The Future of Cancer Therapy: How Base Editing at Beam Therapeutics is Changing the Game (BEAM-201)

The Future of Cancer Therapy: How Base Editing at Beam Therapeutics is Changing the Game (BEAM-201)

Uh up until now Ray doing more than two Or three without some challenging Engineering in the lab with crispr Um was a non-starter but now with base Editing we see that especially T cells Are highly amenable to this process and We can knock out multiple things at once Which are necessary to create these Allergenic RTS so hello and welcome to The cheeky science show where in this Video I spoke with Ryan Murray a PhD Student at Northeastern University who Has also spent the past seven years Working at beam Therapeutics a company Developing Precision genetic medicines Where Ryan has been involved in Developing beam 201 and immunotherapy That involves base editing of immune Cells to treat cancer So hi Ryan thank you for joining me Today and welcome to the cheeky Science Show Thanks for the invite I’m really happy To be here and talk about anything Science related excellent well what I Know about you so far is that you spent Around six or seven years at beam Therapeutics and so uh beam Therapeutics Is a biotech company that is developing A Precision genetic medicines in Particular using a tool called base Editing so I thought that a logical Place to begin would be to ask the Question what exactly is base editing

And how does that fit into this umbrella Term of Gene editing Yeah so base editing is Um a derivative of crispr cas9 so I Think everyone’s probably pretty Familiar with Um crispr at this point it’s sort of the Next evolution of crispr so Um this technology started out at David Lou’s Lab at Harvard and was licensed to Beam so we utilized this platform to do All of our Gene editing and Um personalized medicine here and Basically it’s a modified version of Christopher cast 9 that doesn’t generate Double strand breaks so the the protein No longer has its nucleus ability but it Is fused to another protein Typically a deaminase which can Chemically modify specific base pairs in The DNA so one of the ones that I’ve Been mainly working with is our sea base Editor so it can chemically modify C’s To tease in the genome and directly Correct point mutations anywhere in the Genome so unlike again the traditional Crispr cas9 where that will cleave a Specific area of the genome we’re Actually going in and chemically Modifying bases from one base pair to Another base pair Okay and so what are the advantages of Using this approach as opposed to the More canonical crispr cas9 approach

So they’re both highly specific and Where we can direct them within the Genome so they they share that ability Of going to uh very specific regions of Interest Um but again the base editing doesn’t Generate any double strand breaks so you Can imagine you know cutting up the Genome cells typically don’t enjoy that So there’s a lot of danger signals that Potentially are turned on especially in More sensitive cell types like stem Cells or neurons Um and the cells have to go through DNA Repair Machinery we don’t induce those Same double strand breaks so there’s not As much of those dangerous signals Um with that base editing can be highly Multiplexed because there’s not a lot of Double strand breaks being generated Within the cells which might cause a lot Of genotoxicity or genomic Rearrangements as there’s a bunch of DNA Fragments floating around within the Cell so we can avoid that toxicity as Well but I think a huge advantage of Base editing which is what beam is Focused on is directly correcting Genetic disease So a vast majority of genetic diseases Are actually caused just by a single Point mutation So you can think of actively pushing a Base Editor to that specific site and

Just correcting that one base and Effectively curing that disease whereas You can do something similar with Um crispr cas9 and it can cut in that Region but that usually Um results in quite random insertions or Deletions in that site so if you’re Looking for a disease that you just need To knock out a protein or temper some Sort of pathway that usually is probably Sufficient and I think that is this First wave of crispr Therapeutics that Are coming out where most of them are Faulty Pathways or faulty proteins that You just want to remove but there’s Plenty of diseases and mutations that You don’t just want to remove you might Actually want to correct so there’s Plenty of other uh Applications of Base editing where you Do not want to actually remove the Protein on top of avoiding those double Strand breaks which could be hazardous I see and so as you mentioned you can Use space editing to change the single Bases so if that was like a genetic Genetic disease that was caused by a Single change in a base you can fix it But in some diseases sometimes you get Overexpression of certain genes and is It true that you can also use space Editing to sort of Silence gene Expression and like if say like where Exactly do you target the base editing

Machinery Yeah so that’s um uh what we do here for Most of the projects that I work on in The Immunology Department we’re focused A lot on gene silencing and Gene Knockout so if we are utilizing that c Bass editor Um we can introduce premature stop Codons by changing specific C’s to T’s And installing those somewhere Midway in A protein so it will prematurely stop Translation of that protein and Effectively knock that out or we can Target conserved regions at the intron Exon boundaries of genes and these are Important in RNA splicing so if we Disrupt those specific regions then RNA Splicing is improper and then those Faulty mrnas are typically degraded Resulting in a knockout of that protein As well so there’s two different ways That we can Um knockout proteins with the sea base Editor we also have an a base editor Which changes A’s to G’s and in that Case we can also Target and disrupt Start sites so there’s no actually Initiation of uh transcription Translation because there’s no no proper Atg start site that we can then mutate With that abase editor so there’s three I guess big Windows of of how we can Knock out protein effectively with the Two different flavors of Base editors

Aku and so you mentioned that you’re Part of the Immunology department and Besides crispr and like this big Umbrella Town being a sort of amazing Advance we’ve had in the like the recent Decades another really big Advance has Been this um idea of using chimeric Antigen receptor T cells uh car T cells Is what they’re also referred to so I Know that you’ve been sort of combining These two tools together in uh beam 201 And so I thought maybe you could explain What are these car T cells and what’s The logic behind how they function Right so yeah we do a lot of work here With car T cells essentially uh car T Cell is this fusion protein that is Derived by engineering uh The Binding Domain of an antibody with internal Signaling proteins from a T Cell so we Can redirect these T cells to Specifically recognize cancer antigens Um and then they’ll effectively kill Them so Our beam 201 concept is a multiplex base Edited car T Cell product targeting T-cell Um t-a-l-l so it’s a T Cell leukemia and The problem with using car T cells for T Cell diseases is there’s a huge problem With fracture side right so the antigen That we are targeting is known as cd7 And it’s expressed on healthy and Malignant T cells so if we engineer a T

Cell to Target cd7 it will also kill Healthy T cells including the car T Cells that we’re putting into the Patients so in order to to enable that We need to remove cd7 from the car T Cell surface so they will no longer be Able to kill other car T cells before They go in and kill the cancer so that’s Relatively straightforward with a crispr Cas9 right and there have been certain Clinical trials that have shown efficacy By just knocking out cd7 with crispr and Reinfusing those into page Um however those strategies right now Are Autologous strategies so Taking the patient’s own T cells out and Then engineering them in the lab and Then reinfusing them back into the Patient Um that means each time that that Therapy is developed it’s Personalized so the manufacturing is Quite challenging because you have to do It for each patient needs its own Manufacturing run these patients Obviously have cancer so their immune System is not Stellar to begin with so getting enough Cells out of the patient and enough Functional cells that can go through the Manufacturing process has been a Challenge so there’s this new Or relatively Resurgence in allogeneic

Car T cells so it’d be taking T cells From a healthy donor engineering them in The lab and reinfusing them to the Patients so you can imagine doing this Outpatient generating a giant Bank of These T cells and keeping them in the Freezer At a hospital and just taking them out And infusing them to the patient Whenever necessary instead of having to Go through some of these manufacturing Processes could be two three four weeks Before the patient can get their their Therapy so it speeds that up and sort of Subverts the potential manufacturing Fields that you might get with diseased Patients T cells but the only problem With that is you know infusing T cells From one person into another creates uh Immunological problems right your body Will then see those T cells as foreign And try to get rid of them and vice Versa right the therapy the car T Cell Therapy will see the patient’s immune System has foreign and tried to get rid Of that so in order to enable that we Need to edit out multiple things on top Of cd7 Which Until you know base editing was much Much more challenging because of this Need to Multiplex and multiplexing with Crispr cas9 as we already went over is A technical hurdle so with base editing

It’s really amenable to multiplexing and We took advantage of that to develop Beam 201 so we removed cd7 to prevent The car T Cell fratricide we then edit Out the endogenous TCR on the car T Cells so they no longer have the ability To recognize the patient cells as Foreign so it reduces our risk of gvhd Or graft versus host disease and then we Also removed cd52 from these T cells so We can combine this with a Lymphodepletion agent cam path which Should remove the host immune system and The cancer cells and then we can Reinfuse our car T cells they won’t bind To cd52 and they have room to grow and Attack the remaining cancer that might Be in the patient And then we also removed pd1 which is Just in a immunosuppressive protein so We’re hoping that that will increase the Efficacy of these car T cells Um once they see any pd1 ligand on the Tumor cells within the patients so we Needed four edits to be able to enable This I would say two were absolutely Necessary right we needed to get rid of Cd7 and needed to get rid of the TCR in Order to enable this allergenic cell Therapy and then cd52 and pd1 were sort Of to enhance the potential power of the T cells once they’re infused back in the Patient so up until now Ray doing more Than two or three without some

Challenging Engineering in the lab with Crispr was a non-starter but now with Base editing we see that especially T Cells are highly amenable to this Process and we can knock out multiple Things at once which are necessary to Create these allergenic artists That was yeah super well explained and You kind of um a lead to the point of How challenging multiplexing can be and I remember seeing some of the data that You you showed on a poster back in 2020 I think where it was shown that you had Really high efficiency for these editing As well like somewhere between like Around 95 and so it sounds kind of like It was a very easy process to generate This but I’m assuming that probably Wasn’t the case and so what sort of Challenges um arose during this Development process and Um how did you achieve such high Efficiencies in these pre-clinical tests Yeah so I guess that is Potentially a downfall for base editing Right so for with crispr cast 9 you just Need it to cut anywhere and wherever it Cuts if you’re knocking on a protein is Great so there’s many more sites that You can direct the the cas9 to that can Cut within your Gene of interest that Will effectively knock out your your Protein but as we talked about before Base editing specifically changes

Certain bases in certain areas so we Need to find a start site we need to Find those intron Exxon Junctions or we Need to find places where we can install Premature stops so that has all to do With the Pam Motif that will direct the Cas9 to those locations so We might be able to find those locations Within the genome but there might not be A place next to it where there’s a start Site or a place we can put a stop if it Was a nucleus it would just cut there Anyway and you would be good to go base Editing has a little bit more limited Subset of places where we can edit that Will effectively knock those out so we Had to do a lot of pre-clinical Discovery work to find guides that go to The right places and have really high Editing efficiencies so just based on You know 3D and 4D structure of DNA and Chromatin whether you can get your Protein there whether that DNA is Accessible and then editable is a Challenge so we had a screen through a Bunch of guides that not only worked by Themselves but in Multiplex and we just Happened to find these couple that had Really really high editing efficiency Again T cells seem to be very amenable To this we got really lucky in that case Where Um you know upwards of 99 editing is is Pretty impressive but it’s not always

The case with every Target for every Cell type right so it takes a lot of Optimization not only of the location of The genome you’re editing but of those Guides themselves right so you can Change the chemistry of the guides in Their specificity To improve their on target editing and Also reduce their off-target editing Right we only want it to edit where we Want it to edit so we don’t make sure That we’re knocking out or changing Anything else in those T cells that Don’t have a therapeutic benefit Yeah so for my understanding this this Approach for the therapy is to have it Being xvivo so the idea is do you have These T cells that you generated that Have these uh correct edits that you can Then give to the patients and so um once You’ve done it once and you’ve created I Guess like correctly edited T cells Um do these T cells replicate and then You can store them or would you have to Sort of repeat this editing process Um like on batch to just keep a fresh Stock Yeah so our clinical strategy is going To be Um essentially isolating T cells from a Healthy donor then we activate them so That we can introduce the car with a Lentivirus and then introduce the base Editors and do the four edits

Um once those two engineering processes Are done we do expand the T cells up Um and then we create a giant Bank of Them so in theory this this Bank lives In the freezer and it should be able to Service A number of patients right so depending On The patients uh and the dosing will Depend on how many we can treat but I Would say you know 50 100 200 is is more Of the ballpark we’re aiming for unlike The autologous ones where it’s one Engineering Process per patient so we Can actually get many more treatments Out of one engineering run than we could Previously with autologous Okay see and so where exactly is uh beam Two one in terms of its clinical Progression So we have just gotten approval from the FDA actually the end of last year to Initiate clinical trials so we’ve have All of our editing strategy Um and uh safety Um okayed and now they’ve been produced We have a donor it’s been produced at GMP scale we’re ready for the clinic so Now we’re just going through the process Of finding clinical sites and enrolling Patients so we’re hoping at some point This year that we can enroll some Patients and actually treat some Patients with beam 201

Oh wow that’s really exciting news Um so given that uh beamta wants to know The success and now heading towards the Clinic what is what is your sort of like Day-to-day look like are you still Working on a similar strategy but Elsewhere Yeah so now that we know that Car T cells are really amenable to base Editing we sort of wanted to take that Knowledge and the success that we saw With beam two on and essentially restart Right so Um our team Works more on the Discovery End so the beginning of the pipeline and Now that beam 201 is in the clinic we Are you know sort of done with that that Process so we’re now focused on Utilizing Multiplex space editing to Really improve allergen and car T cell Therapy right so I only mentioned that We we knocked out the TCR in beam 201 to Prevent graft versus hosts but there is A number of ways that the host can Affect the graft right so the patient Immune system might see these cells as Foreign and effectively get rid of our Car T cells before they’re able to see And kill any of the cancer so that’s a Really big problem with allergen ant car T right now is their durability And how long they can persist within the Patients before they can actually do Their job

So we are now looking at multiple ways To use base editing to improve that Durability so there’s a number of Different ways an immune system can see Something as foreign and remove it and We’re trying to alter or silence those Pathways to give the car T cells a Better chance at persisting and Expanding within the patients so that They can fully you know exert their Anti-cancer potential okay and just out Of interest because this is not so much My specialty but what is the durability So far is it noon Durability so far so for autologous Cells usually you can see efficacy Within a couple weeks right the T cells Most of the success has been in blood Cancer so the T cells are highly Proliferative in the blood there’s a Bunch of cancer in the blood So within a Couple weeks to a month you can see car T Cell efficacy and then in autologous Patients right those aren’t then removed Because they’re your own cells so they Can live in theory indefinitely there’s Been a number of years where they can Still detect car T cells in patient Blood for allergenic car T cells because Of all of those barriers with the Mismatching the durability On average I would say is around a month It’s getting better and better with I Think they have some indication of car T

Cells at least durability of response Going out to a year but for most of them The the immune response kicks in pretty Quickly and durability around a month or Two is is more common so we’re looking To expand that in hopes of Increasing the time that the therapy Remains in the patient and increasing The anti-cancer potential of those cars As well okay see and I guess yeah the Second benefit from knots is if you can Increase the durability then the number Of times you have to give the patients The T cells can also decrease right Right yes so so you’re you’re hoping That you know your dose effective dose Will remain high because the T cells the Car T cells aren’t being removed by the Patient immune system and I think that Is is probably one of the major problems Where the effective dose that we’re Giving the patients actually decreases Over time because of the immune response So we’re hoping to to avoid that Situation and Um keep the car T cells in there as long As they need to do their job Say I’m aware that you’re doing a sort Of you see at the moment but it’s more Of like an industrial PhD and also You’ve been spending a lot of time Working out beams so as a PhD student Myself I’m just kind of curious like What is this program that you’re doing

And how are you um what does it really Involve Yeah so I’m doing Um an industry PhD at Northeastern University in Boston so essentially I You know went through the process as a Typical grad student of applying getting In picking a lab picking a project And have to go through you know passing Qualification exams publication and Thesis defense but the unique Interesting part of this program is it’s Industry sponsored so I’m doing my PhD Joint with Bean right so I’m a full-time Beam employee but also a full-time grad Student hello So I’m using beams platform to do some Discovery work around the PHD thesis So it sort of works as a PhD that’s Sponsored by the company so I get to use Their platform do a bunch of Discovery Work for beam as we’re always trying to You know push the bounds of Base editing Really figure out what a can and can’t Do and that typically right is not top Of company priority we’re here to Understand the biology and get things to The clinic and get things to the Patients sometimes Discovery can take a Back seat so this was an interesting Avenue for the company to sponsor some Academic research to actually go into More basic science and really understand How to utilize space editing for car T

Cell therapy right and then the University also you know gets a little Bit more of a translational Bend of the Research because Beam still wants to Potentially utilize this in a clinical Setting Um if the the research works out right Some sort of on this line in between Both which has been really exciting but Really awesome to be able to utilize Beam space editing technology and really Dive deeper into the details and how to Use that for car T and then also you Know be an academic but have a really Translational project that if works Could hopefully be translational to the Clinic in the future Do you like having this ability to be in Sort of Both Worlds Yeah I like the so I’ve always been in Sort of discovery type groups I’m in the Discovery Immunology here and I really Like that sort of as basic as you can Get in a company research there’s a lot Of freedom with what targets we can go After what indications we can go after Because essentially we’re just trying to Discover anything that works and once Something works we can then formalize That into a clinical program Um I really like that tangible aspect of Industry and biotech of you know that Can potentially like be 201 right to Come from the lab and go into a human

Therapeutic I think for me for Academia I love the freedom I love that it’s even More freedom than I’m used to having Here Um with a traditional biotech job where You really can do anything and really be Exploratory so I find that Intellectual challenge really Stimulating I think that that is scary At times but really really fun to sort Of go in any direction the science takes You go any direction that you’re you can Think of Um but it does still then lose that Really tangible concrete you know Product at the end that I I really enjoy Um so I like being on this this fence Where You can do a lot of exploring but then You bring that back and then you Hopefully try to formalize that into a Therapeutic so I think I’ll probably Stay in biotech but hopefully I can stay In the beginning of the pipeline like This and really try to Keep it as empirical as I can That’s cool and I’m currently if I’m Wrong but I believe you I guess novel applications or trying to Commercialize early stage research and So um besides base editing like what are Your thoughts on biotech in general and Are there any other like exciting Technologies that you’re like sort of

Excited about Yeah I think so base editing I would say Is new Um I think maybe one of the seminal Papers came out Maybe in like 2017 so it’s fairly new Fairly fast to Clinic I would say but Already there’s so many other Gene editing technologies that have come Up so Christopher cast9 probably came Out you know a couple years before that And we’ve already replaced it with base Editing which is already replaced with Some other things so whether it’s you Know RNA editing DNA writing there’s a Bunch of Different applications and different Editors which I find very exciting They’ll all have I think their own Little niche and how they can be used as A therapeutic so they’re sort of more Additive than replaced Um I obviously think that’s really exciting I think the alginate Excel Space is Really interesting and whether that’s Gene editing as the technology that Enables that or not I think that will be Really transformative I think cell Therapies in general have shown really Great promise whether it’s car t or Otherwise but that I think is now the Next major hurdle is how can we actually Make them fully immune silent to really

Do this at scale really do this for a Wide variety of diseases Um I think the in Vivo Uh therapeutic landscape is really Exciting so not having to remove these From patients anymore and do all the Engineering in the lab which takes you Know a lot of technical expertise but Being able to do that in the body or Utilize cells within the body that can Already Um do this for you I think could be huge Right I think it would treat a lot more Patients I think it would be a lot Easier on clinicians so I think that Could be a really Powerful therapeutic modality in the Future I think it’s still pretty early I Think everyone’s really comfortable with Taking things X Vivo and doing it in the Lab because you can do whatever you want And you have full control so figuring Out how to create those in Vivo Therapeutics safely and effectively I Think is the challenge for that but There’s a ton of work being done on it And I I think that we’ll get there quite Soon There’s so many exciting Technologies Um being the fellets right now I mean as You mentioned it’s like Prime editing There’s things like face uh paste Editing that I think a preprint came out End of last year too so um yeah many

Exciting things happening and I know That with beam toe one this is uh the First multiplex space editor is that Crowds yes yes I think this is the Highest plexed editor that will be Um in the clinic so we we got four for Now but we’re working on adding more Since base editing is quite flexible so I would stay tuned and I think we might Be seeing more than four edits from beam And from some of these other companies That have things that are uh Advanced Upon base editing I think it’s going to Be quite the norm to uh do things that Are highly Gene edited but also highly Orthogonal in their engineering Strategies right so it might be you know 4G edits and then four synthetic biology Approaches or something right so I think That cancer Especially is really really challenging Um so I think multiple modalities are Going to be needed to be paired together To really create effective Therapies in The future so this is just the beginning Nice why the most an excellent way to End that conversation it’s been great to Talk to you Ryan and you’ve explained Everything so nicely but um it’s been Very easy for me to sit here and like Ask simple questions so yeah I’m excited To see um the progression with these Clinical studies and hopefully seem Being Taiwan um too too well

Yeah yeah we’re really excited to to see What it can do this year we already got A a little Glimmer from um Great Ormond Street hospital so UCL put in a very Similar Therapeutic and they’re seeing really Great results with that as well so we Are very excited to see how beam 201 Doesn’t compare to that Oh best of luck with that and yeah thank You again Onto the show yeah thanks for having me So I hope you’ve learned something in This video thank you to my patreon Supporters and thank you for listening

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