Immune Checkpoint Therapy - Rearming Our Body Against Cancer
The coveted Nobel Prize in Physiology or Medicine was bagged by James P. Allison and Tasuku Honjo for their discovery of ‘Cancer Therapy by Inhibition of Negative Immune Regulation’. Sounds mighty complicated right? Let's try and break it down into simple pieces and understand what a profound impact this discovery shall have on Cancer Treatment and Research in the years to come.
Cancer is characterised by uncontrolled cellular proliferation followed by unchecked migration (metastasis) to various sites in the body. The Global Cancer Observatory has estimated that 18 million people in the world have been diagnosed with cancer in 2018. A novel way of combating cancer is to stimulate our own immune system to destroy the mutated cells. There have been incidents of cancer remission following an attack of infectious disease which suggested that the infection might have activated the immune system and helped destroy the cancer cells. This is based on the ability of the immune system to recognise ‘self’ from ‘non-self’.
The goal is to unleash the inherent power of the human body to defeat a ‘mammoth’ that threatens the medical community today.
So how exactly did Allison and Honjo rewire the immune system to work for our bodies? In order to understand, let’s first under the normal immune response of the body.
T cells which provide cell mediated immunity possess 2 receptors called CD28 and CTLA-4. These bind to CD80 on antigen presenting cells. CD28 acts as a co- stimulator for the T cells whereas, CTLA-4 acts as an inhibitor. Both CD28 and CTLA-4 belong to the immunoglobulin superfamily.
CTLA-4 resides intracellularly and rapidly translocates to the cell membrane after activation. It binds to CD80 on antigen presenting cells with greater affinity than CD28 and leads to negative regulation of T cells. Simply put, CD28 causes the T cell to work harder and be more aggressive whereas CTLA-4 makes the T cell moot.
James P. Allison used this knowledge to inhibit the activity of CTLA-4 by binding it with monoclonal antibodies to in turn stimulate T cells to attack the cancer cells. It showed promising results in animal experiments. A drug was developed based on this discovery that was administered to Melanoma patients as part of a clinical trial. The drug called ‘MDX-010’ when given to these patients caused complete tumour regression and increased long term survival, something which had not been seen before. However, every treatment comes with its burden of side-effects. The pitfall of a powerful immune response (as in this case) can lead to the development of several autoimmune diseases. This was observed in some of the 9 clinical trial patients suffering from melanoma.
Tasuku Honjo on the other hand discovered the PD-1/PD-L1 pathway which behaves similarly as the CTLA-4/CD80 pathway. Antibodies against PD-1 (nivolumab and pembrolizumab) were developed and tested against various kinds of cancer such as non small cell lung cancer, renal cancer, melanoma. Many patients showed tumour regression and remission providing further evidence for the use of negative immune regulation as a therapy for cancer.
More than 15 years have passed since treatment of the first patient with anti-CTLA-4 antibodies and 12 years since the use of anti-PD-1 antibodies in cancer therapy. A combination of both these modalities of treatment have shown promising results in patients of metastatic melanoma. This is a remarkable progress as earlier, a diagnosis of metastatic melanoma meant death within 2 years for the patient.
All anti-cancer drugs come with some crippling side-effects. The use of these immunomodulatory drugs can give rise to life threatening adrenal insufficiency (inability to produce cortisol- a hormone essential for survival) due to adrenal gland destruction or inflammation of the pituitary. This can be managed by hydrocortisone supplementation treatment. Pneumonitis is another important unwanted effect. This is managed using synthetic steroids and monoclonal antibodies against tumour necrosis factor. As with all anti-cancer therapies, immune checkpoint therapy can too have fatal consequences. Despite the side-effects, these miracle drugs have shown to work wonders in patients with unresectable tumors who were earlier considered a ‘lost case’ in the battle against cancer.
Immune Checkpoint Therapy is being amalgamated with Chemotherapy and Radiation Therapy for the treatment of metastatic cancers. This year’s Nobel Prize in Medicine or Physiology has been dedicated to the scientists who have added another pillar to cancer treatment marking a new dawn in our relentless war against cancer.
Author: Meenakshi Khemka
Sources and citations
The Nobel Prize in Physiology or Medicine 2018. NobelPrize.org. Nobel Media AB 2018. Thu. 22 Nov 2018.