(upbeat music)
- My topic for today is cellular therapy
for acute respiratory failure
with a focus on mesenchymal stromal cells or MSCs.
This slide shows my disclosures.
There are no conflicts for this presentation.
A variety of support from NIH funds,
as well as importantly from the California Institute
of Regenerative Medicine,
for both our alpha stem cell clinic
and recent support for our clinical trial
to expand to UC Davis.
Now, what do I do at work at UCSF?
Well I am a pulmonary and critical care physician
working in the intensive care unit.
I do in addition,
basic and clinical research into acute respiratory failure,
primarily from the Acute Respiratory Distress Syndrome.
I spend a good deal of my time running clinical trials
and critically ill patients.
And the rest of my time is spent mentoring students,
residents,
fellows,
and young faculty.
Now this slide is intended to give a brief overview,
both visually
and otherwise of the Acute Respiratory Distress Syndrome.
Also known as ARDS.
The left hand side, you see a chest radiograph
with bilateral pulmonary infiltrates.
And on the right hand side,
you see proteinaceous edema fluid in the alveoli.
This is a form of non cardiogenic pulmonary edema.
ARDS occurs in 200,000 patients annually
in the US
with the chest radiograph, as I've shown you here,
as well as the criteria of having mild to moderate
or severe hypoxemia with a PaO2 FiO2 ratio,
less than 300.
And mortality ranges from 25 to 45%.
The main etiologies are bacterial and viral pneumonia,
sepsis aspiration, and trauma.
We have made progress with supportive treatment
with lung protective ventilation,
prone positioning,
and a fluid conservative strategy.
These have all improved clinical outcomes
as shown in the citations below.
However, as shown on this slide,
many therapies, pharmacologic therapies
have not been successful in improving clinical outcomes.
There is mixed data on corticosteroids,
but overall there has not been a consistent beneficial
effect.
And the rest of the agents listed here,
including surfactant,
prostaglandin,
and anti-cytokines,
statins
ketoconazole
activated protein C
beta-agonists,
and others have not been successful
perhaps in part, because there are single agent therapies.
Now the next slide provides on the left hand side,
a visual idea of what are the pathways of injury in ARDS.
And in this figure, we have modeled an alveolus.
And on the left hand side, it's air filled
where you can see a normal macrophage
normal epithelium with a type two cell
that produces surfactant,
which is denoted by that white line,
and then a normal capillary with oxygenated red blood cells.
But on this side,
you see the injured alveolus
with pink protein rich edema fluid,
a loss of the epithelial barrier
replaced by hyaline membranes,
a injured type two cell
and inflammatory cells in the alveolus,
including neutrophils and alveolar macrophages,
and other pro-inflammatory factors.
The primary lesion is over here at the capillary level,
where you see these gaps between the endothelial cells,
which allows protein rich plasma
to exude into the interstitial space the lung,
and then translocate into the air spaces.
Now MSCs are attractive as a potential therapy for ARDS
because they have multiple properties that may be beneficial
in several of the different pathways of injury.
They produce anti-inflammatory factors
such as like lipoxin A4,
interleukin one receptor antagonist,
IL-10
and macrophage two pro-resolving monocytes.
They also can restore endothelial
and epithelial barrier integrity by various pathways,
including increasing type two cell regeneration.
They can enhance alveolar
and lung edema fluid clearance,
and interestingly, they even have antimicrobial properties.
Now the next slide just gives one example
of one of our preclinical studies
in which we gave MSCs to mice
who had endotoxin lung injury.
And you can see on the right hand side,
the injury, when the mice are treated just with control PBS,
and on the left hand side the MSC,
as you can see a much improved histologic section
with less edema and a fewer inflammatory cells.
And this was born out on a lung injury score,
as well as measurement of lung edema,
being reduced to the MSCs.
Similar studies showed an increase in survival
and benefit in live bacterial pneumonia.
Now the next slide shows a novel preparation
that we've used in our laboratory for several years.
And what we have displayed here is a human lung,
which we receive from brain dead donors
when the lungs are not transplanted.
And the lungs arrive at four degrees
and are in generally very good shape.
And we then, if they are in a good shape,
we set them up for perfusion.
Warm them to the 37 degrees,
cannulate the airway
so they can be inflated with C-PAP
and then add fresh blood
to the circuit from one of us in the laboratory.
And this constitutes a short term model of lung injury.
In the studies relevant to MSCs
we've ventured the lungs with endotoxin or live bacteria.
And the effects were quite beneficial,
providing preclinical evidence
that this therapy might be beneficial in patients.
This slide shows an example of the results
of one of those studies
in which the permeability of the lung vasculature
is on the Y axis here.
You can see that endotoxin or LPS increased at threefold
and MSCs when delivered into the air spaces, reduced it.
And even the conditioned medium did.
And we found this same effect
when we measured the amount of pulmonary edema in the lung
where the MSCs reduced the quantity of pulmonary edema
as did the condition medium.
In these same studies,
we also measured the effects of live bacteria,
and we again found that the MSCs reduced lung injury
with the live bacteria
and in addition as you can see visually here,
MSCs whether given in the bronchus
or in the perfuse aid
increase the phagocytosis of the bacteria,
and this is shown in graph form in the bottom part
of the slide.
So this was a novel discovery
that MSCs can increase bacterial clearance.
And this has been confirmed
by several other laboratories as well.
And the final preclinical model to just mention to you
is our sheep model,
in which we created Pseudomonas pneumonia
and sepsis,
and tested the effect of two doses of MSCs.
This was a severe sepsis pneumonia model over 24 hours.
And you can see on this slide,
that oxygenation as measured on the Y axis
over 24 hours on the X axis was markedly improved
with two different doses of MSCs given one time.
And these are human mesenchymal stem cells
that are harvested from normal donors,
cryopreserved,
and then shipped to us for treatment.
And you can see in red or green,
how the oxygenation was definitely improved
with either five or 10 millions MSCs per kilogram.
The next slide shows that in the same experiments,
the higher dose of MSCs resulted in a reduction
in pulmonary edema in the lungs after 24 hours.
The red indicates the higher dose,
and it had a greater effect than the lower dose.
So this is the one we selected for clinical trials.
This slide is just a quick summary of the mechanisms
by which MSCs may be effective in the injured lung.
They can reduce pro resolving factors,
such as like lipoxin A4,
ANG-1
and growth factors such as KGF.
They actually can reprogram macrophages
through these exosomes to be more pro resolving
as well as to be antibacterial,
and they can even transfer mitochondria
to injured epithelial cells to improve their function
by increasing ATP levels.
Now, the next slide shows you briefly
the results of our phase one trial,
just nine patients to get the clinical application going.
In which we tested for safety,
three different doses of MSCs in nine patients
with moderate to severe ARDS.
And there were no safety issues.
So FDA said we could advance to do a phase two trial,
which is shown on this slide,
was a multicenter randomized blinded placebo-controlled
trial.
The MSCs given over one hour, 60 patients
with two to one randomization.
Primary end points for safety
and efficacy end points for secondary small trial.
And we measured biomarkers in the plasma
and mBAL
This was published in 2018.
And you can see on this slide,
that plasma Angiopoietin 2 declined significantly,
in the patients who received the MSCs.
This is an important finding
'cause Angiopoietin 2 is a marker of endothelial injury
and also a mediator.
And it almost achieved a significance
at a later time point as well.
And in brief,
the conclusions from this phase to a START Trial
was that there were no infusion related adverse events
within six hours of infusion.
As in the phase one trial,
as I showed you,
there was a favorable biologic effect
in reducing Ang-2 in the plasma.
The results data that suggested
to trend for short term efficacy of the MSCs
and reducing the lung entry
as measured by the oxygenation index,
during the first three days of ARDSM.
Post-hoc analysis indicated the MSC viability
is an important factor in the clinical
and biological effects in this small phase 2a trial.
Now the current trial that we are conducting
is shown here and it's called The STAT-Trial
as opposed to the START Trial.
And this is a 2b trial of MSCs for trauma
and non-traumatic causes of ARDs.
It's multicenter, randomized blinded placebo control.
The study agent is given over one hour intravenously.
The plan is to enroll 120 patients
with one-to-one randomization.
The primary efficacy endpoint is oxygenation index,
and the patients will be stratified by trauma
versus non-trauma
and a PaO2 FiO2 of greater than or less than 150.
We will measure biomarkers in the plasma urine in mBal,
as well as RNA and DNA.
And it's funded by the Department of Defense,
NIH,
and CIRM.
The next slide shows the participating clinical sites
for this STAT Phase 2b Trial of MSCs for ARDs.
Note the blue arrow here denotes two hospitals
in San Francisco.
University of California, San Francisco,
and Zuckerberg San Francisco General Hospital.
And we're adding thanks to CIRM,
later this month,
another center at UC Davis.
Our other participating centers
are University of Washington, Seattle,
University of Texas, Houston
and Vanderbilt
and Nashville.
This slide just highlights the primary end point
that I mentioned of oxygenation index,
which will be measured at six, 12,
18, 24,
30 and 36 hours as our primary evidence of efficacy.
What is the status of the trial to date?
Well in the four hospitals that have been active,
we've enrolled 29 patients.
26 of whom were COVID-19 positive.
Most of the patients were enrolled at UCSF
and Zuckerberg San Francisco General Hospital,
22 of the 29 patients.
Texas and Oregon have enrolled seven patients.
And we're hoping to open Vanderbilt University
Washington, Seattle, and UC Davis in September.
And then this slide is an important acknowledgement
to so many individuals who have worked
to make these trials possible,
including my Co-Pi Kathleen Liu,
Medical director of the ICU at UC Parnassus,
Carolyn Hendrickson,
who is Medical Director at San Francisco General Hospital.
Dr Pati, Gotts,
To Calcutt who'll be the PI at UC Davis,
Dr Kornblith, who's been a major part of this trial.
And we just wanna thank the DSMB,
Department of Defense,
NHLBI,
and CIRM for the support.
And finally for the patients
who consent to be part of these trials
and the ICU nursing and respiratory care staff.
Thank you very much.
(upbeat music)