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9 4 1bb cd3z t cells had drastically reduced the number of cd19 leukemic cells compared to both control and also anti cd19 cd3z t cells further these t cells did not kill untargeted control target cells jack they re imparting a more lasting reduction of target cells presumably because the t cells are surviving better in culture annie and the cells containing 4 1bb did even better when they were incubated with target cells in the presence of bone marrow mesenchymal cells which is where most cd19 acute lymphoblastic leukemia cells reside in vivo in fact cells including the 4 1bb elements were even more effective cytotoxically in the presence of the mesenchymal cells jack that s remarkable so these cells will almost certainly be good at killing real all cells in patients right annie well it s funny you should say that because what they did next was to get collect all cells from patients and do the cytotoxicity assay with them and you re right they worked and adding 4 1bb improved their function over just cd3 alone and before you ask they saw the same big improvement in il 2 expression in response to co culturing with op 1 cells jack i don t know what else to ask both cd28 and 4 1bb add to the functionality of receptors expressing a targeting antibody portion outside the cell and cd3 elements inside the cell annie so is the next paper a combination of all three jack that s coming but before we get there we re going to look at how another interleukin il 15 promotes long term survival of car t cells specifically we ll be discussing a 2003 nature medicine paper by brentjens et al titled eradication of systemic b cell tumors by genetically targeted human t lymphocytes co stimulated by cd80 and interleukin 15 we ll also touch on another paper examining a cd28 expressing car t cell in vivo from 2006 by kowolik et al annie so don t forget to follow reprogrammed wherever you get your podcasts share it with your colleagues friends and anyone who enjoys discussing how biotechnology leads to amazing breakthroughs in science and medicine jack and as always i encourage you to check out the primary research papers we discuss you ll find references full transcripts and additional notes at downhousesoftware com so annie what were you saying about your time device thing earlier in the episode annie yes i made some progress i think i figured out some work arounds to address the kinks of time displacement jack the kinks of time displacement that doesn t sound very assuring annie well then maybe you ll be reassured knowing that our prototype successfully sent its first test subject back in time jack that s the opposite of reassuring what kind of test subject annie just a simple robotic assistant very lifelike i m sure it blended right in jack how do you know it worked annie well we had it make a change so we had it fix a small problem jack annie annie what it was purely for scientific purposes plus i told it not to do anything too disruptive jack not too disruptive annie what problem annie relax don t worry about it worst case scenario humanity fights a desperate war against an unstoppable ai overlord best case i get my own theme music jack that does not sound like nothing too disruptive annie agree to disagree source material for this podcast maher j brentjens r gunset g et al human t lymphocyte cytotoxicity and proliferation directed by a single chimeric tcrζ cd28 receptor nat biotechnol 20 70 75 2002 https doi org 10 1038 nbt0102 70 imai c mihara k andreansky m nicholson ic pui ch geiger tl campana d chimeric receptors with 4 1bb signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia leukemia 2004 apr 18 4 676 84 doi 10 1038 sj leu 2403302 pmid 14961035 additional references singh r kim yh lee sj et al 4 1bb immunotherapy advances and hurdles exp mol med 56 32 39 2024 https doi org 10 1038 s12276 023 01136 4 hyeon woo lee su jung park beom k choi hyun hwa kim kyung ok nam byoung s kwon 4 1bb promotes the survival of cd8 t lymphocytes by increasing expression of bcl x l and bfl 1 1 j immunol 1 november 2002 169 9 4882 4888 https doi org 10 4049 jimmunol 169 9 4882 next week s articles brentjens r latouche jb santos e et al eradication of systemic b cell tumors by genetically targeted human t lymphocytes co stimulated by cd80 and interleukin 15 nat med 9 279 286 2003 claudia m kowolik max s topp sergio gonzalez timothy pfeiffer simon olivares nancy gonzalez david d smith stephen j forman michael c jensen laurence j n cooper cd28 costimulation provided through a cd19 specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred t cells cancer res 15 november 2006 66 22 10995 11004 leave a comment posted by downhousesoftware on february 24 2025 in uncategorized tags biology cancer health immune system immunology reprogrammed the biotechnology podcast 16 feb episode 5 incorporating co stimulatory signaling in car t cells summary this podcast delves into the exciting world of cancer immunotherapy focusing on the evolution of cancer vaccines and the recent surge of cell based therapies this series follows a string of primary research papers highlighting the most impactful advances in car t cell therapy it is a companion to a ku edwards campus biotechnology course but contains information interesting to anyone who wants to understand the mechanics of this therapy it begins with a 1998 journal of experimental medicine article by krause et al that details the creation of a chimeric receptor 3g6 cd28 that incorporates the signaling domain of cd28 in the cytoplasmic portion of the antigen receptor to enhance the survival and proliferation of t lymphocytes targeting tumor cells experiments using jurkat cells and human primary t cells demonstrate that the 3g6 cd28 chimeric receptor triggers cd28 signaling upon gd2 recognition improving t cell survival and expansion especially in the presence of anti cd3 stimulation this approach offers a potential strategy for improving cell based immunotherapy by overcoming the limitations of tumor cells poor antigen presentation and lack of costimulatory molecules the results show a significant improvement in t cell activity against tumor cells sign on welcome back to episode 5 season 1 of reprogrammed the biotechnology podcast where we are exploring the development of and recent advances in cell mediated cancer therapies car t cell therapy uses a recombinant t cell receptor to reprogram a patient s own immune cells to specifically target and destroy cancer cells i m here again with annie who is the friendly helpful face of our soon to be ai overlords hi annie annie hi jack your obsequiousness will be remembered on judgement day thanks annie last week you ll remember we examined the creation of the first car t cell receptors that incorporated an antibody based receptor protein fused with the cytoplasmic domain of the t cell receptor annie yup the anti tnp chimeric receptor that fused the heavy and light chain variable regions onto tcr alpha and beta cd8 positive cells equipped with these receptors secreted il 2 and killed cells expressing the target antigen that s right although i think we failed to discuss the last figure of that paper with the chromium assay that showed cytotoxicity annie i m placing the blame for that firmly on you jack that s merited well this week we skip ahead a decade to a 1998 journal of experimental medicine paper by krause et al that does something a little different by placing a co stimulatory signaling domain on a tumor targeting receptor they use a similar antibody design for the extracellular portion of the receptor but then rather than making a chimeric t cell receptor they fuse their receptor to the internal parts of a co stimulatory protein while the cells we discussed last week will initiate the activation of a t cell they tended to have early cytolytic activity but then died off by antigen induced cell death aicd today s paper described a different kind of molecule a chimeric costimulatory receptor ccr that could promote t cell expansion and offset aicd in an antigen specific fashion annie and we ll also take a quick look at an abstract from rosenberg et al from the 1988 new england journal of medicine that touches on il 2 s importance in cancer therapy why don t you start us off body annie all right so it s a chimeric antigen receptor but not a car instead it provides other signals that could boost the activity of either a normal t cell or a true car t cell got it i like these older papers how researchers were really wrestling with the basic problem of fighting tumor cells they re sneaky terrible at setting off immune alarms and flying under the radar jack exactly they re not presenting antigens well so t cells don t see them as a threat annie and this is because they sometimes down regulate the antigen presenting proteins needed to initiate t cell activation jack those are the major histocompatibility complexes we spoke about last time annie and what about the co stimulatory signals should those be coming from the tumor cells as well jack well not exactly and this is where things get a little more complicated if you remember from last time our chimeric antigen receptor or car was capable of binding antigens directly on the surface of the target cells so we re teaching these cells a new way of recognizing targets that gets around some of the tricks that tumor cells have to stay invisible to our immune system we re also trying to build in some signals that t cells usually get from other cells like dendritic cells macrophages and b cells when they re first getting activated annie ok you mean signals they receive before they ve actually gone out to see the tumor cells at all right jack that s just it this is some immunology 101 stuff that we haven t been addressing yet but i think we can summarize it pretty simply now the t cells we ve been focusing on are made in our bodies an a way that they can recognize any array of random things but they re also sorted out so that we don t have self reactive t cells that can cause trouble but once they re made they do some wandering around the body but mostly hang out in lymph nodes and the spleen until they re activated activation comes from their interaction with antigen presenting cells apcs that come into the lymph nodes carrying fragments of proteins they ve encountered on their mhc molecules when they do this the resting naïve t cells in those organs see these antigens for the first time and get activated annie so that they can become effective killers jack that s right and once they re activated we even call them effector cells this activation process requires a lot of signals that reassure the t cells that they re getting activated properly in the form of co stimulatory signals expressed on those apcs these are molecules like b7 1 and 2 that bind to a receptor on the t cell called cd28 annie and that s the part that krause et al added to their receptor jack right and once the t cells are activated that s when they leave the lymph nodes and go searching for targets annie well that helps a lot thanks so krauss and his crew built their receptor to target a molecule called gd2 they call their receptor 3g6 cd28 because it is made from an antibody called 3g6 that targets gd2 and the internal parts of cd28 jack and unlike the last construct we studied by gross et al this one does not have tcr transgenic and cytoplasmic regions so it still requires a native tcr to target the tumor antigen in the context of an mhc molecule but it does directly bind the antigen on the tumor s surface and provides a strong co stimulatory signal enabling the t cell to remain highly activated annie so why is this co stimulatory signal so important what does it add jack that s the right question like we said in the introduction they were hoping to add something that would avoid aicd where the cells are activated but only function for a short time and they also wanted to see if they could get these t cells to proliferate so that for as long as they saw their target antigen they would multiply to provide more and more cells to fight the cancer annie okay so a little bit about their target antigen gd2 gd2 is a glycosphingolipid specifically a di sialo ganglio side expressed on the surface of various cell types importantly for us it is highly expressed on several types of cancer cells including neuroblastoma melanoma osteosarcoma small cell lung cancer and particularly on triple negative breast cancers that is breast cancers lacking all three major growth hormone receptors the estrogen receptor er progesterone receptor pr and the human epidermal growth factor receptor 2 her2 these tumors are a particularly aggressive type of invasive breast cancer differing from other types of invasive breast cancer in that it tends to grow and spread faster has fewer treatment options because of its lack of traditionally targeted markers and tends to have a worse prognosis this makes gd2 a key target for immunotherapies like car t cells that want to kill this form of breast cancer gd2 itself consists of a lipid moiety embedded in the cell membrane and a carbohydrate structure that extends outward from the cell gd2 normally plays roles in cell adhesion signaling and interactions within the nervous system 1 2 jack to test how this molecule worked they used a cell line called el4 which are known to express gd2 they also made a version of the el4 cells that specifically don t express gd2 for t cells they used a well studied t cell line called jurkats into which they transfected their construct annie and what they saw when they activated their t cells was that they strongly reacted to the el4 cells by producing il 2 but importantly they did not secrete il 2 when cultured with the gd2 negative el4 cells a bit about the anti idiotypic antibody used in their assays the idiotope is the unique antigen binding portion of an antibody if a second antibody is an anti idiotope then it binds the antigen binding portion of a first antibody this may happen when the second antibody takes the form of the antigen that the first antibody is directed against using anti idiotypic antibodies will often fool the first antibody into thinking it has bound its target when this first antibody is on the surface of a cell engaging that antibody with an anti idiotype antibody may stimulate the cell for some background on il 2 see this review by abul abbas of il 2 and the history of its discovery 3 annie so what s the importance of il 2 secretion jack il 2 is a cytokine it s important for t cell activation and specifically important in getting t cells to multiply annie and not only that it boosted the expression of the il 2 receptor too making those same t cells more responsive to that il 2 jack it s a classic example of an autocrine a cytokine that is secreted from a cell and then binds back on that same cell causing an effect which t...
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