Cancer and our Microbiome

People who are diagnosed with cancer have a relatively delicate immune balance. We are not truly sure about the factors involved in the immunological cascade.

People take lots of medicines, supplements and more to enhance their immune system. This has become a multi-billion dollar business. Unfortunately, most of these have low or no benefit.

One of the exciting and intriguing things which is emerging is the role of the gut in the immune system. What we eat and what our guts produce are becoming increasingly important from an immune perspective.

Probiotics are a bad idea for patients on immunotherapy. The logic being that immune systems are created on the normal gut flora – which is amazingly diverse. Taking probiotics spoils the equilibrium in the gut. Not a good idea.

Antibiotics have the similar problem. They kill the normal gut bugs and change the dynamics of the intestinal flora. Do not take antibiotics for things like viral infections or suspected infections.

It is so humbling to know that everytime we think we have found a new and wonderful door of understanding…. it just opens another maze to tackle.

Immunotherapy: Nobel Prize 2018

This text is taken from the ESMO (European Society of Medical Oncology) website.

ESMO Link

On 1 October 2018, the Nobel Assembly at Karolinska Institutet has decided to award the 2018 Nobel Prize in Physiology or Medicine jointly to James P. Allison and Tasuku Honjo

“for their discovery of cancer therapy by inhibition of negative immune regulation”. By stimulating the inherent ability of immune system to attack tumour cells this year’s Nobel Laureates have established an entirely new principle for cancer therapy. For more than 100 years scientists attempted to engage the immune system in the fight against cancer. Until the seminal discoveries by the two laureates, progress into clinical development was modest. Immune checkpoint therapy has now revolutionized cancer treatment and has fundamentally changed the way we view how cancer can be managed.

A number of therapeutic approaches are available for cancer treatment, including surgery, radiation, and other strategies, some of which have been awarded previous Nobel Prizes. These include methods for hormone treatment for prostate cancer (Huggins, 1966), chemotherapy (Elion and Hitchins, 1988), and bone marrow transplantation for leukaemia (Thomas 1990). However, advanced cancer remains immensely difficult to treat, and novel therapeutic strategies are desperately needed.

In the late 19th century and beginning of the 20th century the concept emerged that activation of the immune system might be a strategy for attacking tumour cells. Attempts were made to infect patients with bacteria to activate the defense. These efforts only had modest effects, but a variant of this strategy is used today in the treatment of bladder cancer. Many scientists engaged in intense basic research and uncovered fundamental mechanisms regulating immunity and also showed how the immune system can recognise cancer cells. Despite remarkable scientific progress, attempts to develop generalizable new strategies against cancer proved difficult.

The fundamental property of our immune system is the ability to discriminate “self” from “non-self” so that invading bacteria, viruses and other dangers can be attacked and eliminated. T cells are key players in this defense. T cells were shown to have receptors that bind to structures recognised as non-self and such interactions trigger the immune system to engage in defense. But additional proteins acting as T-cell accelerators are also required to trigger a full-blown immune response. Many scientists contributed to this important basic research and identified other proteins that function as brakes on the T cells, inhibiting immune activation. This intricate balance between accelerators and brakes is essential for tight control. It ensures that the immune system is sufficiently engaged in attack against foreign microorganisms while avoiding the excessive activation that can lead to autoimmune destruction of healthy cells and tissues.

During the 1990s, in his laboratory at the University of California, Berkeley, James P. Allison studied the T-cell protein CTLA-4. He was one of several scientists who had made the observation that CTLA-4 functions as a brake on T cells. Other research teams exploited the mechanism as a target in the treatment of autoimmune disease. Allison, however, had an entirely different idea. He had already developed an antibody that could bind to CTLA-4 and block its function. He now set out to investigate if CTLA-4 blockade could disengage the T-cell brake and unleash the immune system to attack cancer cells. Allison and co-workers performed a first experiment at the end of 1994, and in their excitement it was immediately repeated over the Christmas break. The results were spectacular. Mice with cancer had been cured by treatment with the antibodies that inhibit the brake and unlock antitumor T-cell activity. Despite little interest from the pharmaceutical industry, Allison continued his intense efforts to develop the strategy into a therapy for humans. Promising results soon emerged from several groups, and in 2010 an important clinical study showed striking effects in patients with advanced melanoma. In several patients signs of remaining cancer disappeared. Such remarkable results had never been seen before in this patient group.

In 1992, a few years before Allison’s discovery, Tasuku Honjo discovered PD-1, another protein expressed on the surface of T-cells. Determined to unravel its role, he meticulously explored its function in a series of elegant experiments performed over many years in his laboratory at Kyoto University. The results showed that PD-1, similar to CTLA-4, functions as a T-cell brake, but operates by a different mechanism. In animal experiments, PD-1 blockade was also shown to be a promising strategy in the fight against cancer, as demonstrated by Honjo and other groups. This paved the way for utilizing PD-1 as a target in the treatment of patients. Clinical development ensued, and in 2012 a key study demonstrated clear efficacy in the treatment of patients with different types of cancer. Results were dramatic, leading to long-term remission and possible cure in several patients with metastatic cancer.

After the initial studies showing the effects of CTLA-4 and PD-1 blockade, the clinical development has been dramatic. We now know that the immune checkpoint therapy has fundamentally changed the outcome for certain groups of patients with advanced cancer.

Similar to other cancer therapies, adverse side effects are seen, which can be serious and even life threatening. They are caused by an overactive immune response leading to autoimmune reactions, but are usually manageable. Intense continuing research is focused on elucidating mechanisms of action, with the aim of improving therapies and reducing side effects.

Of the two treatment strategies, checkpoint therapy against PD-1 has proven more effective and positive results are being observed in several types of cancer, including lung cancer, renal cancer, lymphoma and melanoma. New clinical studies indicate that combination therapy, targeting both CTLA-4 and PD-1, can be even more effective, as demonstrated in patients with melanoma. Thus, Allison and Honjo have inspired efforts to combine different strategies to release the brakes on the immune system with the aim of eliminating tumour cells even more efficiently.

A large number of checkpoint therapy trials are currently underway against most types of cancer, and new checkpoint proteins are being tested as targets.

The Nobel Assembly, consisting of 50 professors at Karolinska Institutet, awards the Nobel Prize in Physiology or Medicine. Its Nobel Committee evaluates the nominations. Since 1901 the Nobel Prize has been awarded to scientists who have made the most important discoveries for the benefit of humankind.

Reference

The Nobel Prize in Physiology or Medicine 2018. NobelPrize.org. Nobel Media AB 2018. Tue. 2 Oct 2018.

Channel 10 Australia News and Immunotherapy

The Channel 10 news program telecast information from the primary kidney cancer study that we had participated in. The results had shown that in the intermediate or poor risk kidney cancer patients, combination therapy with Ipilimumab and Nivolumab was much better that the standard of care tablets. Immunotherapy was better than just simple targeted therapies.

It focused on a story of a gentleman who was diagnosed with kidney cancer a few years ago and was then started on the combination immunotherapy (as part of a clinical trial). He did exceedingly well on the study and has no measurable cancer (on CT scans). He is doing well and is back to his normal routine of life.

Brilliant stuff.

Channel 10 Adelaide News

Nobel Prize and Immunotherapy

This is taken from Ars Technica:

The Nobel Prize Committee has honored two researchers for their role in pioneering a new avenue for cancer treatment, one where the therapy targets the immune system, which then goes on to attack the cancer. The researchers, James Allison of the MD Anderson Cancer Center and Tasuku Honjo of Kyoto University, worked separately to identify and target proteins that help keep the immune system from attacking other cells in the body. When these proteins are inhibited, the immune system can target cancers, although at the risk of autoimmune disorders.

Immunotherapy discoverers get Nobel Prize in Medicine