune checkpoint inhibitors act on T cells to enhance
antitumour responses. As well as this, it will discuss other therapies for more efficacious treatment
with a reduction of inducible adverse effects. Lastly, this essay will discuss the next steps needed to
improve this therapy.
The tumour microenvironment: Host immune responses
T cells need to be activated in a 2-signal process to mount an immune response. These T cells can be
T regulatory or effector CD4 cells or cytotoxic CD8 T cells. Firstly, when there is the presence of
foreign antigens, dendritic cells (DC) are activated by taking the antigen up through pathogen
recognition receptors. This stimulates the DCs migration and maturation. The T cell then binds to the
antigen presented to it by a professional DC on major histocompatibility complex 2. This does not
activate the T cell however and instead needs another signal to inform the T cell that this is a foreign
antigen and not a self-antigen. Therefore, a co-stimulatory receptor CD80/86 (B7) will bind to CD28
on the T cell causing activation and differentiation of tumour specific T cell. The DC can also release
cytokines such as IL-12 and IL-4 to enhance further differentiation of T cells (Figure 1).
In homeostatic conditions, as well as these activation receptors, there are also negative regulatory
receptors which are known as checkpoints expressed on T cells and other effector cells. These
checkpoints are vital for the prevention of autoimmune disease and promoting self-tolerance.
Furthermore, this means that the balancing and fine-tuning of immune mechanisms is crucial for an
effective response. These inhibitory pathways are manipulated by tumours as they upregulate B7
and the ligand PD-L1 which bind to inhibitory receptors CTLA-4 and PD-1 on activated T cells
respectively (Figure 1). To continue, immune checkpoint inhibitors (ICI) conducted through the
receptors CTLA-4 and PD-1 are blocked using monoclonal antibodies. This prevents
immunosuppression and reverses exhaustion in cytotoxic T cells restoring anti-tumour responses
(Rotte and Bhandaru,2016, p. 219). This treatment overall leads to durable clinical responses and
enhanced overall survival that can last for years and possibly decades.
2
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