Introduction to Immunotherapy (Immunotherapy Documentary Part I)

[Music] over the past 10 years the use of immunotherapies in the treatment of cancers has exploded what was once considered a pipe dream by many cancer researchers has now become an exciting therapeutic success story since 2011 there have been seven checkpoint inhibitors a type of immunotherapy approved by the FDA which has become the standard of care for sixteen different types of cancer in this series we talk to the researchers that are making these therapies a reality and explore the technologies that make this promising field possible [Music] it's a pretty small mission we want to cure cancer using the immune system and basically when Sean Parker had the idea to create the Institute and he asked me to lead it it was really with the idea that we could use the immune system to start really curing cancers now that was back in late 2010 2011 that he and I started talking about this at the time this was just when an acetal a4 was getting an approval as a drug an EPT one wasn't even in the mix yet and so it seemed like this was we were part of a world that was isolated out in the wilderness you know with people like you know Jim Allison and Bob Schreiber and others who had been at this and would always be in the back room of the big meetings and never but of course things have changed in the last six or seven years and now immunotherapy is the hottest thing going and you go to a meeting and every talk is on immunotherapy the term immunotherapy is actually an umbrella term for a number of different modalities that are all designed to use the body's own immune system to help fight cancer the specifics of each therapy differ but they all rely on a deep understanding of how the immune system is regulated and how that regulation can be modified to get the desired outcome it has been known for some time that the immune system plays an important role in monitoring the formation of potentially cancerous cells it's estimated that an individual cell can have as many as 20,000 DNA damaging events a day the vast majority of these are identified and repaired by specific DNA repair pathways those cells that do acquire a malignancy that are not repaired are usually removed by the body's immune surveillance system this generally involves cell mediated immune mechanisms that rely on differentiating between self and non-self antigens often this DNA damage results in a single point mutation in a nucleotide that leads to a unique peptide that may be recognized by the immune system as non-self these tumor associated antigens are presented on the surface of cells in conjunction with major histocompatibility or MHC molecules this taa MHC complex can then be recognized by a t-cell with an appropriate t-cell antigen receptor but in order for the T cell to become activated a complex mix of co stimulatory signals are required one example of this is the cd28 cd80 86 activation signal the second signal then activates the t-cell to allow it to carry out its effective function but just as there are signals that activate T cells there are counteracting signals that can inhibit activation these inhibitory signals mediated by cell surface proteins known as checkpoint molecules normally play an important role in regulating autoimmunity but their actions can also potentially inhibit a robust immune response to tumors when a T cell interacts with an antigen presenting cell the cell surface marker ctla-4 on the T cell can interact with cd80 86 on the dendritic cell causing an inhibitory signal to be sent essentially down regulating the T cells response to the antigen these inhibitory signals can also be found on some tumor cells in these cases the tumor expresses the antigen PD l1 which binds to PD 1 on the T cell this inhibits its activation even though the T cell receptor has bound the MHC tumor associated antigen complex thus the tumor cell escapes the immune system surveillance by co-opting checkpoint molecules but if an antibody to either pd 1 or PDL 1 were added to the system it could block the interaction and prevent the inhibitory signal this is the premise of the class of immunotherapy drugs known as checkpoint inhibitors by preventing the inhibition of the immune response this new class of drugs allows the immune system to recognize and fight the tumor cells nobody in fact there was thinking of the checkpoint molecules we used to call them Co inhibitory molecules with relation to tumor immunity they were mostly thinking about its role in art immunity because you can regulate t-cell responses you can regulate threshold of the t-cells to select your antigens and you can see the deletion of these molecules and see teleph for when you delete the seed level molecule and the mice come down with disease and die within six weeks with tissue infiltration autoimmunity then the same story with PD one molecule expressed on t-cells you're deleted you get a massive autoimmunity if it's an appropriate strains of mice and initially they were all thought to be core inhibitory molecules that evolved to regulate t-cell expansion in fact they are normally used for T cells to contract once you have an infection or looking Wireless on a bacteria so your T cells expand and they actually infiltrate your lymph nodes and spleens and and ultimately once the infection has been cleared you want to shrink this system and bring it back to homeostasis and that's where they play the most important role is that actually they bring down the whole size of a robot or back to the normal almost abnormal cancer is controlled autoimmunity we're trying to break tolerance there to generate an autoimmune response against the cancer cell which of course has a lot of similarities to other self tissues uses a lot of the same regulatory pathways to shut down immune responses and so the way I look at it is it's sort of two sides of the same coin the inhibitory signals being targeted can come from a number of sources but they have been extensively characterized in professional antigen presenting cells and in a subset of T cells known as regulatory t-cells the primary purpose of this t-cell subset is to suppress an immune response and maintain homeostasis preventing autoimmunity although the exact mechanisms are still an area of intense study what is known is that they appear to work through four basic modes of action these include the production of inhibitory cytokines suppression by cytolysis suppression by metabolic disruption and suppression by the modulation of dendritic cell maturation of function these interactions between the immune system and tumor cells are complex and lie at the heart of immunotherapy as we begin to understand the molecular basis for these interactions we can start to see how we can use them to address a disease like cancer well immunotherapy I think is is changing because of the knowledge of the immune system I mean all of the clinical breakthroughs that are coming about came from mechanistic preclinical in-depth studies that understood their mechanism ctla-4 pd-1 it was understood before it went into the world of cancer as how it inhibited autoimmunity or how you could re-energize a t-cell response to a viral infection in a mouse L CMV so a typical virus model and mice this all came about because of good preclinical evidence on what they did biologically and now as the negative co-stimulatory world is expanding and people understand how t---cells work and how the signaling pathways you know come about you start to understand how positive and negative signaling interacts together and if if you get usurped by negative signaling in the tumor microenvironment you use antibodies to pd12 ctla4 to lagg-3 to Tim 3 to a bunch of these others you can block a negative and enhance the positive signaling of t-cells in the micro environment and that's what's going on it's not by luck it's not by chance it's because of good basic science the focus sharply went on to these role of these molecules on immune cells in tumors and that's because of two reasons number one their blockade in tumors short success in human tumors and number two is that if you respond to checkpoint blockade therapy you are pretty much immune and you get long-lasting durable responses which you can't see with chemotherapy see this is one of the advantages of checkpoint blockade or immunotherapy is that you get long lasting responses so in targeted therapies you can give a drug it will impact the tumor tumor will shrink and six months later or a year later the tumor comes back with vengeance and such that the the tumor does not respond to the targeted therapy or chemotherapy anymore but one good thing about the immunotherapy is this almost like your immunizing or your vaccinating the immune system against the tumor so once you do the checkpoint blockade therapy you are blocking these inhibitory molecules on the immune cells and immune cells start recognizing tumor they start proliferating as the tumors and they kill the tumor and finally that you have immune memory site that if the tumor comes again you have an army of lymphocytes ready to react like as if it was an infection some of the early work on immunotherapies focused on identifying tumor specific markers using monoclonal antibodies and in some cases creating antibody drug conjugates directed towards the tumor in addition some early immunotherapy treatments explored isolating tumor infiltrating lymphocytes or tills expanding them ex vivo and reintroducing them to the patient's the most recent advances in this field stems from efforts directed at uncoupling the signals that down regulate a t-cell response these checkpoint inhibitors can theoretically target a number of proteins on the surface of t-cells both the effector and regulatory t-cell as well as myeloid derived suppressor cells antigen presenting cells or tumor cells still another class of immunotherapy is known as chimeric antigen receptor or car t-cells with this treatment t-cells are modified to express an anti tumor antigen specific T cell receptor along with co stimulatory domains the resulting t-cells are modified and expanded ex vivo before being returned to the patient there are also cytokine therapies and vaccine therapies that stimulate the immune system to better fight the tumor and all of these therapy types must be examined in the context of the micro environment of the tumor itself an environment that can impact the way a tumor grows metastasizes and ultimately reacts to the immune system while all of these therapies have shown some promise they are not yet at the point where any one of them works for all patients with a specific type of cancer the work of exploring how and why these therapies do and do not work for some patients is now getting underway in earnest and while the questions being asked become more precise and difficult to tease apart the tools that are being used to ask these questions are fortunately becoming more sophisticated the way I look at it is the technologies are geared towards a better understanding of mune system certainly but the ones that have been driving the revolution allow us to measure more molecules at once that paradigm that that pushed to measure more and more molecules at once has kind of been happening independently of the development of the immunotherapy drugs and now where we're at that that meeting point I think that what is starting to happen and will happen more and more is that these cutting-edge technologies are going to now be incorporated into clinical trials and into support for whether these drugs are efficacious and safe and so on and I think as that happens then the real power will start to emerge if I think of my own experience working in the industry and I started in the laboratory but now working in industry there's this backhand for so the scientists want to look at something and they can push the technology to a certain level and then they go back to the manufacturing said if only I had another laser if only I had more colors or if only I could do smaller samples or if I had an analysis software that could help me look at this cell population and then companies look at that as an opportunity and do it and so now that same scientist has additional tools to look deeper into their own work while many of the technologies that are being used in immunotherapy research have been available for a long time some of the newer tools being used have pushed the limits of science and what scientists are looking for now require precision at the single cell level this includes advances in next-generation sequencing RNA seek multi parameter flow cytometry imaging mass cytometry and much more an important piece of this is that we want people to be educated about this because if there's no education about what technology to use they'll either grab whatever comes along first whatever's closeby or whatever the shiniest object is which is often the case with sequencing or this sometimes the imaging mass cytometry is really exciting technologies and so you think to grab those first even though they might not be right for the problem and then we waste money and energy and our funding resources on things that that aren't suited to the to the questions that we want to answer and so it's really important to understand the basic premise of why you would use each of these technologies in this series to follow we will look at what technologies are currently being used to further our understanding of immunotherapy we will interview researchers in academia and in industry to find out what tools and technologies they think will help us gain a better understanding of just how the immune system works in the next segment we will look at how scientists are approaching tumor immune profiling and understanding the tumor microenvironment to find out exactly what techniques are being used to address these critical issues

Channel: BioLegend

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Id: 8Z0Gyv-3NL8

Length: 15min 50sec (950 seconds)

Published: Fri Jun 26 2020