The microbiome is emerging as a key player in the effectiveness of CAR-T therapy, and today, Dr. Melody Smith, Assistant Professor of Medicine at Stanford University, sheds light on this fascinating intersection. Join us as we explore how advancements in CAR T-cell therapy are reshaping patient demographics and treatment approaches. Dr. Smith will discuss the implications of genetic engineering techniques like CRISPR, the importance of a multidisciplinary treatment strategy, and the role of antibiotic stewardship in optimizing outcomes. With insights into innovative therapies and ongoing clinical trials, this conversation promises to deepen your understanding of CAR-T therapy and its complexities, offering a glimpse into the future of cancer treatment.
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Episode Transcript
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(00:00):
(upbeat music)
- Welcome to "Stanford Medcast,"
the podcast from Stanford CME
that brings you the latest insights
from the world's leadingphysicians and scientists.
If you are joining us for the first time,
be sure to subscribe on Apple Podcast,
Amazon Music, Spotify,
(00:22):
or YouTube to stay updatedwith our newest episodes.
I am your host, Dr. Ruth Adewuya.
Today I am joined by Dr. Melody Smith,
who is a board-certifiedmedical oncologist
and hematologist at Stanford University,
where she serves as an assistant professor
in the Department of Medicine,
Division of Blood andMarrow Transplantation
(00:44):
and Cellular Therapy.
A nationally recognizedexpert in CAR T-cell therapy,
Dr. Smith leads atranslational research lab
investigating how intrinsiccellular mechanisms
and extrinsic factorslike the gut microbiome
influence the efficacy andtoxicity of cellular therapies.
Her pioneering work hasuncovered critical links
(01:06):
between antibiotic exposureCAR T therapy outcomes,
advancing the conversationon antimicrobial stewardship
in immunotherapy.
Clinically, she cares for patients
undergoing bone marrowtransplantation and cellular therapy.
And she's deeply committedto improving access, safety,
and long-term outcomes for patients
with hematologic malignancies.
(01:28):
Through her research, mentorship,and clinical practice,
Dr. Smith is helping redefine the future
of immune-based cancer treatment.
Dr. Smith, thank you so muchfor being on the podcast today.
- Thank you for the invitation
and the opportunity to sharea little bit about our work.
- For clinicians who maybe familiar with the term
but not the latest applications,
(01:48):
how would you describe CAR T-cell therapy
and how it's evolved in recent years?
- CAR T-cell therapy,
or chimeric antigenreceptor T-cell therapy,
is a type of cancer immunotherapy
that is indicated forpatients with relapsed
or refractory malignancies.
The current regulatoryapprovals from the FDA
(02:10):
are for patients withhematologic malignancies
or blood cancers,
but there's also a lot ofwork that's being investigated
for patients with solid tumors,
assessing both targetsfor CAR T-cell therapy
as well as the optimal waysto administer these therapies.
In terms of manufacturing
or developing CAR T-cell therapies,
they are isolated for the most part
(02:32):
from a recipient withan underlying cancer.
These would be autologousCAR T-cell therapy,
so from that patient or self.
These cells are then brought to the lab
where they're introduced with a receptor
that allows the T cell torecognize an antigen on the tumor.
These are receptors that arenot native to the T cell,
and that's why it's called chimeric.
(02:53):
It's a receptor that'sforeign to the T cell,
introduced into the T cellwith the approach being
that it's going to target the tumor
in a more antigen-specific fashion.
This has really revolutionizedhematologic malignancies
and I think more to comein the solid tumor space.
- You've provided a greatoverview of where CAR T started
and how far it's comenot only in indications
(03:15):
but also in the engineering.
As these therapies become more refined,
I imagine that also shiftsthe clinical decision-making.
Can you walk us through
how that evolution has changed
the kind of patients beingreferred for CAR T today
and how has that shifted fromwhen it was first introduced?
- From the time that CAR Tcell was first introduced,
the initial indication
(03:36):
was for pediatric B-cellacute lymphoblastic leukemia,
and now the indications encompass
both CD19 positive malignancies, B-ALL,
as well as non-Hodgkin's leukemia.
There are five FDA-approved CAR T cells
across those two indications,
and there are two FDA-approved CAR T cells
for multiple myeloma.
(03:56):
From the perspectiveof evolution over time,
how CAR T cell indications have changed?
First of all, there are more diseases
that are approved for their use.
Additionally, their approvalsencompass both pediatric
and adult populations.
From the perspective of CAR T cell
where it presents in the order of therapy,
(04:18):
there are CAR T cells that are approved
as second-line therapies
and then ones that areapproved for later lines
for patients who have relapsed.
Additional lines of therapy.
Certainly CAR T cells havemoved a little bit earlier
in the treatment process,
but there are no frontline CAR T cells
that are approved for cancertreatment as it stands.
That can continue to evolve
and likely will change over time.
(04:39):
Those are some of the ways
in which the FDA-approvedCAR T cells have evolved.
I think also what's really exciting
is some of the workthat's being investigated
in the preclinical state andearly-stage clinical trials
that are looking at CAR T cells
from not only autologous sources
but also donor or allogeneic sources.
(05:00):
CAR T cells not just fromconventional T-cell sources,
but also from non-conventional T cells,
such as gamma delta cells or NK T cells.
As well as using geneticengineering with CRISPR
and other strategies toengineer CAR T cells,
there's really been sucha robust groundswell
(05:20):
of investigation of this therapy
because of the therapeuticpromise that has been observed,
and so I think that'll continueto reveal itself over time.
- Can you talk a littlebit about this question
as it relates to the referralcriteria due to toxicity risk?
- The specific toxicitiesthat we evaluate for
that are CAR-associated toxicities
(05:41):
predominantly presentwithin that acute setting
within those first 30days after CAR T cells.
We are much more astute
and able to not only diagnosethese at an earlier stage
but also treat them.
Even though these toxicitiescan present morbidity
for some patients,
they're much better managed
than when we first get in CART-cell therapy in the clinic.
(06:04):
The other thing that we've gotten better
as a field at over time
is trying to differentiate
which patients would be a better candidate
based upon the therapeuticand toxicity profile.
Patients who are older
or maybe have more comorbiditiesmight be recommended
to receive a certain product
that has a more modesttoxicity profile than another.
(06:25):
- I appreciate what you said,
that there is this increasing nuance
in how you evaluate fitness per therapy.
I'm hearing also that there is complexity
in patient selection,
balancing the potentialbenefit with clinical risk,
especially in patients.
How do you typicallyapproach these discussions
with patients and theirfamilies about the risks
and benefits of CAR T,
especially those thatmight not exactly fit
(06:47):
the eligibility criteria?
- When we have patients whoare a little bit older in age
or who have notable comorbidities
where we really want toensure that do no harm
and balancing benefit versus risk,
in those patients who you see that,
we just have a conversation very openly.
These are the CAR T-cellproducts that are available,
(07:09):
but we would recommendthis one for this reason
as opposed to that one.
We recommend to them basedupon these various factors,
including toxicity,
and generally patients understand
that we're giving our bestrecommendation to them
so that we can see the benefit
from the anti-tumorside of the CAR T cells
without a prolonged hospital stay
with various complications.
(07:31):
It's usually a very open conversation,
and patients understand our experience
and expertise that playsinto those recommendations.
- I imagine part of that conversation
is also about the logisticsof their caregiving needs,
post-treatment monitoring.
Do you also talk at that time
about exploring clinicaltrials with the patient?
- From the perspective of clinical trials,
(07:52):
anytime a patient's referredto us for a CAR T cell,
so let's say, for example, a given,
patient with diffuselarge B-cell lymphoma.
We always present to them
at the time that we'rediscussing CAR T cells,
both the FDA-approved CAR T cells
that they would be candidates to receive
as well as any CAR T cells
that we have available on clinical trial
(08:12):
that we screen them for.
So we present them at the same time
with the transparency that clinical trials
and we may have a certain amount of data
or very limited data to share with them,
but we provide with them the rationale
as to why a clinicaltrial might be a good fit
compared to a commercial product.
But that is always mentioned
in our discussion with patients
if there is a trial thatthey're eligible for.
(08:33):
- What you're saying,
it's ultimately about theshared decision-making
that you have with the patient
and a very personalized discussion
around all of the componentsthat you just talked about,
the goals of care,
what's available interms of clinical trials,
and what available data that you have.
- Definitely.
And I would say that CAR T cells
are a potentially curative approach.
All of that conversation istaken from that perspective
(08:54):
that we're trying to give atherapy that has a potential
for a long-term durableremission for patients
and the potential for cure
such that they may not need todeal with their cancer again
or for a very long time.
And so that nuance is really important
in terms of developing eachpatient's treatment plan.
An important piece of CAR T-cell therapy
(09:14):
and cellular therapies
that we administer here inthe bone marrow transplant
and cell therapy division,
which is that it's a verymultidisciplinary approach
to treatment involved fromthe first day social workers
throughout the hospital stay,
both with physical therapy,occupational therapy,
our advanced practice providers,
and all of these pieces together
(09:34):
help to care for the patients.
All of these pieces come together
as we're designing a treatmentplan for our patients.
- CAR T has really transformedoutcomes for some patients,
but it's not a panacea.
What are some of the biggest hurdles,
scientifically or clinically,
that you think we'restill trying to overcome?
- Relapse is a reallybig risk for patients
who receive CAR T-cell therapy.
(09:55):
About 60% of patients still relapse.
With many of thoserelapses happening early,
when we look at the long-term data
for patients who'vereceived CAR T-cell therapy,
the first 12, and Iwould say even 18 months,
is when many of those patientswho are going to relapse,
with later relapses
beyond that time pointbeing much more rare,
(10:15):
we know some of themechanisms for relapse,
whether from the tumor side,
the tumor losing ordownregulating the antigen
or the marker on the tumorthat the CAR is targeting.
Another aspect of relapse
that a lot of folks areinvestigating is the T-cell fitness,
so what T cells are going to be the ones
that are gonna best persist,
not lead to T-cell exhaustion
(10:37):
from the immunologic perspective.
One of the areas that mylab is really focused on,
both from the clinical sidebut also more so in the lab,
is endogenous factors within the host,
the intestinal microbiome,
and understanding how that is a factor
that may modulate CAR T-cell response.
- You've highlighted someof the critical challenges
that gets overshadowed bya lot of the excitement
(10:59):
around CAR T success stories,
but also some of theinnovations that have come up
through those challenges as well.
On the clinical side,
we've also seen significant strides
in how we manage toxicity.
In your practice,
what advances in toxicity management
have made the mostsignificant clinical impact?
- There have been some really nice studies
(11:21):
from the clinical trial perspective
that have looked at prophylactictreatments to mitigate
or decrease the severity of toxicity.
From the clinical perspective,
I think those have hada really notable impact.
Also, both clinicaland preclinical studies
that have helped to elucidate the cytokine
and inflammatory profilethat is associated
(11:43):
with various CAR-related toxicities.
That's also been very instructive for us
to not only understand more
of the pathophysiology of these toxicities
but also the targeted therapies
that we can use to treat them.
For an emerging toxicity that we've seen
called immune effector cell-associated
hemophagocytic lymphohistiocytosis,
(12:03):
which is like a HLH-type syndrome
that can occur after CAR T-cell therapy.
Really, research from various studies
has illuminated what isthat inflammatory profile
and what are the laboratory
and inflammatory markersthat we need to monitor
in that setting.
As a result of that being seen
across various clinical trials,
we now have a consensus scoring
(12:25):
and assessment for that therapy.
Various researchers
across different institutionsusing CAR T cells
coming together with theirinsights in the clinical scenario
has helped us to be able tomanage these things better
for our patients.
- That kind of precisionin response management
has likely made a meaningful difference
not just in outcomes
but really in the overallpatient's experience.
(12:47):
I wanna shift to you talk a little bit
about the work thatyou're doing in your lab
and the gut microbiome.
Most clinicians know thatthe gut microbiome matters
in general health,
but how did it become suchan important piece in CAR T?
- In terms of in general health,
there's a lot of discussionof the gut microbiome
in popular literature.
People are intrigued by it,
(13:07):
and I think it is an areathat is diverse, so complex,
and still there's a lotthat we need to investigate
to understand it better.
The gut microbiome has been implicated
across a range of diseasesnot just in cancer
but specifically in cancer
over the past, more than a decade,
there's been emerging data interms of the gut microbiome
(13:30):
and the response to variouschemotherapeutic agents,
but specifically for cancerimmunotherapy in the fields
of allogeneic hematopoieticcell transplantation
and also for immune checkpoint block,
for example, with anti-CTLA-4and anti-PD-1 agents,
there's been a lot of data characterizing
in clinical cohorts
and also in preclinical models
that the intestinal microbiome,
(13:52):
the bacteria, the fungi
and even the virusesthat are within the host
play a role in various outcomesfollowing these therapies.
I became intrigued bythis research question
and started collectingsamples from our patients
who were receiving CAR T-cell therapy.
And in collaboration with theUniversity of Pennsylvania,
I was at Memorial Sloan Kettering
(14:12):
at the time that I started this research,
we published the first study
that highlighted thatthe intestinal microbiome
is correlated with responses
to patients who receiveCAR T-cell therapy.
And in our study,
we focused on patientswith non-Hodgkin's lymphoma
and B-cell acute lymphoblastic leukemia,
characterizing how antibioticsprior to CAR T-cell therapy
lead to worse outcomes
(14:33):
and also profilingspecific bacterial attacks
that were correlatedwith CAR T-cell response.
So from there,
that paper was publishedabout three years ago now,
and from that time onward,
there have been subsequent studies
that have validatedseveral of our key findings
and illuminated additional insights
as it relates to the intestinal microbiome
in CAR T-cell therapy.
(14:53):
- I wanna touch on what youmentioned towards the end
of your response around antibiotics.
And you and others have shown
that antibiotics given beforeCAR T can influence outcomes.
Can you explain the mechanisms
or the hypotheses behind that connection.
- For the antibiotics,
we looked at four weeksbefore CAR T-cell therapy.
Subsequent studies havelooked at three weeks before,
(15:15):
and another one has looked at six,
and found that exposure to antibiotics
in the weeks before CAR T-cell therapy,
just any antibiotics,
is associated withdecreased overall survival
and progression-free survivalafter CAR T-cell therapy.
Because not all antibiotics
are equally disruptive to the gut,
we, in our study and others,
have honed in on a subgroup of antibiotics
(15:37):
that we classified
as obligate anaerobe-targetingantibiotics.
These are antibiotics thatdisrupt commensals in the gut
that are obligate anaerobes.
And we found that exposureto these antibiotics
and they're antibiotics thatwe're all really familiar with,
piperacillin-tazobactam,imipenem, meropenem,
antibiotics that are given to patients
who have neutropenic fever
predominantly before CAR T-cell therapy,
(15:59):
we found that exposure to one
of these antibiotics was associated
with even a more profounddecrease in overall survival
and progression-free survival.
Likely our hypothesisis that the disruption
or loss of these commensals,the obligate anaerobes,
is what's mediating that.
In my lab here at Stanford,
we are mechanistically now interrogating
how these bacterial taxa
(16:21):
and how the variouspathways that they utilize,
how this is directlyimpacting CAR T-cell therapy.
We not only found that exposure
to these antibiotics was associated
with decreased overall survival,
but we also found thatantibiotic exposures
was associated withincreased neurotoxicity,
one of those toxicities thatwe were talking about before,
(16:41):
so that's something else
that we are analyzing mechanistically
in our preclinical models.
- The level of interactionthat you talk about
between the microbiome
and immune cell function reallyadds an entirely new layer
to how we think about pre-treatment care.
What I'm hearing from you
is that the antibioticsthat we choose days
or weeks before infusioncan shape outcomes.
(17:02):
That really challenges someof our traditional approaches
to supportive care.
What are some practical ways you think
antimicrobial stewardship can
or should evolve in CAR T programs,
especially for teams that maynot yet be incorporating this
into their decision-making?
- The word of caution that I always have
whenever I'm discussing this data
(17:22):
is that what our findings suggest
is not that antibioticsshould not be administered
before CAR T-cell therapy,
but that, to your point,
antibiotic stewardship is really important
and critical for us toconsider moving forward.
Exposure to cefepime,
which is also a broad-spectrum antibiotic
that's usually givenfor a neutropenic fever,
(17:44):
was not associated withdecrease in overall survival
or progression-free survival.
And cefepime does targetobligate anaerobes,
but not to the same degree
as those other obligateanaerobic-targeting antibiotics
that I mentioned.
And so, going back to the pointof antibiotic stewardship,
if a patient has a neutropenic fever
or a fever before CAR T-cell therapy
(18:06):
and they need a broad-spectrum antibiotic,
cefepime may be a better choice
compared to piperacillin-tazobactam.
We're already having somediscussions internally
as to how we can really refine
and streamline our approach to management
of fever in patients who aregetting CAR T-cell therapy,
and so I'm hoping that we can come up
with some uniformapproaches to manage this,
(18:26):
especially given the really strong
and now reproducible data
that's been seen acrossdifferent clinical cohorts.
- It sounds like we need a paradigm shift
to think about not just new protocols
but really a new mindset,
especially among infectiousdisease, oncology,
and pharmacy teams.
Let's talk about innovationin another front,
donor-derived CAR T cell.
(18:47):
What do you see as the clinical future
for these, quote, unquote,"off-the-shelf approaches,"
and how might they reshapethe current CAR T landscape?
- I think of donor-derivedCAR T-cell therapies
as a really importantaspect of future innovation
for next-generation CART cells in two streams.
First, as a transplanter,
it's really interestingto consider the potential
(19:10):
of CAR T cells to be addedfollowing allogeneic transplant.
That was also some of the workthat I did during my postdoc,
and here at Stanford
in our Bone Marrow Transplantand Cell Therapy Division,
we've really innovated
and translated that to a clinical trial
that is led by Dr. Lori Muffly
as the principal investigator,
in which, following an allo transplant,
(19:30):
we're giving CAR T cells again
as a strategy to decrease relapse
because relapse is a significant issue
after allo transplant as well,
and it's a leading causeof morbidity and mortality
even after an allo transplant.
So what we do is we have agraft-engineered allo transplant.
Then after that, give CAR T-cell therapy,
and we have a trial that's open,
is now completing accrual for patients
(19:52):
with high-risk B-cell acutelymphoblastic leukemia
and is shown really promising outcomes.
We do plan to continue with another study
that's going to being investigating that
for donor-derived CAR Tcells using donor cells
after transplant to improve outcomes.
Then there's the off-the-shelfstrategies, as you mentioned.
We're really interested in those.
That can incorporate genetic engineering
(20:14):
or alternative donor sources for T cells
from non-conventional T cells.
There are a lot of reasonswhy donor cell therapies
could be really revolutionaryfor the CAR T-cell field
because you have cellsfrom a healthy donor
that might just be more fit.
Having a bank of readily available cells
will potentially help to drive down cost
(20:35):
because right now CAR T cells are,
by definition, a bespoke therapy
because they're engineeredfrom the patient.
We could also obviate
or just shorten some of thedelays that we currently have
with the manufacturingof CAR T-cell therapy.
The manufacturing timelineshave already decreased in size
in the autologous settingcompared to where we started,
but still off-the-shelf
or donor cell therapies couldfurther improve upon that.
(20:58):
There's a lot of promise in the allo
and off-the-shelf space that me
and others are investigating now.
- It sounds like there's an ability
for off-the-shelf CAR T cells
could potentially democratizeaccess to the treatment,
but I imagine that there's a lot of nuance
in managing the immunologic risk
when you're moving fromautologous to allogeneic products.
(21:19):
What are some of the keyimmune-related challenges
that your team is focused on solving?
How close are we to clinical scalability?
- Some of the biggest risk
when you think about any allogeneic,
specifically T-cell therapy,
is graft versus host disease.
So where the T cells from adonor inside the recipient
may recognize various aspectsof the recipient is foreign
(21:42):
and can attack organs.
Another issue could berejection of those donor T cells
by the host's immune system,
leading to a loss of persistence
or just basically clearance of the cells.
That's another big issue.
From the perspective
of how close are we to translating that.
We've already translatedsome preclinical data
(22:03):
with the donor CAR T cellsafter allo transplant
to this phase one clinical trial,
which, I'll say, has shownreally promising results.
And then on the side ofnon-conventional T-cell sources
or genetically engineered T cells,
there's a lot ofearly-stage clinical trials
and even companies thatare looking at this
with varying levels of success.
(22:23):
- What you've describedreally speaks to you.
The level of engineeringprecision that is required,
not just in targeting the cancer
but in modulating the cells'interaction with the host.
These kinds of innovations
are really making CAR T moreaccessible and adaptable.
But I'm curious, is therea piece of the CAR T puzzle
that you feel isn't gettingenough attention right now?
(22:45):
Something that's quietly limitingsuccess behind the scenes?
- I actually was gonnaanswer the opposite first.
Something I haven't mentioned,
which is in vivo editing orengineering of CAR T cells.
There are some early studies
that are giving essentiallyCAR T cells in such a way
that they're beingengineered inside the host,
(23:05):
and I think there's goingto be some exciting data.
Other things that are limitingengineering of CAR T cells,
I think there's a lot of workbeing done in that space.
One of the key limitations
from a non-engineering perspective
is there are a lot of patientswho have these diseases,
lymphoma, leukemia,
that are not currently gettingaccess to these therapies
(23:27):
because of a lack of feelingsfrom their primary oncologists
that they would be well suited for it.
And then there are alsovarious social factors
that maybe patients aren't being referred,
given concern for cost
or the way in whichCAR T cell does require
for patients to be withinthe treatment center.
So there are various things Ithink in terms of education,
(23:49):
providing more of a knowledge base
as to the actual therapeutic plan,
as well as the supportthat can be provided
to patients who aregetting CAR T-cell therapy
that is limiting patients frombeing more broadly referred
to centers that can administerthis treatment for them.
- As CAR T therapiesbecome more mainstream,
what policies do you think need to evolve
(24:11):
to ensure equitableaccess across populations?
- When CAR T cells werefirst FDA-approved,
we didn't know exactly how todetect the toxicities as early
or treat them as effectively.
There were a lot ofguardrails placed around
how we administer CAR T-cell therapy,
which I think were very important
because we wanna make sure
(24:32):
that anytime we'rerolling out a new therapy
that it's done in a waythat's safe for patients,
that clinicians can manage it,
and that the right folks
who know how to managepotential side effects
are taking care of those patients.
Now that we have several years
of experience with these therapies,
going back and reevaluatingthose therapies
that have less severe toxicity profile,
(24:54):
trying to understandwhether a 30-day requirement
of being within the treatment center
is still absolutelynecessary might be valuable,
and that would probably need to be done
on a case-by-case basis with experts
and regulatory bodies, et cetera,
that would help to open up the therapy
to a broader population of patients.
Patients have to havea dedicated caregiver.
(25:17):
Not only do they have to move,
but also their caregiverhas to be with them,
and that is a limitation.
That's a huge factor that can be impacting
who is getting to see these therapies
and who is receiving them.
- I'm also curious about whetherthe landscape has changed
in terms of clinical trials
and the population that is being included
in clinical trials to CAR T.
(25:37):
Have you seen a shift?
- I can't say that I'venecessarily seen a shift,
but I can see that there'smore intentionality
in trying to ensure that the patients
that are enrolled on the clinicaltrials are representative
of the populations that areimpacted by the diseases.
So that is encouraging.
That could lead to some moredemonstrative change over time.
(25:58):
There's just even moreconsciousness around the fact
that we need to have arepresentative population
and so that gives me a lotof hope for the future.
- It's a powerful reminder
that the science can be transformative,
but only if we have thesystems that are in place
to deliver it equitably to the population.
How do you see cellular therapies
and microbiome science reshaping
(26:20):
how we think about cancer treatment
in the next five to 10 years?
- Cellular therapies, I'llstart with that first.
Cellular therapies have so much promise
for reshaping the care of patients.
When we think about cellular therapies,
there are now two cellular therapies
within the past few years
that are approved for solid tumors,
not CAR T-cell therapies,
(26:40):
but one peer-approved tumorinfiltrating lymphocyte therapy,
or TIL therapy.
More recently,
there is an FDA-approvedT-cell receptor therapy
that's approved, respectively,for melanoma and sarcoma.
Cellular therapy is goingto continue to advance
for patients with cancer.
But also for patientsoutside of the cancer space
(27:02):
for autoimmune diseases,
there is a lot of workon CAR T-cell therapy
for autoimmune disease, whichwe haven't touched on today,
just to keep our scope more refined.
But I think as we moveforward in the next few years,
there may be some interestingapprovals in that space too,
because already the preliminary data
has shown some promisingoutcomes for patients
(27:22):
with various autoimmune diseases,
such as lupus or systemic sclerosis.
And then for the gut microbiome,
one thing that really encourages me
is that now in the fieldof cellular therapy,
there is data in distinct clinical cohorts
showing the relevanceof the gut microbiome
to clinical outcomes, bothsafety and the efficacy.
(27:44):
In the future,
I think we're gonna see morestudies looking at mechanism
and refining what is the mechanism
for these microbiome associations
and also developingtailored interventions,
whether through bacterialtaxa or metabolite.
Now that we have a strongbase of clinical data
that supports delvingdeeper into mechanism,
(28:05):
we're gonna see that inthe coming years as well.
- There's such a sense of optimism
in what you just said in that vision,
one where we're notonly refining the tools,
learning more about themechanisms that we use to treat,
but also rethinking the ecosystem
in which those tools operate.
It's very clear to methat your work is helping
to define what thatfuture might look like,
(28:25):
so, Dr. Smith, thank you somuch for sharing your expertise
and giving us a little bit of a window
into the evolving science
and clinical practice of CAR T therapy.
And for our listeners,
I hope today's conversationsparked new questions
and ideas about how wedeliver precision care
in an increasingly complextherapeutic landscape.
(28:46):
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- Welcome to "Stanford Medcast,"
the podcast from Stanford CME
that brings you the latest insights
from the world's leadingphysicians and scientists.
If you are joining us for the first time,
be sure to subscribe on Apple Podcast,
Amazon Music, Spotify,
(00:22):
or YouTube to stay updatedwith our newest episodes.
I am your host, Dr. Ruth Adewuya.
Today I am joined by Dr. Melody Smith,
who is a board-certifiedmedical oncologist
and hematologist at Stanford University,
where she serves as an assistant professor
in the Department of Medicine,
Division of Blood andMarrow Transplantation
(00:44):
and Cellular Therapy.
A nationally recognizedexpert in CAR T-cell therapy,
Dr. Smith leads atranslational research lab
investigating how intrinsiccellular mechanisms
and extrinsic factorslike the gut microbiome
influence the efficacy andtoxicity of cellular therapies.
Her pioneering work hasuncovered critical links
(01:06):
between antibiotic exposureCAR T therapy outcomes,
advancing the conversationon antimicrobial stewardship
in immunotherapy.
Clinically, she cares for patients
undergoing bone marrowtransplantation and cellular therapy.
And she's deeply committedto improving access, safety,
and long-term outcomes for patients
with hematologic malignancies.
(01:28):
Through her research, mentorship,and clinical practice,
Dr. Smith is helping redefine the future
of immune-based cancer treatment.
Dr. Smith, thank you so muchfor being on the podcast today.
- Thank you for the invitation
and the opportunity to sharea little bit about our work.
- For clinicians who maybe familiar with the term
but not the latest applications,
(01:48):
how would you describe CAR T-cell therapy
and how it's evolved in recent years?
- CAR T-cell therapy,
or chimeric antigenreceptor T-cell therapy,
is a type of cancer immunotherapy
that is indicated forpatients with relapsed
or refractory malignancies.
The current regulatoryapprovals from the FDA
(02:10):
are for patients withhematologic malignancies
or blood cancers,
but there's also a lot ofwork that's being investigated
for patients with solid tumors,
assessing both targetsfor CAR T-cell therapy
as well as the optimal waysto administer these therapies.
In terms of manufacturing
or developing CAR T-cell therapies,
they are isolated for the most part
(02:32):
from a recipient withan underlying cancer.
These would be autologousCAR T-cell therapy,
so from that patient or self.
These cells are then brought to the lab
where they're introduced with a receptor
that allows the T cell torecognize an antigen on the tumor.
These are receptors that arenot native to the T cell,
and that's why it's called chimeric.
(02:53):
It's a receptor that'sforeign to the T cell,
introduced into the T cellwith the approach being
that it's going to target the tumor
in a more antigen-specific fashion.
This has really revolutionizedhematologic malignancies
and I think more to comein the solid tumor space.
- You've provided a greatoverview of where CAR T started
and how far it's comenot only in indications
(03:15):
but also in the engineering.
As these therapies become more refined,
I imagine that also shiftsthe clinical decision-making.
Can you walk us through
how that evolution has changed
the kind of patients beingreferred for CAR T today
and how has that shifted fromwhen it was first introduced?
- From the time that CAR Tcell was first introduced,
the initial indication
(03:36):
was for pediatric B-cellacute lymphoblastic leukemia,
and now the indications encompass
both CD19 positive malignancies, B-ALL,
as well as non-Hodgkin's leukemia.
There are five FDA-approved CAR T cells
across those two indications,
and there are two FDA-approved CAR T cells
for multiple myeloma.
(03:56):
From the perspectiveof evolution over time,
how CAR T cell indications have changed?
First of all, there are more diseases
that are approved for their use.
Additionally, their approvalsencompass both pediatric
and adult populations.
From the perspective of CAR T cell
where it presents in the order of therapy,
(04:18):
there are CAR T cells that are approved
as second-line therapies
and then ones that areapproved for later lines
for patients who have relapsed.
Additional lines of therapy.
Certainly CAR T cells havemoved a little bit earlier
in the treatment process,
but there are no frontline CAR T cells
that are approved for cancertreatment as it stands.
That can continue to evolve
and likely will change over time.
(04:39):
Those are some of the ways
in which the FDA-approvedCAR T cells have evolved.
I think also what's really exciting
is some of the workthat's being investigated
in the preclinical state andearly-stage clinical trials
that are looking at CAR T cells
from not only autologous sources
but also donor or allogeneic sources.
(05:00):
CAR T cells not just fromconventional T-cell sources,
but also from non-conventional T cells,
such as gamma delta cells or NK T cells.
As well as using geneticengineering with CRISPR
and other strategies toengineer CAR T cells,
there's really been sucha robust groundswell
(05:20):
of investigation of this therapy
because of the therapeuticpromise that has been observed,
and so I think that'll continueto reveal itself over time.
- Can you talk a littlebit about this question
as it relates to the referralcriteria due to toxicity risk?
- The specific toxicitiesthat we evaluate for
that are CAR-associated toxicities
(05:41):
predominantly presentwithin that acute setting
within those first 30days after CAR T cells.
We are much more astute
and able to not only diagnosethese at an earlier stage
but also treat them.
Even though these toxicitiescan present morbidity
for some patients,
they're much better managed
than when we first get in CART-cell therapy in the clinic.
(06:04):
The other thing that we've gotten better
as a field at over time
is trying to differentiate
which patients would be a better candidate
based upon the therapeuticand toxicity profile.
Patients who are older
or maybe have more comorbiditiesmight be recommended
to receive a certain product
that has a more modesttoxicity profile than another.
(06:25):
- I appreciate what you said,
that there is this increasing nuance
in how you evaluate fitness per therapy.
I'm hearing also that there is complexity
in patient selection,
balancing the potentialbenefit with clinical risk,
especially in patients.
How do you typicallyapproach these discussions
with patients and theirfamilies about the risks
and benefits of CAR T,
especially those thatmight not exactly fit
(06:47):
the eligibility criteria?
- When we have patients whoare a little bit older in age
or who have notable comorbidities
where we really want toensure that do no harm
and balancing benefit versus risk,
in those patients who you see that,
we just have a conversation very openly.
These are the CAR T-cellproducts that are available,
(07:09):
but we would recommendthis one for this reason
as opposed to that one.
We recommend to them basedupon these various factors,
including toxicity,
and generally patients understand
that we're giving our bestrecommendation to them
so that we can see the benefit
from the anti-tumorside of the CAR T cells
without a prolonged hospital stay
with various complications.
(07:31):
It's usually a very open conversation,
and patients understand our experience
and expertise that playsinto those recommendations.
- I imagine part of that conversation
is also about the logisticsof their caregiving needs,
post-treatment monitoring.
Do you also talk at that time
about exploring clinicaltrials with the patient?
- From the perspective of clinical trials,
(07:52):
anytime a patient's referredto us for a CAR T cell,
so let's say, for example, a given,
patient with diffuselarge B-cell lymphoma.
We always present to them
at the time that we'rediscussing CAR T cells,
both the FDA-approved CAR T cells
that they would be candidates to receive
as well as any CAR T cells
that we have available on clinical trial
(08:12):
that we screen them for.
So we present them at the same time
with the transparency that clinical trials
and we may have a certain amount of data
or very limited data to share with them,
but we provide with them the rationale
as to why a clinicaltrial might be a good fit
compared to a commercial product.
But that is always mentioned
in our discussion with patients
if there is a trial thatthey're eligible for.
(08:33):
- What you're saying,
it's ultimately about theshared decision-making
that you have with the patient
and a very personalized discussion
around all of the componentsthat you just talked about,
the goals of care,
what's available interms of clinical trials,
and what available data that you have.
- Definitely.
And I would say that CAR T cells
are a potentially curative approach.
All of that conversation istaken from that perspective
(08:54):
that we're trying to give atherapy that has a potential
for a long-term durableremission for patients
and the potential for cure
such that they may not need todeal with their cancer again
or for a very long time.
And so that nuance is really important
in terms of developing eachpatient's treatment plan.
An important piece of CAR T-cell therapy
(09:14):
and cellular therapies
that we administer here inthe bone marrow transplant
and cell therapy division,
which is that it's a verymultidisciplinary approach
to treatment involved fromthe first day social workers
throughout the hospital stay,
both with physical therapy,occupational therapy,
our advanced practice providers,
and all of these pieces together
(09:34):
help to care for the patients.
All of these pieces come together
as we're designing a treatmentplan for our patients.
- CAR T has really transformedoutcomes for some patients,
but it's not a panacea.
What are some of the biggest hurdles,
scientifically or clinically,
that you think we'restill trying to overcome?
- Relapse is a reallybig risk for patients
who receive CAR T-cell therapy.
(09:55):
About 60% of patients still relapse.
With many of thoserelapses happening early,
when we look at the long-term data
for patients who'vereceived CAR T-cell therapy,
the first 12, and Iwould say even 18 months,
is when many of those patientswho are going to relapse,
with later relapses
beyond that time pointbeing much more rare,
(10:15):
we know some of themechanisms for relapse,
whether from the tumor side,
the tumor losing ordownregulating the antigen
or the marker on the tumorthat the CAR is targeting.
Another aspect of relapse
that a lot of folks areinvestigating is the T-cell fitness,
so what T cells are going to be the ones
that are gonna best persist,
not lead to T-cell exhaustion
(10:37):
from the immunologic perspective.
One of the areas that mylab is really focused on,
both from the clinical sidebut also more so in the lab,
is endogenous factors within the host,
the intestinal microbiome,
and understanding how that is a factor
that may modulate CAR T-cell response.
- You've highlighted someof the critical challenges
that gets overshadowed bya lot of the excitement
(10:59):
around CAR T success stories,
but also some of theinnovations that have come up
through those challenges as well.
On the clinical side,
we've also seen significant strides
in how we manage toxicity.
In your practice,
what advances in toxicity management
have made the mostsignificant clinical impact?
- There have been some really nice studies
(11:21):
from the clinical trial perspective
that have looked at prophylactictreatments to mitigate
or decrease the severity of toxicity.
From the clinical perspective,
I think those have hada really notable impact.
Also, both clinicaland preclinical studies
that have helped to elucidate the cytokine
and inflammatory profilethat is associated
(11:43):
with various CAR-related toxicities.
That's also been very instructive for us
to not only understand more
of the pathophysiology of these toxicities
but also the targeted therapies
that we can use to treat them.
For an emerging toxicity that we've seen
called immune effector cell-associated
hemophagocytic lymphohistiocytosis,
(12:03):
which is like a HLH-type syndrome
that can occur after CAR T-cell therapy.
Really, research from various studies
has illuminated what isthat inflammatory profile
and what are the laboratory
and inflammatory markersthat we need to monitor
in that setting.
As a result of that being seen
across various clinical trials,
we now have a consensus scoring
(12:25):
and assessment for that therapy.
Various researchers
across different institutionsusing CAR T cells
coming together with theirinsights in the clinical scenario
has helped us to be able tomanage these things better
for our patients.
- That kind of precisionin response management
has likely made a meaningful difference
not just in outcomes
but really in the overallpatient's experience.
(12:47):
I wanna shift to you talk a little bit
about the work thatyou're doing in your lab
and the gut microbiome.
Most clinicians know thatthe gut microbiome matters
in general health,
but how did it become suchan important piece in CAR T?
- In terms of in general health,
there's a lot of discussionof the gut microbiome
in popular literature.
People are intrigued by it,
(13:07):
and I think it is an areathat is diverse, so complex,
and still there's a lotthat we need to investigate
to understand it better.
The gut microbiome has been implicated
across a range of diseasesnot just in cancer
but specifically in cancer
over the past, more than a decade,
there's been emerging data interms of the gut microbiome
(13:30):
and the response to variouschemotherapeutic agents,
but specifically for cancerimmunotherapy in the fields
of allogeneic hematopoieticcell transplantation
and also for immune checkpoint block,
for example, with anti-CTLA-4and anti-PD-1 agents,
there's been a lot of data characterizing
in clinical cohorts
and also in preclinical models
that the intestinal microbiome,
(13:52):
the bacteria, the fungi
and even the virusesthat are within the host
play a role in various outcomesfollowing these therapies.
I became intrigued bythis research question
and started collectingsamples from our patients
who were receiving CAR T-cell therapy.
And in collaboration with theUniversity of Pennsylvania,
I was at Memorial Sloan Kettering
(14:12):
at the time that I started this research,
we published the first study
that highlighted thatthe intestinal microbiome
is correlated with responses
to patients who receiveCAR T-cell therapy.
And in our study,
we focused on patientswith non-Hodgkin's lymphoma
and B-cell acute lymphoblastic leukemia,
characterizing how antibioticsprior to CAR T-cell therapy
lead to worse outcomes
(14:33):
and also profilingspecific bacterial attacks
that were correlatedwith CAR T-cell response.
So from there,
that paper was publishedabout three years ago now,
and from that time onward,
there have been subsequent studies
that have validatedseveral of our key findings
and illuminated additional insights
as it relates to the intestinal microbiome
in CAR T-cell therapy.
(14:53):
- I wanna touch on what youmentioned towards the end
of your response around antibiotics.
And you and others have shown
that antibiotics given beforeCAR T can influence outcomes.
Can you explain the mechanisms
or the hypotheses behind that connection.
- For the antibiotics,
we looked at four weeksbefore CAR T-cell therapy.
Subsequent studies havelooked at three weeks before,
(15:15):
and another one has looked at six,
and found that exposure to antibiotics
in the weeks before CAR T-cell therapy,
just any antibiotics,
is associated withdecreased overall survival
and progression-free survivalafter CAR T-cell therapy.
Because not all antibiotics
are equally disruptive to the gut,
we, in our study and others,
have honed in on a subgroup of antibiotics
(15:37):
that we classified
as obligate anaerobe-targetingantibiotics.
These are antibiotics thatdisrupt commensals in the gut
that are obligate anaerobes.
And we found that exposureto these antibiotics
and they're antibiotics thatwe're all really familiar with,
piperacillin-tazobactam,imipenem, meropenem,
antibiotics that are given to patients
who have neutropenic fever
predominantly before CAR T-cell therapy,
(15:59):
we found that exposure to one
of these antibiotics was associated
with even a more profounddecrease in overall survival
and progression-free survival.
Likely our hypothesisis that the disruption
or loss of these commensals,the obligate anaerobes,
is what's mediating that.
In my lab here at Stanford,
we are mechanistically now interrogating
how these bacterial taxa
(16:21):
and how the variouspathways that they utilize,
how this is directlyimpacting CAR T-cell therapy.
We not only found that exposure
to these antibiotics was associated
with decreased overall survival,
but we also found thatantibiotic exposures
was associated withincreased neurotoxicity,
one of those toxicities thatwe were talking about before,
(16:41):
so that's something else
that we are analyzing mechanistically
in our preclinical models.
- The level of interactionthat you talk about
between the microbiome
and immune cell function reallyadds an entirely new layer
to how we think about pre-treatment care.
What I'm hearing from you
is that the antibioticsthat we choose days
or weeks before infusioncan shape outcomes.
(17:02):
That really challenges someof our traditional approaches
to supportive care.
What are some practical ways you think
antimicrobial stewardship can
or should evolve in CAR T programs,
especially for teams that maynot yet be incorporating this
into their decision-making?
- The word of caution that I always have
whenever I'm discussing this data
(17:22):
is that what our findings suggest
is not that antibioticsshould not be administered
before CAR T-cell therapy,
but that, to your point,
antibiotic stewardship is really important
and critical for us toconsider moving forward.
Exposure to cefepime,
which is also a broad-spectrum antibiotic
that's usually givenfor a neutropenic fever,
(17:44):
was not associated withdecrease in overall survival
or progression-free survival.
And cefepime does targetobligate anaerobes,
but not to the same degree
as those other obligateanaerobic-targeting antibiotics
that I mentioned.
And so, going back to the pointof antibiotic stewardship,
if a patient has a neutropenic fever
or a fever before CAR T-cell therapy
(18:06):
and they need a broad-spectrum antibiotic,
cefepime may be a better choice
compared to piperacillin-tazobactam.
We're already having somediscussions internally
as to how we can really refine
and streamline our approach to management
of fever in patients who aregetting CAR T-cell therapy,
and so I'm hoping that we can come up
with some uniformapproaches to manage this,
(18:26):
especially given the really strong
and now reproducible data
that's been seen acrossdifferent clinical cohorts.
- It sounds like we need a paradigm shift
to think about not just new protocols
but really a new mindset,
especially among infectiousdisease, oncology,
and pharmacy teams.
Let's talk about innovationin another front,
donor-derived CAR T cell.
(18:47):
What do you see as the clinical future
for these, quote, unquote,"off-the-shelf approaches,"
and how might they reshapethe current CAR T landscape?
- I think of donor-derivedCAR T-cell therapies
as a really importantaspect of future innovation
for next-generation CART cells in two streams.
First, as a transplanter,
it's really interestingto consider the potential
(19:10):
of CAR T cells to be addedfollowing allogeneic transplant.
That was also some of the workthat I did during my postdoc,
and here at Stanford
in our Bone Marrow Transplantand Cell Therapy Division,
we've really innovated
and translated that to a clinical trial
that is led by Dr. Lori Muffly
as the principal investigator,
in which, following an allo transplant,
(19:30):
we're giving CAR T cells again
as a strategy to decrease relapse
because relapse is a significant issue
after allo transplant as well,
and it's a leading causeof morbidity and mortality
even after an allo transplant.
So what we do is we have agraft-engineered allo transplant.
Then after that, give CAR T-cell therapy,
and we have a trial that's open,
is now completing accrual for patients
(19:52):
with high-risk B-cell acutelymphoblastic leukemia
and is shown really promising outcomes.
We do plan to continue with another study
that's going to being investigating that
for donor-derived CAR Tcells using donor cells
after transplant to improve outcomes.
Then there's the off-the-shelfstrategies, as you mentioned.
We're really interested in those.
That can incorporate genetic engineering
(20:14):
or alternative donor sources for T cells
from non-conventional T cells.
There are a lot of reasonswhy donor cell therapies
could be really revolutionaryfor the CAR T-cell field
because you have cellsfrom a healthy donor
that might just be more fit.
Having a bank of readily available cells
will potentially help to drive down cost
(20:35):
because right now CAR T cells are,
by definition, a bespoke therapy
because they're engineeredfrom the patient.
We could also obviate
or just shorten some of thedelays that we currently have
with the manufacturingof CAR T-cell therapy.
The manufacturing timelineshave already decreased in size
in the autologous settingcompared to where we started,
but still off-the-shelf
or donor cell therapies couldfurther improve upon that.
(20:58):
There's a lot of promise in the allo
and off-the-shelf space that me
and others are investigating now.
- It sounds like there's an ability
for off-the-shelf CAR T cells
could potentially democratizeaccess to the treatment,
but I imagine that there's a lot of nuance
in managing the immunologic risk
when you're moving fromautologous to allogeneic products.
(21:19):
What are some of the keyimmune-related challenges
that your team is focused on solving?
How close are we to clinical scalability?
- Some of the biggest risk
when you think about any allogeneic,
specifically T-cell therapy,
is graft versus host disease.
So where the T cells from adonor inside the recipient
may recognize various aspectsof the recipient is foreign
(21:42):
and can attack organs.
Another issue could berejection of those donor T cells
by the host's immune system,
leading to a loss of persistence
or just basically clearance of the cells.
That's another big issue.
From the perspective
of how close are we to translating that.
We've already translatedsome preclinical data
(22:03):
with the donor CAR T cellsafter allo transplant
to this phase one clinical trial,
which, I'll say, has shownreally promising results.
And then on the side ofnon-conventional T-cell sources
or genetically engineered T cells,
there's a lot ofearly-stage clinical trials
and even companies thatare looking at this
with varying levels of success.
(22:23):
- What you've describedreally speaks to you.
The level of engineeringprecision that is required,
not just in targeting the cancer
but in modulating the cells'interaction with the host.
These kinds of innovations
are really making CAR T moreaccessible and adaptable.
But I'm curious, is therea piece of the CAR T puzzle
that you feel isn't gettingenough attention right now?
(22:45):
Something that's quietly limitingsuccess behind the scenes?
- I actually was gonnaanswer the opposite first.
Something I haven't mentioned,
which is in vivo editing orengineering of CAR T cells.
There are some early studies
that are giving essentiallyCAR T cells in such a way
that they're beingengineered inside the host,
(23:05):
and I think there's goingto be some exciting data.
Other things that are limitingengineering of CAR T cells,
I think there's a lot of workbeing done in that space.
One of the key limitations
from a non-engineering perspective
is there are a lot of patientswho have these diseases,
lymphoma, leukemia,
that are not currently gettingaccess to these therapies
(23:27):
because of a lack of feelingsfrom their primary oncologists
that they would be well suited for it.
And then there are alsovarious social factors
that maybe patients aren't being referred,
given concern for cost
or the way in whichCAR T cell does require
for patients to be withinthe treatment center.
So there are various things Ithink in terms of education,
(23:49):
providing more of a knowledge base
as to the actual therapeutic plan,
as well as the supportthat can be provided
to patients who aregetting CAR T-cell therapy
that is limiting patients frombeing more broadly referred
to centers that can administerthis treatment for them.
- As CAR T therapiesbecome more mainstream,
what policies do you think need to evolve
(24:11):
to ensure equitableaccess across populations?
- When CAR T cells werefirst FDA-approved,
we didn't know exactly how todetect the toxicities as early
or treat them as effectively.
There were a lot ofguardrails placed around
how we administer CAR T-cell therapy,
which I think were very important
because we wanna make sure
(24:32):
that anytime we'rerolling out a new therapy
that it's done in a waythat's safe for patients,
that clinicians can manage it,
and that the right folks
who know how to managepotential side effects
are taking care of those patients.
Now that we have several years
of experience with these therapies,
going back and reevaluatingthose therapies
that have less severe toxicity profile,
(24:54):
trying to understandwhether a 30-day requirement
of being within the treatment center
is still absolutelynecessary might be valuable,
and that would probably need to be done
on a case-by-case basis with experts
and regulatory bodies, et cetera,
that would help to open up the therapy
to a broader population of patients.
Patients have to havea dedicated caregiver.
(25:17):
Not only do they have to move,
but also their caregiverhas to be with them,
and that is a limitation.
That's a huge factor that can be impacting
who is getting to see these therapies
and who is receiving them.
- I'm also curious about whetherthe landscape has changed
in terms of clinical trials
and the population that is being included
in clinical trials to CAR T.
(25:37):
Have you seen a shift?
- I can't say that I'venecessarily seen a shift,
but I can see that there'smore intentionality
in trying to ensure that the patients
that are enrolled on the clinicaltrials are representative
of the populations that areimpacted by the diseases.
So that is encouraging.
That could lead to some moredemonstrative change over time.
(25:58):
There's just even moreconsciousness around the fact
that we need to have arepresentative population
and so that gives me a lotof hope for the future.
- It's a powerful reminder
that the science can be transformative,
but only if we have thesystems that are in place
to deliver it equitably to the population.
How do you see cellular therapies
and microbiome science reshaping
(26:20):
how we think about cancer treatment
in the next five to 10 years?
- Cellular therapies, I'llstart with that first.
Cellular therapies have so much promise
for reshaping the care of patients.
When we think about cellular therapies,
there are now two cellular therapies
within the past few years
that are approved for solid tumors,
not CAR T-cell therapies,
(26:40):
but one peer-approved tumorinfiltrating lymphocyte therapy,
or TIL therapy.
More recently,
there is an FDA-approvedT-cell receptor therapy
that's approved, respectively,for melanoma and sarcoma.
Cellular therapy is goingto continue to advance
for patients with cancer.
But also for patientsoutside of the cancer space
(27:02):
for autoimmune diseases,
there is a lot of workon CAR T-cell therapy
for autoimmune disease, whichwe haven't touched on today,
just to keep our scope more refined.
But I think as we moveforward in the next few years,
there may be some interestingapprovals in that space too,
because already the preliminary data
has shown some promisingoutcomes for patients
(27:22):
with various autoimmune diseases,
such as lupus or systemic sclerosis.
And then for the gut microbiome,
one thing that really encourages me
is that now in the fieldof cellular therapy,
there is data in distinct clinical cohorts
showing the relevanceof the gut microbiome
to clinical outcomes, bothsafety and the efficacy.
(27:44):
In the future,
I think we're gonna see morestudies looking at mechanism
and refining what is the mechanism
for these microbiome associations
and also developingtailored interventions,
whether through bacterialtaxa or metabolite.
Now that we have a strongbase of clinical data
that supports delvingdeeper into mechanism,
(28:05):
we're gonna see that inthe coming years as well.
- There's such a sense of optimism
in what you just said in that vision,
one where we're notonly refining the tools,
learning more about themechanisms that we use to treat,
but also rethinking the ecosystem
in which those tools operate.
It's very clear to methat your work is helping
to define what thatfuture might look like,
(28:25):
so, Dr. Smith, thank you somuch for sharing your expertise
and giving us a little bit of a window
into the evolving science
and clinical practice of CAR T therapy.
And for our listeners,
I hope today's conversationsparked new questions
and ideas about how wedeliver precision care
in an increasingly complextherapeutic landscape.
(28:46):
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CrimeLess: Hillbilly Heist
It’s 1996 in rural North Carolina, and an oddball crew makes history when they pull off America’s third largest cash heist. But it’s all downhill from there. Join host Johnny Knoxville as he unspools a wild and woolly tale about a group of regular ‘ol folks who risked it all for a chance at a better life. CrimeLess: Hillbilly Heist answers the question: what would you do with 17.3 million dollars? The answer includes diamond rings, mansions, velvet Elvis paintings, plus a run for the border, murder-for-hire-plots, and FBI busts.