CAR T-cell therapy: Reprogramming the immune system to treat cancer | Rob Weinkove | TEDxTauranga

Hello, now I wanted to start this talk with a moving story about my motivations for studying medicine, but the reality is that I think I became a doctor because my father was here now, he is Cyril, he is the person at the bottom left of this image and One of my father's achievements was establishing a successful weight loss clinic at a place called Hope Hospital in the north of England, near Manchester. Now Dad loves to tell and retell jokes, but he came up with a great motto for his weight loss clinic and it was this. We hope to see you less but jokes aside with dad jokes aside the longer I have been working in medicine the more accurate I think that this phrase is my job and that of any doctor is to try to make our illnesses smaller. part of our lives so that we can spend more time with the people we love or doing things we enjoy and less time in distress or pain, fear or in hospitals or clinics.

I am leaving a research program at the Mulligan Institute that aims to do just that, we are now working on a new form of

cancer

immuno

therapy

. I didn't start out as an immunology researcher. I started as a junior doctor working in the London and Hannover wards in Germany. Here I am in the room. I was in Hannover with my colleagues and now, looking back, it is terrifying to imagine lying like a sick person in a hospital bed and seeing this group of very young-looking doctors taking care of everything I trained in a specialty called hematology that they deals with diagnosis and

treat

ment. of blood diseases and much of the time we spend is

treat

ing conditions we call blood

cancer

s, such as leukemias and lymphomas.

Now, since the 1970s, doctors like me have been recommending something called bone marrow transplants and these are procedures where we give patients chemo

therapy

. or radiation therapy to weaken your own bone marrow and then we give you bone marrow stem

cell

s from a healthy donor. This results in complete replacement of the blood and

immune

system

and this procedure kills tens of thousands of people with blood cancers each year, but it replaces the overall

immune

system

as this can have side effects that can go seriously wrong. I would like to tell you about a couple of patients I treated during my hematology training.

John was in his 40s with the young family and had a type of lymphoma that had come back again and again, he had received over ten different lines of chemotherapy over a decade and in the end we offered him a bone marrow transplant in the hope that The new immune system this would give could prevent the lymphoma from coming back again and again. Upon returning we were not very optimistic that this would work and we thought that our fears were confirmed just a few weeks after the transplant, we saw some signs that the new sparkling was being produced and in what was really a last attempt, we gave it a Para to our surprise and delight, and certainly to him, an extra dose of immune

cell

s taken from the blood of his bone marrow donor, and certainly to him, the lymphoma went into remission and, in fact, remained in remission for over a decade .

Another patient we treated, Sarah was still in school. she and she developed fatigue, she felt tired and went to a doctor to get her blood tested and everyone was surprised when the result came back and she showed a type of leukemia. She was rushed to a hospital and we gave her treatment that put her leukemia into remission. We thought her best chances of staying in remission were to continue with a bone marrow transplant. We thought that by replacing her blood and her immune system we could prevent that leukemia from occurring due to her young age and the particular type of leukemia. she had, we were optimistic that this would work, but a few weeks after the transplant she developed a serious side effect, the new immune cells began to turn against her body, she became ill and tragically died.

These two stories have stayed with me. Bone marrow transplants. They're tremendously powerful, but they still feel a bit like die-cast paper. We can estimate the chances of success, but we simply cannot say with a great degree of precision who will get better from the procedure and who will actually get sicker. There have to be better ways to use the immune system against cancer. Now her immune system is really remarkable. The green dots in this image represent your lymph glands and lymph glands are like centers or gathering places for the cells of our immune system. Clustered in areas of the body where we come into contact with the outside world, for example, we have many lymph nodes around the back of the nose and in the center of the lungs to help us defend against pathogenic infections in the air we breathe.

We have lymph nodes at the back of our throat and around our intestines to look for infections in the water we drink or the food we eat, and we have clusters of lymph nodes where our arms and legs join our torso in case we get infected. We hurt our limbs and infections get under our skin. There is also a large lymph node under our ribs called the spleen, which tests our blood for infections. Now, inside those lymph nodes, the cells of a key part of our immune system, the meat of the adaptive immune system, and two of those key cells.

They are called B cells and T cells and the reason they have to meet all the time is to exchange information every moment, every minute, there are billions of interactions between B cells and T cells that take place within the ganglia. lymphatics they are trying to discover. If a cell from each arm of the immune system has detected the same pathogen, the same infection, and if Abby's T cells meet and have seen the same infection, this triggers a huge alert, the T cells and particularly the B cells expand. in great quantities. Extremely quickly, have you ever had a sore throat and noticed that the lymph nodes around your neck become swollen or tender?

She can see that she's feeling something she probably has this right now. If so, she is literally feeling her immune system in action. If we feel this happening, what's happening on the inside is that the B cells in particular expand very rapidly and can expand in numbers within hours. There is an important reason why bacteria and viruses also proliferate quickly and, in a serious infection, our lives can literally be at stake. Now what's happening inside those lymph nodes is more than just an increase in the number of B cells, they're also adapting, they're learning, they're changing to better recognize this infection and their B cells are very different than any other cells.

The tissues in your body have a unique property: they can selectively modify their own genetic code so that within that lymph node each B cell can recognize the pathogen in a slightly different way than its neighbor - no other cell in the body can. This is so, while you may feel the trivial irritation of having that swollen lymph node, what is actually happening inside is a dramatic survival of the fittest, the B cells that are best able to recognize the infection grow in number. They expand more and more and those that are less able to give up it's a form of Darwinian selection we call it affinity maturation now your immune system is even more than this it's not just like an army that helps defend your body against invading infections from the outside, it also functions as a domestic army police force that is helping to protect you against cells within your own body going bad and developing potentially dangerous mutations all the time, even right now in this auditorium we are being bombarded with low levels of radiation and we are breathing in toxins and chemicals that can damage or alter our DNA, our genetic code, most of these mutations are harmless, but some of them could cause a cell to proliferate more quickly and lead it down the path of becoming malignant or cancerous.

Fortunately, our T cells help defend against this, they patrol around. Our body looks for cells that show signs of these mutations and when it finds them, it can destroy them. Clearly, this process can and does sometimes fail. Sometimes a cell acquires a particular set of mutations that allow it to grow but also allow it to evade T cells. Go incognito and then we might develop a growth, a tumor, and if we're lucky, this is caught early and can be removed. with surgery or completely eradicated with radiotherapy, if we are less fortunate, some cells within that Shema could detect an additional capacity to invade other tissues or spread to metastasize and then we might need other treatments such as chemotherapy or increasingly immunotherapy.

Immunotherapies are now increasingly used to treat cancers of various types and there are several ways in which we currently use immunotherapy in hospital clinics. Today we can provide artificial antibodies, synthetic versions of those antibodies produced by B cells during an infection that, instead of recognizing an infection, recognize that tumor cells attach and help destroy it, or we can administer treatments that activate that force national police that increase the activity of T cells by improving their ability to detect and eradicate the cells in your body that carry the mutations or, as we did with John and Sarah, we can replace the entire immune system through a bone marrow transplant of each Of those treatments have really important roles to play in the way we treat malignancies today and will continue to do so, but each has limitations in that they work for all malignancies, they do not work for all people, and they all have effects. secondary ones that we need new and more. targeted immunotherapies for cancer at the Mulligan Institute we are working to achieve this, the new treatment that is coming is called chimeric antigen receptor T cell therapy and sorry for the long name, you can call it auto T cell therapy for short and what this implies is

reprogramming

.

Redirect patience T cells against malignancy. So how do we do this? First we take blood from a patient and we separate the T cells and then we modify them and we do it by introducing a new gene into the cells and that gene codes. a new protein, the chimeric antigen receptor, car, and what it does is it provides a new capacity to that t cell, so a car t cell has the best properties of b cells and a car t cells . A cell can recognize a tumor cell using the best portions of an antibody from a highly selected B cell and then deploy the internal police function of a T cell to eradicate that cancer cell once we have created the car's T cells.

In the lab, we scale them up in large quantities, usually a hundredfold in seven to ten days, and then we cryopreserve them in liquid nitrogen and do this so we can do safety testing on the car's T cells before we're ready to know. they can be administered once we are happy to have auto T cells that can be administered if we call the patient to the hospital. Now we don't want the Car T cells to be rejected as soon as they are administered. We have to give the patient a low dose of chemotherapy that we call conditioning beforehand and then give him auto T cells into the vein.

Very unspectacular, what happens then is that auto T cells are a reviving drug, they are not like a normal medicine that you actually sell, they find their way to the tumor sites and when they see the tumor cells, they not only activate but rather they expand the increase in number just as normal immune cells do during an infection and each of their descendants will carry this same car. The same modification now, this period which usually lasts one to two weeks, may be associated with inflammatory reactions, so we have to observe patients closely during this time and sometimes we may need to administer treatments to buffer the immune response, then the car-t cells. decrease in the number of their work done, although some may remain providing long-term protection in clinical trials in some patients with blood cancers, more than four in five people have gone into remission with car t cell therapy and, which What's more, these responses can occur even in people who have been refractory to other chemotherapies or who have their diseases relapse after a bone marrow transplant.

At the Mulligan Institute we are working to try to make this type of treatment available here this image showsour cell therapy suite at the Mulligan Institute in Wellington and I would like to point out a few things about this image. The first is that if you squint closely, you might see a ghostly reflection of me taking an accidental selfie and the reason why I have to do it. taking the photograph through glass is that even though I am leading this program I am not allowed to enter that room the entrance to the facilities is strictly controlled and there are only specially trained personnel wearing all their protective attire there in the photograph they are Brigitta and Evelyn The reason we have to have such a controlled environment is that we are going to be returning these cells to the veins of people whose immune systems are compromised, so we have to make sure that they are free of bacteria, fungi or viruses to the left of the image Brigitta is working in a biosafety cabinet and the air inside that cabinet is extremely clean.

We call it a Grade A environment, so it's over ten thousand times cleaner than the air you and I breathe right now. On the right, Evelyn is looking at a procedures manual and the reason she does so is because everything in this room has to follow procedures and be documented, believe it or not, there is even a detailed written operating procedure that explains how to open and close the doors today. Researchers, including ourselves, are producing Carty cells from patients themselves in this way, but some people are working on ways to produce Carty cells from healthy donors.

This requires additional modifications to the cell to make it safe, but if they are successful, we may reach a future where doctors like me can look at a patient's biopsy, look at their gene subtype, and then simply order a batch of car-t cells. In the same way that we currently order blood from a blood bank, it is possible that some of you who are It is possible that in the future blood donors would not only be donating their red blood cells, but could also donate their T cells and help others. people get rid of their cancers.

Wouldn't that be great? So what do we need to do to make this type of treatment available here? Clinicians who are familiar with the safe and effective use of auto T cell therapies may have significant toxicities. We need regulations for these new types of therapy and we have been working with regulators on this. Regulations must ensure safety, but they must also To be practical, we need to find ways to ensure equity of access for those people, those of us who live outside our main cities, to make sure that we don't have inequity there and we need support to In our health services it is difficult to change practice and this type of treatment involves a lot of logistics and regulation and let's face it, cost considerations, but clinical research showing that ours can help To overcome these problems in conducting our trials, we are working on regulatory issues.

We are working through the logistics of manufacturing and collecting cells and returning them and I think it is through trials like these that we will be in a much better position to implement these types of treatments more widely in the future. At a tremendously exciting time in immunotherapy we can modify the immune system in ways I never thought possible. Now we are training in medicine 20 years ago or even when just eight years ago I was writing my doctoral thesis in cancer immunotherapy with the wonderful distraction of my son Henry at that time that photo was taken shortly before my family moved back to New Zealand to raise our family here and expand our family and take up a permanent position and hopefully make a difference.

I am very excited. about a future where at least four more of us can beat the dice roll and deliver safe and effective cancer immunotherapy and yes, hopefully, a future where we at the hospital see less of you and your friends, colleagues and family can see a lot. more of you we can be