Transcript

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

[Music] [Applause] hello now I wanted to start this talk with a heartwarming story about my motivations for training in medicine but the reality is I think I became a doctor because my father was now here he is cyril he's the person at the bottom left of this image and one of my dad'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 telling and retelling a joke but he did come up with a fantastic motto for his weight loss clinic and it was this we hope to see less of you but the joking aside with the dad joking aside the longer that I've worked in medicine the more apt I actually think this phrase is my job and that of any doctor is to try to make our illnesses a smaller part of our lives so that we can spend more time with people that we love or doing things that we enjoy and less time in distress or pain in fear or in hospitals or clinics I'm leaving a program of research at the Mulligan Institute that aims to do just that we're working on a new form of cancer immunotherapy now I didn't start out as an immunology researcher I started out as a junior doctor working on the wards in London and in Hanover in Germany Here I am on the ward in Hanover with my colleagues and looking back now I find it terrifying to imagine lying down in a sick in a hospital bed and seeing this group of very young-looking doctors ministering to everything I trained in a specialty called hematology which deals with diagnosis and treatment of diseases of the blood and a lot of the time we spend is treating conditions we call blood cancers 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 chemotherapy or radiotherapy to weaken their own bone marrow and then we give stem cells bone marrow stem cells from a healthy donor this results in complete replacement of the blood and the immune system and this procedure kills tens of thousands of people with blood cancers every year but replacing the immune system wholesale like this can have side effects that can go seriously wrong I'd like to tell you about a couple of patients that I treated during my training in hematology John was in his 40s with the young family and he had a type of lymphoma that had kept coming back time after time he'd received more than ten different lines of chemotherapy over a decade and in the end we offered a bone marrow transplant in the hope that the new immune system this would afford him might prevent the lymphoma from coming back we weren't terribly optimistic that this would work and we thought our fears were confirmed in just a few weeks after the transplant we saw some signs of the new foamer occurring and in what really was a last-ditch attempt we gave him an extra dose of immune cells taken from the blood of his bone-marrow donor to our surprise and delight and certainly to his the lymphoma went into remission and in fact his stayed in remission for longer than a decade another patient we treated Sarah was still at school and she developed fatigue she was feeling tired and she went to a doctor for a blood test and everyone was shocked when the result came back and showed a type of leukemia she was rushed to a hospital and we gave her treatment that put her leukemia into remission we thought the best chances of it's staying in remission were to follow this up with a bone-marrow transplant we thought that by replacing her blood and immune system we could prevent that leukemia from ever occurring because of 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 severe side effect the new immune cells started to turn against her body she became sick and tragically she died these two stories have stuck with me bone-marrow transplants are tremendously powerful but they still feel a bit like the role of a dice we can estimate the chances of success but we simply can't say with any great degree of accuracy who will be made better by the procedure and who will actually be made sicker there have to be better ways to use the immune system against cancers now your immune system is truly remarkable the green dots on this image represent your lymph glands and the lymph glands are like hubs or meeting places for the cells of our immune system they're clustered in areas of the body where we come into contact with the outside world for example we have lots of lymph glands around the back of our noses and the the center of our lungs to help defend us against pathogens infections in the air that we breathe we have lymph glands at the back of our throats and around our intestines to look for infections in the water we drink or the food that we eat and we have clusters of lymph glands where our arms and legs meet our torso in case we injure our limbs and infections get beneath our skin there's also one great big lymph gland beneath our ribs called the spleen that screens our blood for infections now inside those lymph glands the cells of a key part of our immune system the adaptive immune system meat and two of those key cells are called the B cells and the T cells and the reason they have to meet all the time is to exchange information every moment every minute there's billions of interactions between B cells and T cells taking place inside your lymph glands they're trying to find out whether a cell from each arm of the immune system has spotted the same pathogen the same infection and if Abby's on T cell meet and they have seen that same infection this triggers a huge alert the T cells and particularly the B cells expand up in huge numbers extremely quickly have you ever had a sore throat and notice the lymph glands around your neck become swollen or tender you can see you're feeling some of you probably have this right now if so you're literally feeling your immune system in action you're feeling this happening what's happening inside is that the b-cells in particular expanding very rapidly and they can expand in numbers within hours there's an important reason for this bacteria and viruses also proliferate rapidly and in a severe infection our lives may literally be at stake now what's happening inside those lymph gland is more than just an increase in numbers of those b-cells they're also adapting they're learning they're changing to recognize this infection better and your b-cells quite unlike any other cell any other tissue in your body have a unique property they can selectively modify their own genetic code so that inside that lymph node each b-cell might be able to recognize the pathogen in a slightly different way to its neighbor again no other cell in the body can do this so while it might feel the trivial irritation to have that swollen lymph node what's actually happening inside is a dramatic survival of the fittest the b-cells that are best able to recognize that infection grow up in number 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 in fact even more than this it's not just like an army that helps defend your body against invading infections from outside it also functions as like a domestic police force that's helping to protect you against cells within your own body that go bad that develop potentially dangerous mutations all the time even right now in this auditorium we're being bombarded with low levels of radiation and we're 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 rapidly and take it on a path towards becoming malignant or cancerous fortunately our t-cells help defend against this they patrol around our body screening for cells displaying signs of these mutations and when find them they can destroy them now clearly this process can and sometimes does fail sometimes a cell acquires a particular set of mutations that both allow it to grow but also let it evade the T cells to go incognito so what then then we might develop a growth a tumor and if we're fortunate this is detected early and can be removed with surgery or eradicated completely with radiotherapy if we're less fortunate some cells within that Shema might pick up an additional ability to invade into other tissues or to spread to metastasize and then we might need other treatments such as chemotherapy or increasingly immunotherapy now immunotherapies are increasingly used to treat cancers of various types and there are several ways that we currently use immunotherapy in the hospital clinics today we can give artificial antibodies synthetic versions of those antibodies produced by your b-cells during an infection that instead of recognizing an infection recognize the tumor cells latch on and help to destroy it or we can give treatments that kick-start that domestic police force that boost the activity of the T cells improving their ability to screen for and eradicate cells in your body that bear the mutations or as we did for John and Sarah we can replace the immune system in its entirety by doing a bone marrow transplant each of those treatments have really important roles to play in the way we treat malignancies today and will continue to do so but they each have limitations that it work for all malignancies they don't work for all people and they all have side effects we need new and more targeted immunotherapies for cancer at the Mulligan Institute we're working towards this the new treatment that's coming along is called chimeric antigen receptor t cell therapy and apologies for the long name you can call it car T cell therapy for short and what this involves is reprogramming redirecting patience t-cells against the malignancy so how do we do this first we take blood from a patient and we separate out the t-cells and then we modify them and we do this by introducing a new gene into the cells and that gene encodes a new protein the chimeric antigen receptor the car and what this does is it provides a new capability to that t-cell so a car t-cell has it combines the very best properties of the b-cells and t-cells a car t-cell can recognize a tumor cell using the very best portions of an antibody from a highly selected b-cell yet then deploy the domestic police force function of a t-cell to eradicate that cancer cell once we've made the car t-cells in the laboratory we expand them up in large numbers usually a hundred fold over seven to ten days and then we cryo preserve them in liquid nitrogen and we do this so we can run safety testing on the car t-cells before we're ready to know they can be administered once we're happy we've got car t-cells that can be administered if we call the patient into hospital now we don't want the car t-cells to be rejected as soon as they're given so we have to give the patient a low dose of chemotherapy we call conditioning beforehand and then give the car T cells into the vein very unspectacular what happens then is that the car t-cells a reliving drug they're not like a normal medicine that actually sells they find their way to the sites of the tumor and when they see the tumor cells they not only become activated but they expand the increase in numbers just like your normal immune cells do during an infection and each of their progeny will carry this same car the same modification now this period which typically lasts one to two weeks can be associated with inflammatory reactions so we have to observe patients closely during this time and sometimes we might need to give treatments to dampen down the immune response after that the car t-cells decrease in number their job done although a few may stick around providing long term protect in clinical trials in some patients with blood cancers more than four out of five people have gone into remission with car t-cell therapy and what's more these responses can happen even in people who've been refractory to other chemo therapies or who have their dues diseases relapsed after a bone-marrow transplant at the Mulligan Institute we're working to try and make this type of treatment available here this image shows our cell therapy suite at the Mulligan Institute in Wellington and I'd like to point out a few things about this picture the first thing is that if you squint carefully you might see a ghostly reflection of me taking an accidental selfie and the reason for that the reason I having to take the photograph through glass is that even though I'm leading this program I'm not allowed in that room the entrance to the facility is strictly controlled and only are specially trained personnel wearing all their protective garb there in the photograph Brigitta and Evelyn are allowed in the reason we have to have such a controlled environment is that we're going to be giving these cells back into the veins of people whose immune system is compromised so we have to be sure that they're free of bacteria or fungi or viruses on the left of the image Brigitta is working at a biosafety cabinet and the air inside that cabinet is extremely clean we call it a grade-a environment so it's more than ten thousand times cleaner than the air that you and I are breathing right now on the right Evelyn is consulting a procedure manual and the reason she's doing that is everything in this room has to follow the procedures and be documented believe it or not there's even a detailed written operating procedure that explains how to open and close the doors now most researchers including ourselves are making Carty cells from patients themselves in this way but some people are working on ways to make Carty cells from healthy donors this requires additional modifications to the cell to make it safe but if they're successful we may reach a future in which doctors like me can look at a patient's biopsy look at their gene sub-type and then simply order a batch of car t-cells in the same way that we currently order blood from a blood bank it may be that some of you who are blood donors might in the future not just be donating your red blood cells but you might also be donating your t-cells and helping other people get rid of their cancers and wouldn't that be great so what do we need to do to make this type of treatment available here we need clinicians who are familiar with the safe and effective use of car T cell therapies they can have significant toxicities we need regulations for these new types of therapy and we've been working with regulators on this the regulations need to ensure safety but they also need to be practical we need to find ways to ensure equity of access for those people those of us who live outside our major cities to make sure we don't have iniquity there and we do need support for game-changing new trials like these it's often very difficult in our health services to change practice and this type of treatment involves a lot of logistic and regulatory and let's face it cost considerations but clinical research that shows ours can help to overcome these issues by running our trials we're working through the regulatory issues we're working through the logistics of manufacturing and harvesting cells and giving them back and I think it's through trials like these that we'll get be in a much better position to roll these types of treatment out more widely in the future we're at a tremendously exciting time in immunotherapy we can modify the immune system in ways that I never thought possible we're now is 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 the time now that photo was taken shortly before my family moved back to New Zealand to bring up our family here and expand our family and take up a permanent position and I hope to make a difference I'm really excited about a future in which we can at least four more people overcome the roll of the dice and give safe and effective cancer immunotherapy and yes hopefully a future in which we at the hospital see less of you and your friends colleagues and family can see a lot more of you we can be [Applause] [Music]