Translational Science in Hematologic Malignancies
February 25, 2021Information
February 23, 2021 | YCC Grand Rounds
Presentations by Dr. Stephanie Halene, Francine Foss, Thomas Prebet, and Natalia Neparidze
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- 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.