With great pleasure. Um uh And, and this is a tandem uh presentation. We, we're, we're very fortunate to have both Doctor Krishna Murthy or a as we know her and uh which is a lot easier than Krishna Murthy. Um and, and doctor uh to give the next two talks and we'll start with, with, with a uh welcome to, welcome to Roswell and uh hope you enjoyed your dinner. I haven't started yet. I ran out of steam. So um thank you for the introduction and thank you for the opportunity to present here today. Um As doctor has already said, we'll be talking about solid tumor cell therapies. Uh We split up the talk so that we will, I'll talk about the immunology component of it up front and then um doctor will talk about all the clinical. Uh And so uh I will start off with the basics. So, um essentially the immune system is a collection of cells, um chemicals that protect the organism from abnormal antigens could be microbes, it could be viruses, cancer cells toxins. In simple terms, the immune system died into two lines of defense, the innate immunity and then the right there, you can see all that comprise of both arms of the. This is obviously simplistic, but at least it's a starting point. Innate immunity is obviously the first line of defense. It's non specific, it is antigen independent memory. So it will not recognize the antigen in the future if it were to encounter it, adaptive immunity is antigen dependent. Um It recognizes self antigens versus non self antigens. Um And uh there is a lag time between exposure to when the, the immune system turns on. Um most importantly, it has memory. So, um on a subsequent encounter, the host will actually mount an efficient and rapid response. Um and it will be a directed response because of the memory component of things. Um The cells of adaptive immunity are the T cells and the B cells and these are antigen specific and that's what we are interested in today. So, um here, I'm going into a bit more detail on T cell activation and regulation and how it drives immune surveillance. Um T cells are essentially produced in the bone marrow and then they mature in the thymus, uh T cells and these T cell receptors bind antigens. Sorry, this all may be very basic for people, but I'm just starting off at the beginning. Um T cells recognize antigens that are presented by antigen presenting cells as the um uh antigen presenting cells um express uh major histocompatibility complexes. And these come in two types type one and type two as you can see up there. So essentially um T cell activation. So there are two types of Mh C class one and class two. Class one is found on all nucleated cells. And class two essentially is found on macrophages and dendritic cells and B cells and they present extracellular peptides. Whereas um class one Mh CS tend to present intracellular peptides. T cells are activated when they encounter an A PC carrying the correct um antigen peptide. Mh C complex. These T cells then differentiate into either cytotoxic T cells or T helper cells. Cytotoxic T cells present CD eight S and T helper cells present CD four S. So um CD eight cytotoxic T cells are activated when their T cell receptor recognizes an antigen bound to MH C class one molecules on any cell. And then they destroy it CD four T cells on the T helper cells. On the other hand, modulate the immune system and the immune response. They don't kill cells. They direct other cells to do their job. Um They are activated by recognizing antigens bound to class two Mh C molecules and then they um secret cytokines. There are many types of T D four T helper cells. You, as you can see, there are regulatory T um T cells T helper cells and these um uh tend to um actually suppress um uh inactive or active uh cytotoxic T cells and T helper cells or A P CS. So this is a little bit about T cell regulation. So, um myeloid derived suppressor cells inhibit T cell responses. Um And they do this by mechanisms that include things like nutrient sequestration, uh reactive oxygen species generation and interference with trafficking to abnormal cells. Um This is a little bit more information about the T cell binding to um uh foreign or abnormal cells I E antigens. And so the way T cells um act when they recognize antigens is by producing preference and grays and these preference form pores in the plasma membrane of the foreign or abnormal cells. And then they result in breakdown of the protein and licence of the cells. Oh, sorry, one second. So this is just a step by step process where I just go through um how T cells detect and eliminate tumor cells through neo antigen recognition. So, um tumor cells express antigens. Um tumor mutations result in tumor specific antigens that can activate the adaptive immune response. Dendritic cells can recognize new antigens and activate cytotoxic cells through antigen presentation to T helper cells. We went through some of this earlier. Um I L two supports the proliferation and tonal expansion of activated cytotoxic T cells. Activated cytotoxic T cells then migrate to the tumor micro environment where if they are targeting tumor antigens, they are called tumor infiltrating lymphocytes. Um completion of immune surveillance destroys tumors and before they even become clinically apparent, um once tumor infiltrating lymphocytes are in the tumor micro environment. They bind to the new antigens presented by the tumor. Resulting in that process that we talked about where tumor lysis eventually occurs. Loss of expression of antigens or reduction of MH CS um enable tumor cells to not be detected. So tumors can modify the tumor micro environment in many ways and suppress the activity of these tills. Um This is what results in um tumor growth and also um in lack of response to immunotherapies. Um tumors engage in immunosuppressive mechanisms that lead to dysfunctional or fewer tills in the tumor micro environment. So, suppression of cytotoxic T cells and helper T cells via regulatory T cells reduces immune surveillance as well. Um This is an immature dendritic cell. These do not present antigens and this is one more way where the tumor modifies its micro environment and suppresses activities of tills. There is also macrophage inhibition of T helper cells and this reduces immune surveillance and then um up regulation of immune checkpoint molecules, uh reduces the potential of tills to eliminate tumors. Um So, suppression of tumor infiltrating lymphocyte activity results in tumor growth and development of the cancer. So this talks a little bit about the checkpoint pathway and um how it gets engaged and how it results in tumor evasion of tumor infiltrating lymphocytes. So, um binding of P D L one to P D one contracts T cell receptors and results in um tumor infiltrating lymphocyte death, a similar process with the binding of C T L A four to CD A T 86 inhibits T cell activation. Um And uh this results in the disruption of the interaction between tumor infiltrating lymphocytes with A P CS. So, in summary, foreign or abnormal cells or antigens are eliminated through immune surveillance and they use both the innate and adaptive immune systems. Um T cells recognize antigens um including ones that are seen on tumors and they are activated and then regulated by other cells in the immune system. Um T cells in the tumor micro environment, they um uh bind to T SAS and are called tills. Tumor cells can suppress the activity of tills by inhibiting immune cells in the tumor micro environment and then they also regulate immune checkpoint molecules. So this is, this was just a basic background on the immunotherapy behind all of this. What do we do with all of this information? So the next steps are to talk about um the evolution of immunotherapy and its approach for cancer treatment. So there are many ways in which the immune system can be harnessed for the treatment of cancer. So, um there, as you can see, there are so many different options here. Checkpoint inhibitors are probably the most uh well known and you can see them there on that side. Um So that's the inhibition of P D one P D L one or C T L A four with monoclonal antibodies. You have bis specific specific antibodies that direct engagement of T cells and tumor cells. You have oncotic viral therapy where um cancer cells uh with genetically engineered viruses end up leading to cancer cell lysis. There is um there are cancer vaccines, um cytokines that simulate um A T cell proliferation. And then there are car T cell therapies that where you the powerful blood T cells express chimeric antigen receptors. And these recognize tumor associated antigens. And then there's still therapies where autologous tills tumor in infiltrating lymphocytes um get taken out from the patient, they get expanded and then they get reintroduced to the patient for tumor elimination. Um And then there are T C R engineered T cells where per blood T cells are modified with T C R S to recognize tumor associated antigens. Um This is a trend in immunotherapy drug development. There has been an increasing interest in cell therapies. So, um if you see here, going from 2017 to 2020 there has been an amazing number of trials that have been included in clinical trials for and particularly, you know, cell therapy, clinical trials. These are the milestones in cancer immunotherapy. Um You know, it leads us way back to the 19 seventies where we see the initial discovery of the dendritic cell. And then as we move on, we see uh in the 19 nineties, uh where I L two was approved for renal cell cancer and melanoma. Um and then we move on and in the two thousands is where we see the checkpoint inhibitors come out initially for advanced Melanoma. Um and then obviously it moved on to be used for many other indications. And then eventually, as we move further along this timeline, we see cart cell therapies being approved for multiple hematologic malignancies and and uh finally, where we are today is where we are um looking at T cell based therapies for solid tumors, which is obviously still in its infancy, but a very popular topic. And I think, understandably. So um so, immunotherapy with checkpoint inhibitors activates T cells within the tumor micro environment. This is C T L A four inhibition. Um And in terms of um where we are at the, as you can see, eli um uh results in uh elimination of tumor cells here. Um I just wanted to complete that um whole timeline and actually just talk a little bit about this um because this is part of immunotherapy and this is P D one P D L one inhibition um with, without immunotherapy. As you can see, um there's elimination of tumor cells there. Um and it, and it works by activating the T cells and then results in uh tumor cell elimination. This is the most interesting part of all of this immunotherapy, I think. So this is adoptive cell transfer immunotherapy. So it introduces autologous or genetically modified T cells into the tumor micro environment. Um in terms of um what those two arms show here um on the far left, there is T C R or car T cell therapy where um you isolate peripheral blood T cells and it gets transducer, um T cell, you transduce these T cells with a viral vector. And um if it is car T cell therapy, then um now these T cells express genetically engineered cars. Um and this is a uh Mh C independent antigen recognition process. On the other hand, T C R cell therapy um is where you have T cells with genetically modified T cell receptors. And this is a MH C dependent antigen recognition process. Um On this very far end of the slide, I'm talking about tumor infiltrating lymphocyte cell therapy. Here, we actually take a component of the tumor itself. It is not peripheral blood and there is in vitro um tumor infiltrating lymphocyte isolation bulk or selected. Um It can go either away some trial. Um Some of these therapies seem to um like to isolate a few of um uh these tills while others seem to take the whole lot of it. And then there is expansion of these tills and then these are given back um to the patient. Um in order to see if there's response to treatment um in terms of the rationale for till cell therapy in solid tumors. Um there are a wide array of tumor specific antigens. Um in uh solid tumors, um tills are poly and they recognize a multi of an individual's tumor specific antigen. So, um in one way, you can think of it as um till cell therapy, possibly overcoming some of the challenges that we have seen with car T cells and T C R therapies in solid tumors. So, there is um uh things that we would be concerned about is the delivery of car T cells or T C R modified T cells into the tumor micro environment. Um immune suppression of car T cells or T C R modified T cells in the tumor micro environment. Um lack of heterogenous, uh tumor specific antigen expression in all tumor cells and incidents of C R S and other adverse events that we typically see with car T cells or T C R modified T cells. So the the idea with still therapy is perhaps it will overcome some of these other issues that we have seen with time with car T cell therapies in solid tumors. Um This slide looks at the differences in the various therapies. So um just looking at tills cars, T C R S and then checkpoint inhibitors. So in terms of targets, um the target for tills is tumor specific antigens. Um for um cars, it's non MC cell surface proteins and then with T C R S, it is um MC peptide complexes. Checkpoint inhibitors obviously are a whole another beast with, you know, um targets uh at you know, that target, it's P D one, P D L one or C T L A four. Um TT therapy tends to be poly, I mentioned that earlier. All the other stuff is monoclonal. Um in terms of production, you need to isolate tilts from tumors and expand X. So you need to sample a good um uh tumor, a biopsy, sample size. Um in terms of cars and T C R S, they're isolated from blood. Um And so you isolate these T cells and then transduce them and expand them. Um in terms of the main toxicity, um in terms of tills, it tends to be uh lympho depletion related and I 02 issues related whereas in cars and um T C R therapies, um you um it's lympho depletion related, of course, but then you can also see um cytokine relief syndrome and neurologic toxicities. Um at this point in time, in terms, uh in um terms of approved indications, um tills and T C R S are still in progress. We don't really have anything yet. Um in terms of solid tumors, we don't have um very much that is approved just yet in terms of adoptive cell transfer immunotherapy. But we are hoping that, that we will have some approvals shortly and Igor will talk more about it in terms of immunotherapy. Obviously, we have many more indications. Um This was just to give you a sense of the various types of um chimeric antigen receptor constructs that exist outside there's first generation, second generation, third generation um so essentially first generation cars tend to have a single chain, variable fragment antigen recognition domain. Um But um and then they have a transmembrane domain and an intracellular T cell activation domain. Second generation cars and third generation cars have an additional co stimulatory domain and the third generation actually has two of those. So, in summary, the immune system can be harnessed for the treatment of cancers through adoptive cell cancer and other immunotherapies, immunotherapy with checkpoint inhibitors activates T cells within the tumor micro environment. Adoptive cell transfer, immunotherapy introduces autologous or genetically modified T cells into the tumor micro environment. There are three types of adoptive cell transfer immunotherapy in um tumor infiltrating lymphocyte cell therapy tills are isolated from the tumor micro environment grown in vitro and transferred to the patient after lympho depletion in um T C R and car T cell therapy. Um her full blood T cells are isolated transducer with T C R or car grown in vitro and transferred to the patient after lympho depletion. Um in terms of um till cell therapy mechanism of action and treatment process, um tilts bind to uh a variety of uh tumor specific antigens and cause tumor cell death. Um solid tumors are prone to multiple uh genomic mutations. Um You see that um A P CS migrate to the um initially I should say the T SAS are presented via A P CS and then the A P CS migrate to the lymphoid organ um which is where the A P CS prime the naive T cells to respond to an array of these tumor specific antigens. And then these, these tills then enter the tumor micro environment, bind to these tumor specific antigens and cause tumor cell death in terms of till cell therapy stages. So this is the first step is obviously tumor tissue procurement. Um And then um they are expanded in vitro. There is preparative lympho depletion where um while the tills are being expanded and that takes a few weeks. Um And then there is till infusion and this is infusion of expanded polyclonal tills in the patient. There is I L two administration and high dose I two to increase the number of T cells in the system. And then eventually there's discharge from the hospital and follow up essentially with tumor tissue procurement. The idea is to procure a viable solid tumor tissue. Um because that that is important in successful production of tills. You need a sufficient tumor sample size and it needs to be an aseptic technique so that there's no contamination um tills are produced in vitro with uh procured tumor tissue. So there's till isolation. Um And then, so there's in vitro expansion of tumor tissue with I L two. And then there is um this actually results in enrichment of till content of the sample and then there is growth and then there is expansion, the tills are then cryo preserved and shipped. Um lympho depletion. This um has um enhanced the anti tumor effects of tills. Um This is being seen in uh uh mouse models uh with a direct relationship between the extent of lympho depletion. And then the anti Tuur effect that you see with the transfer tills. Um several mechanisms explain the enhanced anti tumor effects of tills with lympho depletion. And this includes the elimination of T regulatory cells and then cellular sinks for I L seven and I L 15. Um So essentially, there is a one time infusion of autologous tills, polyclonal tills that recognize the tumor specific antigens that are patient specific. And then, of course, there's the I 02 administration that, that I touched upon earlier and then eventually um recovery of the patient's blood cell counts before they get discharged from hospital. Um So tumor cell depths from tills, it is um it involves uh presentation of multiple tumor specific antigens by A P CS, the A PC prime priming of naive T cells and then um T cells primed with multiple tumor specific antigens enter the tumor micro environment, bind to different tumor specific antigens and cause tumor cell death. Um um The uh till cell therapy involves tumor tissue procurement, um production of the tills in vitro preparative lympho depletion infusion of tills I 02 administration and recovery. And so with that, I will hand over to uh Eagle who will talk about uh clinical data summary.
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