Translational Science in Hematologic Malignancies

Transcript

• 00:00Welcome again to Cancer Center.
• 00:02Grand rounds, good afternoon
• 00:04and as is often the case,
• 00:07is always the case in our forum.
• 00:10We have some really exciting data and
• 00:13progress and science and clinical
• 00:16care to share with you in this.
• 00:18The theme for today,
• 00:20which is a really interesting one and
• 00:23different because we have multiple speakers,
• 00:26is in hematology where we've made,
• 00:29I think, enormous progress.
• 00:31And we're both biology translational work,
• 00:34population science and clinical care in
• 00:37the major hematologic latency is leukemia
• 00:41and myeloid malignancy's lymphoma.
• 00:43Multiple myeloma where I think we have
• 00:46really talented people working on these
• 00:50problems and really translating science
• 00:53into progress for our patients and
• 00:56looking forward to all four presentations.
• 00:59But I I will actually turn to our.
• 01:04Essentially, our leader and host for
• 01:06the session to make the introductions,
• 01:09so I'll start simply by introducing
• 01:12Doctor Stephanie Allyne.
• 01:13As you know,
• 01:14Stephanie is the chief of hematology at Yale,
• 01:18as well as an associate
• 01:20professor of medicine.
• 01:22In addition,
• 01:22Stephanie Overseas the DeLuca Center
• 01:24for Innovation and Hematology Research,
• 01:27which is really an exciting
• 01:29addition to our work in hematology,
• 01:32with the promise that not only
• 01:34translating our discoveries
• 01:36into clinical care innovation.
• 01:38But also in furthering the support
• 01:41of our faculty and trainees.
• 01:44Stephanie joined the faculty in Yale in 2006.
• 01:48An we were so pleased that she was
• 01:51selected as our new Chief in 2020
• 01:53and is doing a great job and looking
• 01:57forward to her an our faculty
• 02:00sharing the exciting work at Yale.
• 02:02So Stephanie I turn to you.
• 02:07Let me share my slides.
• 02:11OK, can you see the slides well?
• 02:14Yes, OK, Alright,
• 02:15let's tally Saturday will preside,
• 02:16present or represent on translational
• 02:18science and hematology.
• 02:19And there will be four of us,
• 02:21so I will be the one driving the slide.
• 02:24So any hiccups blame me.
• 02:26Um, so I'll be.
• 02:27I'll be giving a brief introduction
• 02:29to hematology and then tomorrow
• 02:32probably will present on behalf
• 02:34of the myeloid malignancies team
• 02:36and traumatizing associate,
• 02:38professor of medicine,
• 02:39hematology,
• 02:39and he's a director of the MLP
• 02:43malignancies disease team and
• 02:44the firm chief of the data firm,
• 02:47and everybody knows just how
• 02:49much moving Anan changes had to
• 02:52happen over the past years to
• 02:54keep our clinical services alive.
• 02:56And to my actually completed his
• 02:59doctor rent in medical hematology oncology.
• 03:02Myung then joined the Paoli
• 03:04Calmettes's Institute in Marseille
• 03:06and did a full ride scholarship
• 03:09at Johns Hopkins University,
• 03:10and I think that's how eventually
• 03:13he landed with us.
• 03:15With Steve Gore recruiting him.
• 03:17After tomorrow, Doctor Francine Foss,
• 03:20Professor of Medicine and
• 03:21hematology and Rheumatology,
• 03:23would present on behalf
• 03:25of the former team and.
• 03:27Francine really is the expert in
• 03:29T cell lymphoma, internationally,
• 03:31nationally, renown,
• 03:32and she's a research director of an
• 03:34informal disease team and obviously
• 03:36director of the Tucson Informer program,
• 03:38and you will hear exciting news
• 03:41what is happening in the format to
• 03:43selling Thelma and last but not least,
• 03:46doesn't Italian infrared,
• 03:47so will present on behalf of the
• 03:49multiple myeloma disease team.
• 03:51And she's the research director
• 03:53of the much more disease team
• 03:56and an assistant professor in.
• 03:58Medicine medical oncology.
• 03:59She actually obtained her medical degree
• 04:01in Tennessee and the country of Georgia,
• 04:04then did postdoctoral fellowships at Emory
• 04:06Northwestern and Lucky for us a deal.
• 04:09She did her residency and fellowship.
• 04:11Odiele refill Oscar left us,
• 04:13but we were able to recruit her
• 04:16back to be part of the team.
• 04:19So um,
• 04:19before I introduce much about hematology,
• 04:22I think it's absolutely time that
• 04:24we all say thank you to Charlie.
• 04:27So Charlie,
• 04:27you took over as our interim
• 04:30section Chief in January 2018
• 04:31and has been a just wonderful,
• 04:34wonderful journey since then.
• 04:35So you can see just how big the
• 04:38group is in hematology and growing.
• 04:40And I just want to read a few
• 04:43of the quotes from our faculty.
• 04:46And that is so Charlie,
• 04:48you recognize the strength,
• 04:50resilience and enthusiasm in
• 04:51the new teologi faculty, staff,
• 04:53advanced practice providers,
• 04:54nurses entry needs,
• 04:56and you supported our teams in so many ways.
• 04:59Thank you for the leadership and
• 05:01commitment you provided as interim Chief.
• 05:04Your strong support and advocacy
• 05:06for our section is not appreciated.
• 05:09Thank you for being an outstanding
• 05:11leader and role model for trainees
• 05:13through your dedication to
• 05:14excellence in patient care,
• 05:15teaching and innovation.
• 05:16It has been an honor to learn from
• 05:19you and the excellent faculty of
• 05:21your Cancer Center and thank you
• 05:22for everything you've done for the
• 05:24Cancer Center and was a section of
• 05:26hematology over the past several
• 05:28years. You have been a wonderful resource
• 05:30and a guide from my academic growth,
• 05:32and I'm extremely grateful to you.
• 05:34So thank you, Charlie.
• 05:37Thank you in the entire division.
• 05:39It's a real point of pride to me
• 05:42to have been a member and now and
• 05:45along of this very August center
• 05:48of excellence. So thank you.
• 05:52And we have a little bit more in store,
• 05:55so the thing we really wanted to thank
• 05:57you for is how you have supported all
• 06:00our people and recruitment of all
• 06:02these people highlighted in yellow.
• 06:04You know Murrayshall is to my like
• 06:06my name is this team chilling costar
• 06:09Intercine safely to the lymphoma team.
• 06:11Barbona is our director of classic
• 06:13hematology, Sabrina Browning as a member
• 06:15of our myeloma and come up as a team.
• 06:18And as you can see,
• 06:20also of our billing team.
• 06:22And then in addition to that,
• 06:24you have recruited hematology
• 06:26focused faculty to the to the Smiler
• 06:28network and the care centers,
• 06:30and we're so fortunate to work
• 06:32with all our colleagues.
• 06:33And of course Mike's mission as a director
• 06:36of the Center for Molecular and Cellular.
• 06:38I always say hematology and oncology
• 06:40in there were so excited about,
• 06:42you know, all our new people and teams
• 06:45and what we can achieve together.
• 06:48So, um,
• 06:49so now in my introduction to hematology.
• 06:51So what you see here is kind of our.
• 06:54These are hematology core teams.
• 06:56I say core because these are the
• 06:58people located in in New Haven,
• 07:00North Haven.
• 07:01And these are the teams that are
• 07:04working hard to bring the best patient
• 07:06care to all patients in Connecticut
• 07:08and beyond through their research
• 07:11that clinical care and collaboration
• 07:13was all the teams we have smile.
• 07:16Oh yeah, even health and University.
• 07:18So we have five teams in my life
• 07:21malignancies team, an informer team,
• 07:23the stem cell transplant,
• 07:24and South Therapies team.
• 07:26We call it classical hematology
• 07:29because as we all know.
• 07:30Behind him, disorders are not that denied.
• 07:33Our patients are quite ill and then our
• 07:35minds from my Loma and commodities team.
• 07:38So as I mentioned before,
• 07:40we're not alone.
• 07:41We're not just a small,
• 07:42tiny little point on the map in New Haven,
• 07:46but through our smaller network we
• 07:48have reached across the entire state
• 07:50and it is just wonderful to know that
• 07:53we can bring the excellent signs and
• 07:55treatment to all patients in Connecticut.
• 07:57Then again,
• 07:58here I'm highlighting our
• 07:59hematology focused faculty,
• 08:00which is also new over the last.
• 08:03Several years and it's just wonderful.
• 08:07How much team building we can do?
• 08:09There are many discussions already going
• 08:12on between our disease team leaders
• 08:14and faculty and tremble in North Haven,
• 08:17Guilford, Hardford and all the other places.
• 08:19So it's wonderful opportunity.
• 08:22Um,
• 08:22we're not alone and we're not
• 08:25doing this in isolation,
• 08:26so we're fortunate to be at a
• 08:29place like here where there are
• 08:31many different centers there.
• 08:33We have our Decker Jews tallied
• 08:35in the clinical Trials Office.
• 08:37Again,
• 08:38Marcus leading that CMC L Michaels
• 08:40bosenberg leading yell center
• 08:41female oncologix Mark Lemon,
• 08:43leading the year Cancer Biology
• 08:45Institute kinda Neugebauer,
• 08:46leading the Larne Center.
• 08:48And then Diane Krause in the my C Age
• 08:52and then cheers of the different departments.
• 08:55Chengdu for pathology.
• 08:56David charts now Department
• 08:57we know immunobiology.
• 08:58We have collaborators in
• 09:00the stem cell center.
• 09:01We have collaborators in the Copper center.
• 09:04Marcella Nunez Smith just gave a
• 09:06talk to to the leaders this morning
• 09:08and Antonio riders and many,
• 09:10many more that I can't even
• 09:12get on this slide.
• 09:16So, um, I just wanted to give a brief
• 09:19update on the Delucas Center for
• 09:22Innovation and Hematology Research,
• 09:24another amazing initiative that Charlie
• 09:26made happen and we are now we've just
• 09:29riding our progress report for the past
• 09:32two years and just to give you an update.
• 09:35So we have a very active hematology
• 09:37tissue bank with samples from patients
• 09:39with all human to logic disorders.
• 09:42We have over 4000 samples from over 2000.
• 09:45Nations, we have a bone marrows prefer blood.
• 09:48We're working **** ** also collecting lymph
• 09:51node tissue and other tissue biopsies.
• 09:53And we also offer specialized processing
• 09:56for clinical trials in hematology.
• 09:58And this is again a huge.
• 10:00Team effort so you see our core people
• 10:03on the right and Michelle Patel,
• 10:06rounder, Feli,
• 10:06Padma Mamillapalli and our latest
• 10:08recruit Jennifer from donor Hoban.
• 10:10But everybody in hematology
• 10:12is contributing to this.
• 10:13All our aips an MP7 in North
• 10:16Haven at Trumbull.
• 10:17Another care centers and we hope to leverage
• 10:21this tissue bank to better understand
• 10:23these users and offering treatments.
• 10:26We have awarded 9 pilot
• 10:28grants or $50,000 each.
• 10:29Our goal is to have these being
• 10:31through these be collaborative between
• 10:33collisions and basic scientists.
• 10:36We have one career development
• 10:38award E chaining cathari.
• 10:39These are two year awards and the
• 10:42our base posted for new applicants.
• 10:45We have many many applications
• 10:47publications that I could not list here.
• 10:49We have installed the freezer
• 10:51works by repository database and
• 10:54we're very close to populating it.
• 10:56This data that eventually will allow
• 10:58clinician scientists in a deidentified
• 11:00manner screen what we have in the
• 11:03database so they can come up with ideas
• 11:05and let us know how we can help them.
• 11:08We're providing access to novel technologies.
• 11:10Jennifer Amisha Jazz performed single
• 11:12site DNA sequencing for clinical
• 11:14trial samples for to Maccabean.
• 11:15We have many more ideas and we are also
• 11:18seeking to provide Technical Support for
• 11:20correlative studies and data analysis.
• 11:24So let me now go over to the disease teams,
• 11:27so this these are the members of the stem
• 11:29cell transplantation cellular therapies team,
• 11:32but they will not present today
• 11:34because you should stay tuned and log
• 11:37into the Young Cancer Center grounds.
• 11:39I think it's March 23rd when
• 11:41Doctor Supinder for her with her
• 11:44present on cellular therapies.
• 11:46You will also not here today from
• 11:48our classical hematology team,
• 11:49because Doctor Boner just presented
• 11:51not so long ago in grand rounds.
• 11:54But we're also very hopeful to getting
• 11:56a slot in the summer when we will have,
• 11:59hopefully exciting new recruits
• 12:01to add to the team.
• 12:02And we can take a full grand
• 12:05rounds for our classic hematology.
• 12:08So the team you will be hearing from today.
• 12:11The first one is on myeloid
• 12:13malignancy's team and Doctor Priebe
• 12:14will present on behalf of this group
• 12:17and so now I'm heading over to Doctor
• 12:19Kirby for the first presentation.
• 12:22OK, thank you. Thanks a lot Stephanie,
• 12:25for this really kind introduction.
• 12:27Within blessed to have
• 12:28already Nikolai in myself.
• 12:29Within single, fewer a few weeks
• 12:32ago on this ground round and I
• 12:34guess that you know probably most
• 12:36of the members of the team already.
• 12:39That on our side and that any color without
• 12:42self on universe recruit Rory share is.
• 12:46Doctor Brokaw from San Francisco
• 12:48and up to it from Trimble that
• 12:51collaboration is basically something
• 12:53that is extremely important for us.
• 12:56And on the translational abside Stephanie
• 13:00for sure that has been instrumental in
• 13:03in the group as well as Manoj Pillai.
• 13:07Next slide, please.
• 13:11So as you may know,
• 13:13in MLP malignancy daughter asked
• 13:15basically 10 years we had a real
• 13:18paradigm shift thanks to the
• 13:20revolution of our understanding
• 13:22of the genomics of the disease.
• 13:24That's been true in acute myeloid leukemia,
• 13:27so that's really fast.
• 13:32Through in the acute myeloid leukemia.
• 13:35Then in my dysplastic syndrome,
• 13:38but is basically representative
• 13:40of what we have seen also in our
• 13:45knowledge of my wife, activities,
• 13:47orders, or bone marrow failures,
• 13:49for example, and this revolution,
• 13:52in our understanding of the disease,
• 13:55translated more recently.
• 13:57And we can switch style.
• 14:01Um, in a boarding shift also in the
• 14:05management of this disease and since
• 14:082017 we add more approval than over
• 14:12the last 2025 years that goes with
• 14:16basically drug at R agnostic of any.
• 14:20Potential genomic amenities such
• 14:23as the CP351 for example or more
• 14:26recently than 8:00 o'clock,
• 14:29but also drug that are no standard of
• 14:32care for basically mutated diseases,
• 14:36such as flat 3 mutated AML or,
• 14:40potentially IDH mutated diseases.
• 14:42Interestingly, this revolution that
• 14:44started with the access my leukemia,
• 14:48we're starting to see seeing,
• 14:50speaking up.
• 14:51Also, in multiple packages,
• 14:53orders with the recent approval of
• 14:56Fedratinib as well as with my dysplastic
• 15:00syndrome with recently the approach
• 15:02the TGF beta inhibitor spider step
• 15:05as well at the oral decide to be in.
• 15:10Stop all of that is extremely
• 15:14important and allow us to basically.
• 15:19Have a real improvement for or
• 15:21patient regarding prognostic
• 15:23forgetting option of treatment.
• 15:25But we still in situation where a cute smile,
• 15:29leukemias and melodies plastic
• 15:30syndromes are how to treat disease.
• 15:33If you standardize the incidence
• 15:35rate of looking at my leukemia,
• 15:38that's still in the top five of
• 15:42the most deadliest cancer that
• 15:44we have to face in the US and one
• 15:48of the goals that we had.
• 15:51In the group has been to really work
• 15:54at different aspect to try to improve
• 15:57the result of the different treatment
• 15:59and we can switch to the next slide.
• 16:02Uh,
• 16:04and.
• 16:05We really tried to to work from
• 16:08single cell to population research
• 16:11and population outcome and that's
• 16:14just not basically to to to to
• 16:18basically have a stun.
• 16:20But that's really what is the
• 16:23MLP malignancy group going from.
• 16:26Stephanie was mentioning our first
• 16:28result in a single cell sequencing
• 16:31in acute myeloid leukemia.
• 16:33As the researcher Stephanie Ann manner.
• 16:37In the labs around uh. Mouse model of.
• 16:44Testing syndromes RNA for montage
• 16:46to the collaboration that we have
• 16:50with the Cobra Group,
• 16:52led by AMR Nikolai and Rory on
• 16:57outcome research.
• 16:58From a pure clinical research,
• 17:01sense points or group has been
• 17:04instrumental in several key studies
• 17:06that led to approval of these
• 17:09drugs over the last few years,
• 17:12but or portfolio and our goal is really
• 17:15focused on early development of a new agent.
• 17:19Right now click portfolio is
• 17:22roughly 40% of phase one trials.
• 17:27With.
• 17:29Basically a good #6 out of 19
• 17:31active trial that our investigator
• 17:34initiated trial and thanks to all
• 17:37the commitment of the research staff.
• 17:40Thanks to all of the commitment
• 17:43of the different members of Group
• 17:45we right now at a rate of index
• 17:48cases included in clinical trials
• 17:51on main campus that is 15 to 20%.
• 17:55Which is pretty remarkable.
• 17:58We definitely aim to do better and
• 18:01we definitely aim to be able to
• 18:05export the research we're doing from
• 18:08the main campus to different side
• 18:11of the network and be able to add
• 18:15better access for our patients in the
• 18:18network as mentioned by Stephanie,
• 18:21we have pretty efficient and pretty large.
• 18:25Think annotate by bank and I think
• 18:28we can give kudos to Stephanie
• 18:30to each of the exports in 2011,
• 18:33so we're in a decade in right now.
• 18:36We should definitely celebrate about that.
• 18:38And that gives us a lot of leverage,
• 18:41potentially to be able to develop some
• 18:44translation translational research.
• 18:45As well as potentially bringing
• 18:48some collaboration from the outside
• 18:51with pharmaceutical companies as
• 18:53well as from academic centers and
• 18:56go to the next next slide.
• 18:58Just wanted to highlight basically two
• 19:00programs more than two studies to program.
• 19:04Basically going on the first one are the
• 19:07efforts led by armor side and on emerging
• 19:10approaches in my late malignancies
• 19:13and probably Anna does not remember,
• 19:16but I've even.
• 19:18Remember first discussion years ago
• 19:20when we were in Hopkins together
• 19:23around potentially all this knew,
• 19:26you know therapies can be instrumental
• 19:29in or disease disease type, basically.
• 19:35What has been done is basically
• 19:37around the additional,
• 19:38uh,
• 19:39the 1st generation,
• 19:40but also right now the second
• 19:42generation of even the energy agent
• 19:45to conventional conventional therapy.
• 19:47We're right now activating.
• 19:51Very broad induction chemotherapy plus volume
• 19:55up study under the umbrella of a sitter.
• 20:00With the first patient that we hope
• 20:04to include in the next few weeks,
• 20:07we just have finished the,
• 20:10uh,
• 20:10cool on the map plus entinostat NDS
• 20:14trial for the group of patients with
• 20:17mild ******* agent Majestik syndrome
• 20:20failed by accommodating agent,
• 20:22and we are looking forward for
• 20:25this data that has been basically
• 20:28possible to to develop thanks to.
• 20:31Elaboration with Yale Science and
• 20:34that's work with initially TK came.
• 20:37One of us still here and we have also a
• 20:41chronic my leukemia studies sponsored
• 20:44by equal on the addition of bambrough
• 20:48on tyrosine kinase inhibitor for a
• 20:52patient with chronic migraine leukemias,
• 20:55an Axia Resul disease.
• 20:58Beside this trial,
• 20:59we also have been implicated.
• 21:02Basically thanks to our leadership
• 21:04on some of the development of the
• 21:07newest generation of Elon College.
• 21:10Agents such as the T in three inhibitor
• 21:14and we hope to have more results to to
• 21:18show that in the near future next slide.
• 21:22So the the idea hmm DS program?
• 21:25That's something that I already.
• 21:28Presented basically a few weeks
• 21:31ago during the ground rounds,
• 21:33but I definitely like this program
• 21:36as it's really a homegrown program
• 21:39thanks to the work and interaction
• 21:42with Stephanie and Ranjit.
• 21:44So that's really a good example of what
• 21:48we can achieve at at yell working together.
• 21:52We have been able to show how
• 21:56we can exploit the weaknesses
• 21:59of IDH mutated AML in NDS.
• 22:02As you can see.
• 22:05When we have an idea of
• 22:08mutation and the presence
• 22:10of two HG in the media that creates
• 22:14some braknis phenotype that can be
• 22:17potentially targeted by using popped
• 22:20inhibitor on the upper right side.
• 22:24Can see that treatment with olaparib
• 22:27in a primary samples in grafted in
• 22:30mice can potentially significantly
• 22:33reduced the disease burden in.
• 22:35Lisa grafted with acute myeloid leukemia.
• 22:39Presenting an IDH mutation including in
• 22:44some samples where we already documented
• 22:48the resistance to IDH inhibitors in the
• 22:53clinic and that led to the step trial.
• 22:58Brentley ongoing with right now.
• 23:01Six patient included,
• 23:03including four at.
• 23:06At here with basically the use
• 23:09of elaborate the parking meter.
• 23:12For a male and MBS patient with IDH mutation.
• 23:17Interestingly,
• 23:17for the discussion with the tap,
• 23:20we've been able to have a patient that
• 23:24were not yet exposed to IDH limit,
• 23:27or potentially integrating the trial
• 23:30with an early evaluation that would also
• 23:33potentially to switch to ID age limit,
• 23:36or there was no some clearcut benefit
• 23:39after a few weeks on treatment, so.
• 23:43That's two of the main program
• 23:45that we have right now.
• 23:47I'm not going to basically talk
• 23:49too much about the outcome.
• 23:51Research as we we add with basically.
• 23:55Nicole,
• 23:55I would review of what was going on
• 23:59on this Group A few a few weeks ago,
• 24:02but as we were discussing we really
• 24:05want to be able to to bridge the
• 24:08most basic science aspect of it.
• 24:10What we're doing in the in the labs
• 24:13to this outcome. Research go go ahead.
• 24:18We still have a lot of people
• 24:20in the results clinical issue.
• 24:22Then that's the topic.
• 24:24We're not the addressing all of them,
• 24:26but some of them are definitely
• 24:28on the focus of the group.
• 24:31The management of high risk disease
• 24:33in AML and MD S complex karyotype.
• 24:36NLL mutated or rearrange disease are one
• 24:38of the focus of development of the group.
• 24:41And I specially Rory is developing
• 24:44some different concepts around.
• 24:46These lines,
• 24:47the optimization of targeted
• 24:48therapies and email steropes.
• 24:50We talked about that one of the challenges,
• 24:53basically that we're still working
• 24:55with the disease that is not as
• 24:58common as breast or colon cancer,
• 25:00and we end up with more combination
• 25:02and sequence of agent then patient.
• 25:04And that's potentially where
• 25:06the interaction with the lab and
• 25:08the work that we're doing with
• 25:10Stephanie is extreme and mineral.
• 25:12Extremely important.
• 25:15Targeting of leukemia stem cell looking
• 25:17initiating cells and management.
• 25:19Measurable residual disease at
• 25:21the molecular level is obviously
• 25:23something that is on our mind,
• 25:25and that's a lot of interaction.
• 25:28Also with the transplant group in
• 25:30South Therapy Group on our potentially
• 25:33to to work around this concept.
• 25:35And last but not least,
• 25:38before getting to the point where
• 25:40we have active disease,
• 25:42working on predisposition
• 25:43and potentially climb.
• 25:45To please,
• 25:45this is something that is extremely
• 25:48interesting right now with.
• 25:49In collaboration we will have.
• 25:52With the cardiology group
• 25:55and the Generation project,
• 25:57I think I have one last slide, so we.
• 26:02Feel that we we're pretty blessed in the
• 26:06group to have already's.
• 26:08Pretty solid foundation,
• 26:09but we wanted to do better and that's
• 26:13gonna be by leveraging the excellence
• 26:15that we have it here the molecular
• 26:18biology aspect with basically right
• 26:20now are some development in single cell
• 26:23sequencing using multi omics approaches
• 26:25that can potentially be used in my life
• 26:28but not only in my right mind agencies.
• 26:31Potential collaboration and avenues
• 26:33of collaboration with the yellow.
• 26:35Center of immuno oncology.
• 26:39And with a group of Marcus mention also to
• 26:43potentially work on resistance disease,
• 26:45immuno oncology in my redemer agencies
• 26:48and the really fruitful and really
• 26:52exciting collaboration we have with
• 26:54the Copper Group carry gross schalmei.
• 26:58With a lot of publication and lots
• 27:01more that will come in the next.
• 27:04Month and year.
• 27:05We want to expand our collaboration.
• 27:07That's going to be more collaboration
• 27:10and the basic Science Group partners
• 27:12like June Liu Shan Quinn Go are
• 27:15definitely people that will be more
• 27:17and more on the stage with us in more
• 27:20portable computers as well as more
• 27:22collaboration on the clinical research side.
• 27:24Obviously with the BMT
• 27:26and cell Therapy Group,
• 27:27but also without regard for
• 27:29the adolescent young adults,
• 27:31and I think that's all I have.
• 27:35Thank you so much tomorrow.
• 27:36This is really awesome,
• 27:37so we'll go straight into our next
• 27:39presentation by Doctor Falls on
• 27:41behalf of Mylan Malignancy's team.
• 27:45Hi, this is Francine and I'd like to
• 27:48thank Stephanie and also Charlie for all
• 27:51of your work to bring us to where we are
• 27:56today with this faculty on the development
• 27:58that we've had in the lymphoma program.
• 28:01So lymphoma program consists of myself,
• 28:04Scott Huntington, ERISA, Soupy,
• 28:06Shalin, Kothari, Toshin Sethi,
• 28:07an Francesco Montanari,
• 28:09both of whom have recently joined us.
• 28:12Francesca is in Greenwich.
• 28:15Next slide. Um?
• 28:17So this is the landscape of lymphoma.
• 28:21So lymphoma really is many different
• 28:23diseases, and that's a challenge for
• 28:25us as a group with limited resources.
• 28:28Terms of trying to figure out how
• 28:30we focus this clinical trial effort.
• 28:32So it turns out that out of the 21,000
• 28:36cases of cancer in Connecticut per year,
• 28:38there are about 900 plus or minus
• 28:40cases of non Hodgkin's lymphoma.
• 28:43So that's really our denominator
• 28:45population in our efforts are to
• 28:47try to get many of these patients.
• 28:49Want to clinical trials?
• 28:50If you look at the curve at the
• 28:53bottom you can see the frequency of
• 28:56the different types of non Hodgkin's
• 28:58lymphoma with diffuse large B cell lymphoma,
• 29:01follicular lymphoma,
• 29:02the low grade marginal zone lymphoma
• 29:04is being the most common subtypes,
• 29:06and T cell,
• 29:07lymphoma and mantle and mantle
• 29:09cell lymphoma and burqas are.
• 29:11You can see are rare compared
• 29:13to these other common subtypes.
• 29:15Next slide.
• 29:18Um, so the unresolved political issues,
• 29:20of course,
• 29:21are how we make sense of 90
• 29:23different subtypes of lymphoma and
• 29:25divide those into general themes.
• 29:27For clinical trials,
• 29:29I'll talk a little bit about
• 29:31that in a minute,
• 29:33but you know,
• 29:34we do have diseases where the
• 29:36modern regimes pretty much are OK
• 29:38in terms of producing favorable
• 29:40outcomes for these patients,
• 29:42but there are within these more
• 29:44favorable subgroups of patients.
• 29:46Those patients with high risk molecular.
• 29:48Features that continue to fail
• 29:50conventional therapy and would be
• 29:52subjects for novel clinical trials
• 29:54and those include double hit diffuse,
• 29:56large B cell lymphoma and
• 29:58one of the things that we.
• 30:00Done with that disease is to combine
• 30:03dose adjusted epoch with Lenalidomide.
• 30:05In addition,
• 30:06we have some patients with low risk
• 30:08lymphoma where we could actually
• 30:10test D escalation of therapy and a
• 30:13good example of that is classical
• 30:15Hodgkin's disease and I'm going
• 30:17to show you another example.
• 30:19For diffuse large B cell lymphoma
• 30:21we also have histologies where the
• 30:24modern regiments are in ineffective,
• 30:26pretty much inadequate for these
• 30:28aggressive patients such as
• 30:29the T cell lymphoma's.
• 30:31The piece of distributing mantle cell
• 30:33lymphoma's and the post transplant
• 30:35lymphoproliferative disorders so
• 30:36in these cases where are trying
• 30:39to incorporate novel agents into
• 30:40the frontline but also trying to
• 30:43figure out how to incorporate
• 30:45allogeneic stem cell transplant and
• 30:47the newer car T cell therapies,
• 30:49would love to use molecular and
• 30:51genetic profiling in these diseases
• 30:52to select patients rationally for
• 30:55pathway directed clinical trials,
• 30:56and those efforts are now underway
• 30:58thanks to the work of Stephanie.
• 31:01To get our tissue bank up and running.
• 31:05Sorry sorry, OK next slide.
• 31:09So, um, just touching on how
• 31:11we're deescalating therapy.
• 31:12This is a really great example of a
• 31:15trial that Scott has opened for relapsed
• 31:18aggressive B cell lymphoma's where
• 31:20we have a non chemotherapy approach.
• 31:22So basically this study involves oral
• 31:24agents of BTK inhibitor and mtor inhibitor,
• 31:27an an image, and it turns out that when
• 31:30you combine these three oral therapies,
• 31:33this is a very effective strategy for
• 31:35patients with aggressive lymphoma who
• 31:37have failed conventional chemotherapy.
• 31:39Some of them have failed transplant as well.
• 31:42On the next slide, Stephanie,
• 31:44you can see an example of one
• 31:46of our patients.
• 31:47It turns out that yell actually has
• 31:50involved the majority of patients that
• 31:5221 patients to date in this trial and
• 31:55responses have been observed among
• 31:57a different subtype of patients.
• 31:59You can see with DL,
• 32:00BCL with low grade lymphoma,
• 32:02mantle cell lymphoma etc and patients
• 32:04with very dramatic responses with
• 32:06large masses and extensive disease.
• 32:08So we were really excited about
• 32:10this approach.
• 32:11And again,
• 32:12we'd all like to start thinking
• 32:14more about oral rather than Ivy
• 32:16therapies for patients that are going
• 32:18to be chronically needing therapy,
• 32:20such as many of our lymphoma patients.
• 32:23Unfortunately,
• 32:23next slide would highlight another approach,
• 32:25which is to take an active drug,
• 32:28look at its resistance mechanisms
• 32:31and come up with.
• 32:33Similar drugs that might be active
• 32:35in resistant mutational settings.
• 32:36In this case.
• 32:37BTK inhibitors are one of our most
• 32:40active newer agents in B cell lymphoma,
• 32:43but most of the failures to these
• 32:45agents are related to the development
• 32:47of specific mutations and now we
• 32:50have these new non covalent BTK
• 32:52inhibitors that actually are able to
• 32:55subvert those mutations and induced
• 32:57responses in patients and this is an
• 32:59agent that we're working with now.
• 33:01Locks 0305.
• 33:02Falls into that category that's
• 33:04highly active.
• 33:05We are currently embarking upon a
• 33:07number of phase two studies that
• 33:10we hope to make available broadly
• 33:12across our care centers looking
• 33:14at a number of different B cell
• 33:16lymphoma is with these novel agents.
• 33:18Next slide.
• 33:21Um,
• 33:21this is some interesting work and
• 33:24translational research done by
• 33:26shelling pathari in our group.
• 33:28So Charlyn is looking at ways of.
• 33:31Dealing with the development of
• 33:33resistance to active agents such as phonetic,
• 33:36LAX,
• 33:36and hear a set of experiments where
• 33:38he has shown that proteasome inhibition
• 33:41is synergistic with phonetic lacks
• 33:43in patients with B cell lymphoma an.
• 33:46In these clinical models,
• 33:47so you can see the bot is mid carve.
• 33:51Is Mebane exacerbated by themselves,
• 33:53which are proteasome inhibitors have
• 33:55some activity to induce a pop ptosis?
• 33:57As does phonetic LAX?
• 33:59But when you combine these agents
• 34:01you can see synergistic activity.
• 34:03And based on this in vitro
• 34:06work that Charlene has done,
• 34:08he's embarking on a seat
• 34:10app sponsored Phase 1,
• 34:12two clinical trial where he's
• 34:14combining genetic LAX with these
• 34:16proteasome inhibitors and we're very
• 34:18excited for Shaolin to get that trial
• 34:21up and running on the next slide,
• 34:23you can see the correlative science that's
• 34:26he's developed around this clinical trial,
• 34:28including a single celled Association
• 34:30to look at these specific BCL,
• 34:33two family members.
• 34:34By Aqua, as well as by mass spec.
• 34:37He's also doing exome sequencing,
• 34:39RNA seek and trying to obtain tissues from
• 34:42these patients for later PDX development.
• 34:45So that's all very exciting and we're
• 34:48really proud of shelling for that.
• 34:50In additional, he's he's doing what other
• 34:53groups are doing to embark on looking for
• 34:56a circulating tumor DNA in these patients,
• 34:59and hopefully some of us will be
• 35:02able to incorporate that into our.
• 35:05A disease group studies as well next slide.
• 35:09So and then the last thing I want
• 35:12to mention is exciting work that
• 35:14Charlene is doing with the Cats lab
• 35:17to use a different approach called
• 35:19protest back to target antiapoptotic
• 35:21protein proteins potentially,
• 35:22but their critic benefit soap Protex
• 35:24basically is a hetero bifunctional
• 35:26small molecule that consists
• 35:27of a linker and two warheads.
• 35:30One of them binding to the target
• 35:32protein such as the BCL two and the other
• 35:35recruiting the E3 ligase to basically
• 35:38leads to the degradation of that.
• 35:40Protein,
• 35:40so we're looking forward to this work coming
• 35:43to fruition in the clinic in the future.
• 35:46Next slide.
• 35:48Just highlights some of the work
• 35:50that Scott has done working with
• 35:52the Copper Group to look at at
• 35:55outcomes in patients with lymphoma.
• 35:57And so Scott has done a number
• 36:00of studies including these two,
• 36:01one of which shows that patients
• 36:03with who are older than 80 have a
• 36:06higher frequency of discontinuing
• 36:08active therapies like a brute,
• 36:10not within the first 180 days.
• 36:12So obviously one has to go back and look
• 36:16at why that is and ways that we can.
• 36:19Alter that therapy so those patients
• 36:21can continue to be treated and then
• 36:23also Scott has done a lot of work
• 36:26with cost effectiveness and this
• 36:27is just one of his studies looking
• 36:30at different treatments for CLL.
• 36:31Getting a brute nip upfront
• 36:33versus getting it later on.
• 36:34So again,
• 36:35Scott has presented some of this
• 36:37work at the national meetings.
• 36:39Then there are a number of
• 36:41studies ongoing with copper.
• 36:43Next slide will then segue us into T cell.
• 36:46Lymphoma is T cell lymphoma.
• 36:48Is overall are heterogeneous as
• 36:50arviso bomas and tend not to do as
• 36:53well with conventional therapies as
• 36:55you can see in the outcomes curve
• 36:58progression free survival in median
• 37:00survival is poor for many of these.
• 37:03Aggressive T cell subtypes.
• 37:05The next slide.
• 37:07Highlights one of the things that
• 37:09we've been trying to do so patients
• 37:11with T cell lymphoma get chop based
• 37:13chemotherapy upfront and only a small
• 37:15percentage of them actually are cured.
• 37:17With this approach,
• 37:18patients would go on to an
• 37:20autologous stem cell transplant if
• 37:22they have a complete remission,
• 37:24but it turns out that when
• 37:26you look at registry studies,
• 37:27one of which we conducted here,
• 37:29only about 25% of patients
• 37:31upfront ever make a transplant.
• 37:33The reason being that many of those
• 37:36patients don't have a good remission.
• 37:38And so this is a study that I worked
• 37:40on with tar Sheen and this study
• 37:43is hopefully going to get started
• 37:45very soon where we combined Mogamu
• 37:48Lizum app with upfront chemotherapy.
• 37:50In this case, epoch for patients
• 37:52with aggressive T cell lymphoma.
• 37:54The idea being that Mogamulizumab is
• 37:56a CCR four monoclonal antibody that
• 37:58targets both tumor cells at but also more
• 38:01importantly T regs in the micro environment,
• 38:04so we're hoping that there's
• 38:06going to be an interaction.
• 38:08Both in the micro environment as well as
• 38:10potential synergy with the tumor cells.
• 38:12When this is combined with chemotherapy,
• 38:13I don't have a slide to show you this, but,
• 38:17uh, she has also developed some very nice
• 38:20correlative studies to go along with this.
• 38:22The next slide.
• 38:25Will take you into the world of relapsed
• 38:27T cell lymphoma and just to demonstrate
• 38:29to you the work of our group to look at
• 38:33a number of different agents targeting
• 38:34a number of different pathways that
• 38:36are relevant and some of these studies.
• 38:38Yale has been the top one or or two
• 38:41in terms of accrual for these studies
• 38:43nationwide and these are novel
• 38:45agents and I'll touch on a couple of
• 38:47them in the next slide or two.
• 38:50Um, go back and this is this is next slide.
• 38:57OK,
• 38:57this is tipifarnib which is a
• 39:00farnesyltransferase inhibitor,
• 39:00but it turns out that that it also
• 39:03down regulates CX CL 12 which is
• 39:06in the micro environment patients
• 39:08who have expression of CX CL 12 in
• 39:10the micro environment don't do as
• 39:12well as you can see on this survival
• 39:15curve and we've had some incredibly
• 39:17dramatic responses using this single
• 39:19oral agent and some of our patients
• 39:21such as this gentleman who has failed
• 39:24multiple therapies in autologous
• 39:25transplant that this is really salvage.
• 39:28A lot of people were hoping to
• 39:30initiate some Iits with this molecule
• 39:32in the next couple of months.
• 39:34Next slide shows you another
• 39:36approach with micro RNA,
• 39:37so this is the first in man study
• 39:39of this micro RNA which targets a
• 39:41number of different types of lymphoma.
• 39:44We put a number of patients with
• 39:46cutaneous lymphoma on this trial and
• 39:48you could see responses in pretty much
• 39:51all of the patients that were treated
• 39:53based on these waterfall plots and
• 39:55on the next slide I think is really.
• 39:58One of the most important findings.
• 40:00This micro RNA,
• 40:01which is its activity in HTLV one
• 40:04associated adult T cell leukemia,
• 40:07and again we put the majority of
• 40:09patients in this cohort on this
• 40:12trial and we also initiated the
• 40:14correlative studies that you see below,
• 40:17showing that the molecule directly
• 40:19inhibits the proliferation of ATL cells.
• 40:21Modulates the expression of various
• 40:24activation markers and you can see
• 40:27the changes in proliferation index
• 40:29with this molecule and this is.
• 40:31All samples from our patients that
• 40:33were drawn at different time points,
• 40:35so we're very excited to get this
• 40:38data published.
• 40:39Next slide. Just a couple
• 40:42of other studies initiated.
• 40:44This is another of Pershing
• 40:46study looking at incorporation of
• 40:48pembrolizumab with an active agent
• 40:50Brentuximab dowtin in CD 30 positive
• 40:52T cell lymphoma is and again this
• 40:54is this is her IIT and there are
• 40:57some correlative studies associated
• 40:59with this and the next slide.
• 41:04Yeah, the next slide will segue into
• 41:06some of the efforts that Francesca has
• 41:09looking at in a couple of different areas.
• 41:12In the context of aggressive lymphomas,
• 41:14this is her global T cell consortium study,
• 41:17which she conducted at Columbia
• 41:19and is now brought to Yale,
• 41:21and this is now a randomized phase
• 41:23two study where she's looking at 5:00
• 41:26or oral is incited gene in Rome and
• 41:29Epson compared to investigators choice.
• 41:31This is a multicenter study.
• 41:33And we're really excited that
• 41:35Francesca has brought this to us and
• 41:39the next slide is another effort in
• 41:41an area that we have not explored.
• 41:44Which is PTLD so post transplant
• 41:46lymphoproliferative disorders.
• 41:47In this study,
• 41:49Francesca is using sequential
• 41:51treatment for patients that are CD
• 41:5320 and CD 30 positive and you can
• 41:56see the scheme for this trial here.
• 41:59This is also an IIT that's being conducted
• 42:02in collaboration with the Mayo Clinic.
• 42:04Would you be a?
• 42:05So I think we have some really nice work
• 42:08from some of our younger investigators
• 42:10and we're very excited about that.
• 42:12The next slide.
• 42:14Is just our summary slide looking at what
• 42:17our future is and where we're hoping
• 42:19to go in the lymphoid malignancy's.
• 42:22So clearly we will benefit from
• 42:24the annotated database that you've
• 42:26heard about and hopefully will be
• 42:28contributing our samples in an
• 42:30ongoing fashion to the biobank.
• 42:32We also need to develop a sequencing
• 42:34platform which we really don't
• 42:36have here at the institution.
• 42:38For lymphoma we're currently
• 42:39sending our samples out,
• 42:41but we certainly would like to
• 42:43do that in the near future.
• 42:46I talked about the biobank and
• 42:47how important that is,
• 42:49but also we're now starting to talk about
• 42:51thematic direction for the program,
• 42:53and one of the areas that we're
• 42:55focusing on at least in T cell lymphoma,
• 42:58as you've seen,
• 42:59is on the micro environment,
• 43:01and you know immunomodulatory strategies
• 43:02that can be used with correlative science
• 43:04in these two cell lymphoma studies,
• 43:07and then finally,
• 43:08I just want to acknowledge the
• 43:10translational science collaborators
• 43:11and this by no means is an
• 43:13exhaustive list of folks,
• 43:14but there have been a number of.
• 43:17Studies that have been funded by both DeLuca
• 43:19as well as other mechanisms for funding,
• 43:22and those include studies done with
• 43:24the Cats lab with Marcus is lab,
• 43:27which is now being engaged
• 43:29with these studies.
• 43:30The Lola slab in pharmacology and
• 43:32even the imaging labs with a nuclear
• 43:35medicine with Doctor Chi and others
• 43:37that I didn't mention as well.
• 43:39So I think we have a very bright future
• 43:42ahead of us in the lymphoid malignancies.
• 43:45Thank you,
• 43:46Stephanie.
• 43:48Thank you for I've jumped.
• 43:50Thank you for seeing that is after
• 43:52you tour Tour de force and lymphoma
• 43:54is so excited about everything that
• 43:56is to come and very excited about
• 43:58our next presentation by Doctor
• 44:00Natalia never eats a on multiple
• 44:02myeloma in commodities.
• 44:03Stephanie, thank you so much for the
• 44:05opportunity to let me present today
• 44:07and I would like to echo some of your
• 44:10comments and thank thank Charlie for his
• 44:12outstanding leadership at the Cancer Center.
• 44:14So today I'm happy to present on
• 44:15behalf of myeloma team with brief
• 44:17clinical and research updates.
• 44:19Here's our team myself. Terry Parker.
• 44:21Know far Bar and Sabrina.
• 44:22Browning as well as Elon Gorshin at Guilford.
• 44:26Next slide please.
• 44:27I'll start with brief Brecht
• 44:29background about the disease.
• 44:31As you all know,
• 44:32multiple myeloma is the clonal plasma cell
• 44:35neoplasm originating in the bone marrow.
• 44:38The diagnosis rests on the bone
• 44:40marrow biopsy and some of the key
• 44:43immunohistochemical stains and protein
• 44:45studies on the blood in the urine.
• 44:47The ETL pathogenesis of this
• 44:49disorder remains largely obscure.
• 44:51We know of certain associations,
• 44:53such as perhaps antigenic stimulation.
• 44:55Role of.
• 44:56Pathogenic microbes,
• 44:57lipid antigens and other associations
• 44:59such as metabolic syndromes,
• 45:01diabetes and such,
• 45:02but in large majority of patients we
• 45:05don't know the cause and much remains
• 45:08to be elucidated in this research.
• 45:11Next slide, please.
• 45:13So as you know,
• 45:14the diseases continuum and we know
• 45:16that myeloma every case is pre
• 45:18preceded by the precursor state
• 45:20called M Gus monoclonal gammopathy of
• 45:23undetermined significance and after
• 45:25years of its presence it progress
• 45:27is to the early phase myeloma,
• 45:29commonly referred to as small
• 45:31during or asymptomatic myeloma.
• 45:33But a full blown clinical disease
• 45:35which requires active therapy is
• 45:37the disease which leads to end organ
• 45:40damage in the form of high calcium,
• 45:42renal failure, anemia and bone lesions.
• 45:44And in the old days we would
• 45:47resort to plane X Rays.
• 45:48However,
• 45:49this has been largely replaced by
• 45:51advanced imaging modalities such as
• 45:53whole body MRI or Whole Body PET CT scans.
• 45:55Next please.
• 45:57So once diagnosed,
• 45:59the treatment pattern of multiple
• 46:01myeloma consists of initial
• 46:02induction therapy with usual 3 drug,
• 46:05or in 2021 you might choose a four
• 46:07drug regimen incorporating some of
• 46:09the monoclonal antibodies upfront,
• 46:11such as daratumumab inappropriate patients.
• 46:13This is then followed by high dose melphalan,
• 46:17an autologous stem cell rescue
• 46:19AKA auto transplant,
• 46:20and then this is subsequently
• 46:22followed by maintenance therapy,
• 46:23which is usually long term and
• 46:26mental progression of disease.
• 46:27So the.
• 46:28Treatment pattern resembles a
• 46:30marathon rather than the Sprint.
• 46:32As we continue maintenance for many years.
• 46:34For those patients who remain
• 46:36in remission next.
• 46:39And invariably, sooner or later,
• 46:41every patient experiences their relapse,
• 46:43and this is due to branching pattern of
• 46:46clonal evolution or push persistence
• 46:48of previous clones and at the time
• 46:51of relapse patients have to sequence
• 46:54through the available therapies,
• 46:56each of which then leads to shorter and
• 46:59shorter overall duration of response,
• 47:01eventually leading to dismal prognosis
• 47:03for many of their refractory patients.
• 47:06Next please. Fortunately,
• 47:08we've had number of drug approvals
• 47:11over the course of the past decade,
• 47:14which includes the novel proteasome
• 47:16inhibitors in the form of carfilzomib
• 47:19novel immunomodulatory agents,
• 47:21pomalidomide, and others.
• 47:22The biggest breakthroughs came in 2015,
• 47:25when we had several approvals,
• 47:27namely IgG monoclonal antibody targeting CD,
• 47:3038 receptor on the plasma cell daratumumab,
• 47:33as well as checkpoint inhibitor,
• 47:35targeting SLAM F7 or CS1 elotuzumab.
• 47:38Orally available Proteus inhibitor
• 47:40exacum Abe.
• 47:41We also had approval for histone
• 47:44deacetylase inhibitor PANOBINOSTAT
• 47:45which is orally available and more
• 47:48recently a drugs of completely different
• 47:50mechanism affection such as selinexor
• 47:53received approval by FDA in 2019.
• 47:56This is a selective nuclear export
• 47:59inhibitor promoting some of the
• 48:01tumor suppressor gene action and
• 48:03within the past year approval of
• 48:06another IgG monoclonal antibody.
• 48:08Against CD 38 is I took some up with
• 48:11slightly different mechanism of action,
• 48:13but very similar to daratumumab and
• 48:16more recently just summer of last year.
• 48:19First antibody drug conjugate
• 48:20got FDA approval.
• 48:21This is Bill on time Out method Odin
• 48:24targeting B cell maturation antigen
• 48:26which is currently approved for
• 48:28relapsed refractory multiple myeloma.
• 48:30Beyond four prior lines of therapy next.
• 48:34So despite these therapeutic advances,
• 48:36number of clinical challenges
• 48:38remain primarily the concerns about
• 48:40what to do for refractory myeloma.
• 48:42Are we able to,
• 48:44in the novel immunotherapy era,
• 48:46replaced the high dose melphalan by
• 48:48some of the novel strategies such as
• 48:50car T cell or other therapeutics?
• 48:53How best to continue the maintenance
• 48:55therapy for patients particularly
• 48:57high risk data genetic subsets?
• 48:59And we're far from understanding the
• 49:01disease biology and choosing this
• 49:03sequential therapy based on biology of
• 49:05disease and its selection of therapy.
• 49:07Any cases is random and this is
• 49:10a clinical challenge.
• 49:11Same is true for a llama.
• 49:13Lodosa is,
• 49:13as you know,
• 49:14about 10% of multiple myeloma
• 49:16patients will develop concurrent
• 49:18soft tissue deposition of the Lambda
• 49:19or Kappa light chains,
• 49:21and this is an unmet need in all of
• 49:23gammopathy world as these patients,
• 49:25the care is not well defined,
• 49:27so it remains to be established
• 49:29what is the optimal first line,
• 49:31second line and beyond therapy for
• 49:33patients with this next please.
• 49:35So while facing these challenging
• 49:37issues in clinic we tried to.
• 49:39Integrate our clinical expertise
• 49:40and incorporate some of the Noble
• 49:43research therapeutic strategies and
• 49:45continue to educate our patients
• 49:47as well as our trainees next.
• 49:52In terms of individual focus of
• 49:54clinical expertise, Terry Parker has
• 49:56an outstanding clinical expertise in
• 49:58a llama low doses having served as.
• 50:00National Pi and number of a alloy doses,
• 50:04trials as well As for
• 50:06relapsed refractory myeloma.
• 50:07Nofar nofar sparkles has been
• 50:09mostly on high dose melphalan.
• 50:11Autologous stem cell transplant for myeloma
• 50:13as well as cellular therapies in myeloma.
• 50:16Sabrina also has an excellent expertise
• 50:18in a llama low doses shoot the
• 50:20separate fellowship in amyloidosis
• 50:22at the Boston Medical Center.
• 50:24She also focuses on understanding
• 50:26the biology of some of the
• 50:29precursor States and my own.
• 50:31Clinical research has focused On's
• 50:33to understanding clonal heterogeneity
• 50:35and incorporating advanced imaging in
• 50:38this disease therapeutic assessment.
• 50:41So education is of course an integral
• 50:43component of our daily work.
• 50:45This is a group of current fellows
• 50:48rotating through myeloma clinics
• 50:49during this academic year,
• 50:51and many of them have been involved
• 50:53in research projects in myeloma.
• 50:55So, for instance,
• 50:56Weixin Lou has been working on
• 50:58myeloma Yale Database project.
• 51:00On looking at outcomes in patients
• 51:02treated with monoclonal antibodies,
• 51:04Talib Dasani has the bone disease in
• 51:06myeloma cohort and looking to develop
• 51:09quality improvement project started.
• 51:10Targeting this Eric Chang will be
• 51:13involved in this promise study,
• 51:15which is the screening and community
• 51:17outreach project for patients with
• 51:20gammopathy's and their families,
• 51:21and it has an important outreach project,
• 51:24and we're partnering with Dana Farber
• 51:27Doctor Ghobrial on this project.
• 51:29And finally,
• 51:30Rose Mirkin will be involved in
• 51:32the collaborative effort where we
• 51:34may study the antigenic targets of
• 51:37monoclonal antibodies of myeloma
• 51:39with the help of immunology. Lab of.
• 51:42Aaron rink next please.
• 51:46So our research consists
• 51:47of different missions.
• 51:48On one hand, we always try to enhance
• 51:51our clinical trial portfolio.
• 51:53We have ongoing trials,
• 51:54both investigator initiated as well as
• 51:57industry and collaborative group trials.
• 51:59In every space of this disease,
• 52:01including early stage,
• 52:02small during as well as newly diagnosed
• 52:05and late relapsed refractory patients.
• 52:07And we always try to develop additional
• 52:10therapeutic concepts for refractory myeloma.
• 52:12Andale Emily doses.
• 52:13On the other hand,
• 52:16we do have certain outcomes,
• 52:18research initiatives and this
• 52:20include both myeloma as well as Mgas
• 52:23database as well as bone disease.
• 52:25In myeloma collaboration with our
• 52:27copper team and finally on the
• 52:30research basic Science Research front,
• 52:32we've been trying to build teams
• 52:34to collaborate with researchers
• 52:36to study monoclonal antibodies.
• 52:38They're driving antigens and Additionally
• 52:40mean profiling to understand predictive
• 52:42biomarkers of disease response.
• 52:44And study extramedullary disease next please.
• 52:49So on the basic science research front,
• 52:51I think the.
• 52:53Stephanie Collins,
• 52:54Biobank project for hematology has
• 52:57been really instrumental in our program
• 52:59at North Haven Myeloma program.
• 53:01We've essentially biobank the bone
• 53:03marrow and peripheral blood on every
• 53:06single patient that we diagnosed
• 53:08with multiple myeloma or gammopathy,
• 53:10and we hope to build collaboration
• 53:13and with the help from David Shatz lab
• 53:16to develop ex vivo multiple myeloma
• 53:18mouse models where we can develop
• 53:21robust preclinical models using this.
• 53:24In addition,
• 53:25studying monoclonal antibodies
• 53:26and understanding the antigenic
• 53:29targets and what drives the disease
• 53:31in collaboration with Aaron Rings
• 53:33lab on clinical research front,
• 53:35we've had active clinical
• 53:38collaboration and couple of IIT's.
• 53:41Closely working with musculoskeletal
• 53:43radiology and in this and
• 53:45haimson ending lishouk,
• 53:46both have been instrumental as
• 53:48well as our pathology colleagues.
• 53:51Mean issue and sang and pen know.
• 53:54Farhan Sabrina have ongoing
• 53:55collaboration with an Habermann from
• 53:57lab laboratory medicine to understand
• 54:00immune profiling of patients to
• 54:02understand the biologic response in
• 54:04different subsets of myeloma patients
• 54:06treated with monoclonal antibodies
• 54:08in terms of outcomes research.
• 54:10We've had active collaboration
• 54:12with hematology copper team.
• 54:14With the leadership of Shammai,
• 54:16my and Scott Huntington,
• 54:18we have several ongoing projects,
• 54:20and one of them a recent one using
• 54:22flat iron database and one particular
• 54:25myeloma project examining patterns of care,
• 54:28especially in the context of kovid period.
• 54:31And Lastly,
• 54:32we've been trying to build this disease team,
• 54:35which we refer to myeloma bone
• 54:38disease program collaboration,
• 54:39under which we try to bring
• 54:42together different departments,
• 54:43including Endocrinology, Carlin, Sonia,
• 54:45as well as orthopedic and spine center,
• 54:47Dieter, Lindskog, and Louise called.
• 54:50And as I said,
• 54:51Talib Dosani has an ongoing outcomes
• 54:53project looking into bone disease in myeloma.
• 54:57So with that I will stop.
• 54:59I'm exciting to have such great
• 55:02collaborators and colleagues on the campus.
• 55:04And I will leave a couple of
• 55:06minutes for questions.
• 55:07Thank you so much.
• 55:09Awesome,
• 55:10alright, so I'll share my screen.
• 55:12Just people know we have
• 55:14hematology joins 2021.
• 55:15We have a Twitter handle
• 55:17so we'll try and use it,
• 55:20so I'm going to unshare so we can
• 55:23see everybody and let me pull up the
• 55:26chat to see if there are questions.
• 55:30Are there questions?
• 55:32Would anybody like to raise their
• 55:34hand and ask the question?
• 55:36If not, I can start with one and then
• 55:39maybe I'll ask Francine since I'm
• 55:41always a molecular person and I know
• 55:44that we have this phenomenal effort
• 55:46to get on this goal panel and whole
• 55:49exome sequencing tower patients.
• 55:50Do you think that that will
• 55:53fulfill your need?
• 55:54Or what do we need to do to improve on that?
• 55:58I think that's certainly a start.
• 56:00You know, as you know Stephanie,
• 56:02we see some of these.
• 56:04We are rare lymphoma patients for whom
• 56:06there's really no treatment algorithm
• 56:08and which is kind of picking out of
• 56:11a hat to try to figure out what to do
• 56:13in the error of precision medicine.
• 56:15I really think that we should be profiling
• 56:17these patients and sequencing them
• 56:19and rationally developing strategies,
• 56:20so we would love to be able
• 56:22to start doing that.
• 56:24I think the critical component of that is,
• 56:26you know, is being able to get hold
• 56:28of that issue when it's biopsied,
• 56:31and to get it to the right place
• 56:33as soon as possible.
• 56:35We're also very interested in
• 56:37looking at circulating tumor cells
• 56:39and whether that's a strategy that
• 56:41we could we could use as well.
• 56:43OK
• 56:44fantastic exciting.
• 56:45Are there any other questions?
• 56:49I don't see any in the chat.
• 56:54So one of the I'm sorry Charlie friends, you
• 56:57know, I guess I would ask and
• 56:59I think you each allude to it,
• 57:02but where do you think cell therapy is going?
• 57:05And obviously it's relevant to each
• 57:07of the domains being described.
• 57:08So where do you think five years from now
• 57:11will be with respect to cell therapies?
• 57:15Well, we talk
• 57:16a lot about that with respect
• 57:17to transplant that we were just
• 57:19talking out at BMT rounds today.
• 57:21About whether we'll be doing autologous
• 57:23transplants in the future or not.
• 57:25I think that that's kind
• 57:27of where we're heading.
• 57:28I just wanted to say that one of
• 57:30the things that yell is doing,
• 57:32by the way, is we are developing
• 57:34our own party and we didn't get
• 57:36a chance to talk about that.
• 57:37But Doctor Katz and colleagues
• 57:38have developed the RNA car strategy
• 57:40and we're working on that.
• 57:41I know he has a B cell construct
• 57:43as well as one vertice Oklahoma,
• 57:45so I think the whole car world
• 57:47is undergoing evolution as well.
• 57:48And hopefully we're going to be
• 57:49at the forefront of some of that.
• 57:55Don't there's a question from the
• 57:58audience will then from Doctor
• 58:01Chi with a new drug substitute
• 58:03of chemotherapy. In treatments.
• 58:06Also, with the new drug substitute
• 58:10chemotherapy treatment. From Doctor chi.
• 58:18Yeah, I mean, I think that's
• 58:20a question to everybody.
• 58:21Can we get rid of chemo?
• 58:23This toxic stuff?
• 58:26We are that we added Temple where
• 58:30we were able to to do that,
• 58:33like I acute firestick leukemias.
• 58:35I mean, that's that's a poster child, I know.
• 58:39But potentially yes, that can be.
• 58:41That can be the one of the goal we have.
• 58:46We should not basically forget that
• 58:48chemotherapy is AB side effects,
• 58:51but targeted therapies have side effects too,
• 58:54and so we should not.
• 58:56Situation where we are really,
• 58:59completely disparaging.
• 58:59Chemo too much as it's as some real
• 59:03basically benefits for for some of
• 59:06the patient and for chemotherapy
• 59:08as well As for cell therapy.
• 59:10I think we need to see the big picture
• 59:14and how we can sequence and combine
• 59:18these different modalities of treatment.
• 59:21Rather than being one again
• 59:23the again the other.
• 59:26Awesome, so I think we have
• 59:29reached 1:00 o'clock or one minute
• 59:31past 1:00 o'clock tomorrow.
• 59:33Francine Natalia thank you for the
• 59:35fantastic presentation, Charlie.
• 59:36Thank you for hosting us and
• 59:38thank you for everything on behalf
• 59:40of everybody in immortality.
• 59:42And thank you to everybody who's attending.
• 59:45Yeah, phenomenal work. I just
• 59:47think about in my tenure what's
• 59:49been going on in hematology.
• 59:51Yeah, it's really exciting.
• 59:53So congratulations to all the
• 59:56speakers and all the investigators
• 59:58and staff working on this. No. OK.