Can this Treatment Empower the Body's Immune System to Root out Cancer?

I saw a patient in early 2013 when I did my first rotation in Surgery. She had breast cancer and after

Breast Cancer Undergoing Programmed Cell Death.
Image credit to Wellcome Trust UK

undergoing what we call a modified radical mastectomy (surgery which involves removing almost all the breast tissue), she died a few days later. Why? The breast cancer had spread a bit to other parts of her body before the surgery; and unfortunately, CT scan of the brain was not done to check whether it was safe before taking her into the operating theatre. And surgery usually suppresses the immune system and in this woman's case it gave room for the already spreading breast cancer to become very aggressive in invading other parts of her body, most painfully including her brain. She started having seizures a day after the surgery and died three days later.

Cancer is one of the leading causes of death in the world: it has robbed many families and friends of their loved ones; it has withered the blossoming dreams of many people.

A Cell from Malignant Skin Cancer (Melanoma).
Image credit to Wellcome Trust UK

Mankind has long been in the battle against cancer with moderate victory-the disease has had much of the victory. And the most common treatment modalities (such as chemotherapy, radiotherapy) available against the disease have untold consequences which sometimes outweigh the benefits; consequences manifesting in the form of adverse effects such as hair loss, skin wrinkling, suppression of the immune system, predisposing the patient to infection, and so on, because these treatment modalities also destroy normal healthy cells and tissues in their course of weeding out the cancerous cells. Removal by surgery is another treatment option whose success largely depends on the time of diagnosis of the cancer: when discovered very early, surgery is likely to open a huge window of extended lifespan (not cure because the cancer may show up again after some years); but if the cancer is diagnosed late, surgery can't do anything because some prodigal cancerous cells would have defied their parent tumour and migrated to very distant and, often dangerous, locations such as the brain, lungs, liver and so on.

Nevertheless, there have been significant efforts and dotted success in the quest to find lasting treatments for cancer in the past 50 years. However, to speak of a cure for a particular type of cancer in its advanced stage, when the possibility of its metastasis (spread to other tissues and organs in the body is very very high), is something that cancer treatment experts at the patient's bedside will meddle in with utmost caution.

But it seems that the phrase "cure for cancer" may just begin to crawl into the vocabulary of cancer treatment in the very near future as insinuated by a research published in the journal Nature on the 27th November, 2014, which details the trial of a new drug class called immune checkpoint inhibitors (belonging to a type of cancer treatment modality called immunotherapy) in patients with late-stage cancer of the bladder and whom doctors have given a maximum of eight months to live. Greater than 50% of the patients enrolled in the trial started recovering after taking the drugs, while two patients out of the total number seemed to have been cured after receiving the treatment as there were no signs of cancer in them. In the patients who responded to the treatment it was found that their own bladder cancer had cells which express a molecule called Programmed Death Ligand (PD-L1) on their surfaces.

Cell Division in a Skin Cancer Cell.
Image credit to Wellcome Trust UK

Immunotherapy is a treatment modality for cancer that aims to help the body's immune system fight these cancers. An aspect entails tweaking the main cells involved in fighting cancer (we call them T cells) genetically to be able to fish out these tumours much more effectively; while another uses a type of chemical interleukin-2 to speed up the immune system's anger towards these cancers, a modality pioneered by scientists at the US National Cancer Institute in 1985 and which was used to cure some patients with melanoma (malignant tumour of the skin). These subforms of immunotherapy have not had the overwhelming success scientists envisaged them to record; but perhaps this new subform called Checkpoint Inhibition therapy may finally fulfil the omnipotence prophecy against cancer being alluded to immunotherapy.

The concept of immune checkpoint inhibition arose when scientists discovered that one of the chemicals, called interferon gamma, released by the T cells fighting cancers made the cancer cells to adapt to the assault of the immune system by developing a molecule called Programmed Death Ligand. Programmed Death Ligand binds to a receptor molecule on the surface of T cells called Programmed Death receptor; this receptor is probably involved in moderating the rage of the immune system cells in their fight against foreign entities that invade our body so that the immune system doesn't go mad and destroy normal healthy cells and tissues in their anger at the foreign agents; and they possibly do this by binding with Programmed Death Ligang-like molecules that are released during inflammatory processes; hence the programmed death ligands and receptors serve as checkpoints of the immune system in the time of war. But cancer, being a smart player in the survival of the fittest, decided to leverage on this cloaking spell. Hence, when T cells infiltrate these cancers and release interferon gamma and other chemicals that signal the rest of the immune system to attack, the cancers release the Programmed Death Ligand to bind the Programmed Death receptors on the surfaces of the T cells, making them think they are about to go crazy in this their fight to liberate our body and leading to the T cells taking their feet off the accelerator: the smart cancer laughs and continues growing.

But cancers aren't smarter than us; in the mid-90s scientists started working on molecules that could block the Programmed Death receptors on the surfaces of T cells and the Programmed Death Ligand produced by the cancer cells in patients so that the immune system will unleash its full wrath on the cancer cells. By 2012 clinical trials have already gone far in the US and some European countries to test a few monoclonal antibodies (drugs that are made by artificially synthesizing antibodies in the lab specific to particular protein fragments in disease antigens, unique protein molecules expressed by different cells-both healthy and diseased ones depending on the choice of a researcher) that have been developed specifically against the PD-1 receptor molecule on the surface of T cells and the PD-L1 molecules produced by cancer cells. The results of the clinical trials have produced spikes of miracles as some of the patients with late-stage cancers (with the cancer having spread to other parts of the body) witnessed their malignant tumours regress very significantly, and some tumours were even totally wiped out, including their colonies in different parts of the body (the lungs and liver where the tumour has spread to were found clean after rounds of cancer-detecting investigations). The development and success of these drugs (monoclonal antibodies) called immune checkpoint inhibitors were heralded as the most significant scientific breakthrough of 2013 by Science Magazine.

While almost half of those that enrolled in the various clinical trials for the immune checkpoint inhibitors seemed to have benefited from the drugs, the remaining half have not responded to the treatment probably because, as some cancer immunologists pointed out, their own cancers might be using a different pathway to leverage on the immune system checkpoint. And I think the way forward in this immune checkpoint inhibition modality is to now look at the genetic basis of the synthesis of programmed death ligand-like molecules in cancers. This may reveal, I believe, rate-limiting steps either at the messenger RNA transcription and translation levels and post-translational modification levels that may be totally different from those of other inflammatory processes in the body in which the immune system checkpoint may be very crucial to preventing autoimmune reactions; it may also throw light to polymorphisms unique to the genes encoding programmed death ligand-like molecules in cancers. Success in this direction will provide a wide range of targets for drug development that will benefit virtually every cancer patient because each group of drugs will target unique points that may be the engine room for a small group of cancer patients (pharmacogenomics and personalised medicine). One feasible way this 'way forward' could be achieved is incorporating this proposal into research initiatives such as the International Cancer Genome Consortium, the UK Cancer Genome Project and the US Cancer Genome Atlas  working to identify the genes involved in cancer development in thousands of patients (and I want to believe that cancer researchers have already thought about this and are moving in that direction); another way is to use animal models to induce cancers and then study the genesis of leverage of the immune checkpoint by the cancer cells right from the genetic level.

I believe we will keep gaining more grounds in the fight against cancer through the development of several weapons to destroy it from virtually every angle; a few weeks ago, Cambridge University reported the approval by the European Union drug regulatory body of a new generation anti-cancer drug developed by its scientists in collaboration with the biopharmaceutical giant, AstraZeneca. The drug called Lynparza exploits a totally different pathway to fight cancer: it inhibits an enzyme called PARP (Poly ADP-Ribose Polymerase) involved in a pathway for the repair of damaged DNA in replicating cells; and its efficacy lies in the fact that some malignant tumours have only this pathway for repairing damages to DNA unlike normal healthy cells that have alternative repair mechanisms such as the homologous recombination pathway. Lynparza has been licensed for use in patients with advanced ovarian cancer (with mutations in two genes called BRCA1 and BRCA2 which are involved in ensuring repair of sustained damages to DNA in healthy cells through the homologous recombination repair mechanism) in Europe; clinical trials have shown Lynparza to have very minimal side effects compared to other chemotherapeutic agents because of its specificity in targeting only cancerous cells; and since some other cancers (breast and pancreatic cancers) have mutations in the BRCA1 and BRCA2 genes, they are potential therapeutic targets for Lynparza.

This new year and the years to come definitely will see us winning most of the war against cancer.