The promise and limits of cancer immunotherapy

[Music] Charles Dickens novel A Tale of Two Cities opens to the famous line it was the best of times it was the worst of times it was the age of wisdom it was the age of foolishness to me that sounds like today in the world of cancer research every day we hear or see headlines on the positive side of new treatments using terms such as the jackpot of immunotherapy immunotherapy prolonging life came change in advances new paradigm for treating cancers and in the financial news we hear about large pharmaceutical companies buying and investing in gene and cell companies for as much as eleven billion dollars on the negative side we see reports that the fda put a clinical hold on car t-cell programs or suspended a new clinical trial for immunotherapy because of safety concerns today if you follow the news on the cancer front it feels like sometimes you cannot open a newspaper a magazine a journal or go online without seeing the term human oncology recently the FDA made history by proving the first gene and cell therapy for cancer this is for pediatric and young adult acute lymphoblastic leukemia patients and it's a first of a new class of drug for immunotherapy called car t-cells I'll come back to that later but first what is the immune system one definition is that's a complex network that functions to protect our body from foreign substances this network uses interacting cells sell products and self forming tissues to defend the body from infectious agents and malignant cells it also removes cellular debris from the body bottom line our immune system is both a policeman and a garbage the immune system includes many organs and cells such as the thymus the spleen lymph nodes lymph tissues stem cells T cells B cells natural killer cells macrophages and neutrophils I have spent a lifetime on a journey to try and understand the immune system and for me it began in 1983 when I was an intern in a hospital in Johannesburg South Africa I was drafted to be the intern on the first the hospital's first-ever foreign air transplant the patient was a young child suffering from aplastic anemia this is when the immune system destroys the bone marrow and to this day we still don't understand exactly how and why the bone marrow is that part of the body it makes the red cells the white cells the platelets and the immune cells sadly the child died of an infectious complication but the experience made me determined to pursue the field of blood and marrow stem cell transplantation so here's some of the key things I've learned the immune system recognizes our body as self and in order to protect us it must be able to differentiate the self from the non-self meaning foreign entities like viruses bacteria fungus and yes malignant cells immune system successfully recognizes many foreign threats from influenza to transplanted organs and in the case of fighting the flu we work to strengthen those responses and in cases like transplant we work to suppress those responses so here's the big question why does the immune system fail to recognize your body is developing cancer this question is the basis of the new immunotherapy research and clinical approach and over the course of many years of pursuing blood and marrow stem cell transplantation and through my work in Pediatrics adolescent and young adults cancer we have learned to successfully treat many liquid tumors such acute leukemia with bone marrow transplant using bone marrow derived stem cells and something surprising happened the transplant therapy created a new side effect that we realized that we could use to our advantage this side effect is called graft mouse pellet gr aft graft versus host disease or GVHD that's when the immune cells from the donated material attack the patient's normal cells the graft is the donated material and the host is the patient again graft-versus-host disease obviously gras versus host disease can prevent the transplant from working it can even kill the patient but then we realized that we could use Gras versus host disease and harness it for our favor and what if instead of draw versus host disease we had graft versus tumor or graph versus leukemia and while researchers were looking at ways to prevent Gras versus host disease a new cell emerged the t cell of the immune system this T cell is a double-edged sword it can cause growth versus host disease but it can also be responsible for growth versus leukemia and scientists thought if you could remove this cell in the lab using something called T cell depletion you could prevent draw first as host disease so they tried it and the good news is they did prevent growth versus host disease but the bad news is the patient's tumor was coming back in the mid-1990s Stephan McAllen and his collaborators in Memorial Sloan Kettering decided that if you could give a small amount of T cells back after you did that T cell depleted transplant you could prevent Gras versus host disease and you could make the cancer not come back and this therapy became known as donor lymphocyte infusion and it is one of the scientific underpinnings of the car T cell world are you with me so far I admit this is a complicated story but research is a long and winding road and we often have to go through these twists and turn to make a great discovery so let's fast-forward to today I could give you a long list of Pioneer researchers who've advanced this field and some of them won Nobel prizes the modern field of immunotherapy could not exist without the work of the transplant teams the immunologist the advent of the discovery of the ability to make monoclonal antibodies the molecular biology techniques that was needed to bring hearing together we now stand on the brink of new therapies being made available we have all the ingredients of our immune system to be able to use to harness against cancer so let's go back to that basic question what's going on in the immune system does not recognize cancer as non-self and one theory about this is called cancer immune editing the hypothesis is that we're developing cancer cells all the time we know that billions of cells have been regenerated in our body every day and that you in cell divisions changes occur that can lead to a cancer cell being formed in other words cancer is not a freak aberration the cancers are normal and immune system takes care of the majority of these cells and we never know we've had cancer hair cancer cells and obviously when this goes right we call it the equilibrium phase because the immune system sees the cancer cell is non-self and destroys it but sometimes the cancer cell escapes this immune surveillance and when that happens we develop full-blown cancer and for reasons we don't understand these surviving cancer cells get ace a network of supporting cells and proteins that protect it from the immune system it's as if the cancer becomes a wolf in sheep's clothing and I immune system looks in and says no problem that's me so the cancers developed a kind of stealth mode that blocks the immune system Jim Allison about 20 years ago was researching this problem he was one of the first to realize that you could reverse the stealth blockade by using new molecules and he can activate the immune system to respond to the cancer cells and destroy the tumors this led to new and exciting drug treatments and mm Oh Bell prizewinners I alluded to Cola and Millstein created and developed what we called monoclonal antibodies and from that we got a powerful new class of drug called an immune checkpoint inhibitor and in 2017 a hundred thousand patients will be treated with drugs that will be developed from this line of research these checkpoint inhibitors are the basis for all the new excitement around immunotherapy but is this excitement warranted we have a lot of exaggerated exaggerated claims going on so it's important to establish is this hype or is this real my answer is it is both on the one hand these cells these drugs simplify current understanding and limit opportunity to one aspect of a very complex immune system and becoming too narrow in our focus can be a problem on the other hand we've seen remarkable responses in a small percentage of patients one of the first diseases this was tried on was metastatic melanoma and we saw small improvements in the overall survival rates unfortunately this did not work for the majority of patients but when it did it was truly amazing today there are long-term survivors on that original patient cohort and the next generation of these immune checkpoint inhibitors allow the immune to be turned back on and attack the non-self the more we learn about the immune system the more complex we realize it is it's like shining the light into a dark room we get answers but sometimes many more questions and if we want to use the immune system for all patients with cancer we need to develop a systems approach and I'm going to use the analogy of a car if we need to learn to change the oil in the engine while it is still running and at the same time change the tire while we're still driving and that's because the immune system succeeds by using both spatial and temporal approaches to win different molecules and cells come into play in everyday new molecules have been discovered that we realize are needed to make the immune system work so I believe it's overly simplistic to believe that just one or two molecules or all that's needed to stop them immune system from attacking cancer cells and it really is overly simplistic to believe is if you give a patient an immune checkpoint inhibitor you get a universal cure the reality is checkpoint inhibitors work for only 10 to 15 percent of cancer patients unfortunately this nuanced view has not been well understood and I said there's a lot of media coverage and corporate message in suggesting that to cure cancer we just have to give an immune checkpoint inhibitor as a silver bullet well that's not possible and for me the more important question is why is it that they mean checkpoint anybody is not working and if we knew that maybe we can trick the immune system to reactivate this itself in the same way the cancer cell tricked her to stop noticing that these were cancer cells and to do this could we use new molecules so let me answer this by surveying the state of the field at the moment we've seen a great success story in children who would have died from acute lymphoblastic leukemia smiling happily celebrating birthdays this group of children for whom all other therapies had failed to put them into remission now are going into remission 83% of the time and this was made possible by creating a new molecule a mixture of cells a chimera of the T cells and B cells in what we are calling chimeric antigen receptor t cells are much easier to say car T cells and the first studies have been done and the first treatment of this class are not fda-approved for b-cell leukemia and lymphoma but even here we have good news and bad news when that new chimeric t cell recognizes a cancer and destroys it rapidly it has a new negative side effect it releases proteins that can put the patient into the intensive care unit and we call this cytokine release syndrome and it can actually kill the patient the good news is we learning how to recognize it early and we can intervene and salvage the patient and we actually use another immunotherapy drug another antibody to try and reduce this risk at the same time that the car t-cells are destroying the cancer it also permanently destroys the patient's normal b-cells and this puts the patient in a lifetime of infectious risk and we have to replace those B cells with a very expensive IV substitute that is given monthly illnesses for life clearly when it comes to the immune system there are no easy answers and at least so far there are no cheap solutions either yes it's amazing and wonderful to see our patients doing well but the estimated cost of immune checkpoint inhibitors run into the hundreds of thousands of dollars and in some cases core t-cells have cost up to a million dollars per patient and no matter how much money we spend we have to face the sobering and tragic reality that the majority of patients tumors do not respond to the current immunotherapy approach we still have a lot of research to fund and to perform and with over 130 companies now getting to the field of immunotherapy and the US government funding numerous initiatives I believe we will see real scientific progress translated to the patients and to the clinic in relatively short order and by that I mean yours and not decade I am confident that we will find a way to use the immune system to treat cancer and I believe we're going to find a way to help many more patients and this approach combined with other anti-cancer therapies gives a strong reason to believe that hope is on the near-term horizon for cancer patients and hopefully as Charles Dickens said we'll be in the best of times so be an age of wisdom and definitely not an age of foolishness thank you

Channel: TEDMED

Views: 44,550

Rating: 4.8589745 out of 5

Keywords: TEDMED, Lennie Sender, Leonard Sender, oncology, cancer, immunotherapy, immunocology, CHOC Children’s Hospital, AYA

Id: NhmNvZKDjJw

Length: 15min 54sec (954 seconds)

Published: Thu Sep 13 2018