NorthWest Biotherapeutics Inc (NWBO)

[ae kusterer]

alphapuppy

Re: CrashOverride post# 528312

Sunday, November 06, 2022 10:32:19 AM

Post#
528342
of 528348
The shorts are getting ready. My broker just contacted me requesting approval to be able to use my fully owned shares to loan out to shorts.

They will pay an interest rate back to my account for allowing them to do this. Shorts are paying a premium for this because they cannot find shares to short.

They want to have a very high number able to short to manipulate down any rise. That and a lot of retail will sell at anytime this goes up and without new buyers, this will put a lot of downward pressure even with good news unfortunately.

We need some new buyers who are institutional and unfortunately we’re never going to get that on the OTC. Even with a cancer cure.!

I did not give them approval on my account to use my enormous share account for this purpose. Even though they would have paid me.

ae kusterer

Re: None

Saturday, November 05, 2022 8:24:36 PM

Post#
528242
of 528354
BlackMountain

Re: None

Saturday, November 05, 2022 2:27:39 PM

Post#
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of 528242
The more I look at the SNO schedule, the more excited I get. I have my scars from May 2022, October 2020, and more (but much, much less than others here). So my excitement is tempered. But Dr. Mitchell's keynote, "The Promise of Immunotherapy in Adult and Pediatric Neuro-Oncology" could be an incredible tee-up for Dr. Liau's remarks.

Here's a link to a presentation by Dr. Mitchell from the summer highlighting the history and evolution of immunotherapy for brain tumors. I can't help but imagine him delivering similar remarks at SNO, with the twist of introducing Dr. Liau to speak about the next chapter in the history of treating GBM.

https://www.youtube.com/watch?v=YbKY4rkrURY&ab_channel=TheIHMC
SkyLimit2022

Member Level
Re: Legend431 post# 528205

Saturday, November 05, 2022 2:05:48 PM

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528207
of 528242
The field of cell-based immunotherapy does not depend on any single technology or on any single clinical study. DCVax appears to be a giant mountain emerging on the barren landscape of immunotherapy with regard to GBM and rGBM, and the peer review will only enlighten our understanding and advance the science. As a platform, DCVax could play a role in the treatment of many types of cancer beyond the most deadly—GBM. The next step after learning is more learning. We continue to learn about all the approved therapies available worldwide as new technologies emerge, evolve, and are refined to make obsolete the toxic drugs that are no longer the only option.

"Now we are in the era of immunotherapy"
-Richard Pazdur, MDSkyLimit2022

Member Level
Re: HyGro post# 528201

Saturday, November 05, 2022 1:50:41 PM

Post#
528206
of 528241
Thank you for reposting that again. As always, we appreciate your opinions about DCVax. We also value the ideas of investors in competing technologies. We like to hear from all sides and never mind seeing repetitive reposts. It’s always good to review and refocus and consider important points more than just one time. I would add that the opinions of licensed oncologists are valuable too and we must be careful to avoid disinformation about medical topics posted online. Please do your own research and consult licensed professionals and trustworthy sources.



Please review some of the links below. I believe you will discover that FDA-NIH has consistently supported DCVax and approved DCVax clinical trials including the current Keytruda combo study at UCLA which is also funded by Merck.

OS is the gold standard. Research this fact to verify it and to get greater context and a more clear understanding: PFS is a surrogate for OS and only used because its data are accessible sooner than OS. When and if OS is reached, OS data either confirms or disproves the accuracy of PFS as a surrogate and as a PREDICTOR of survival. OS naturally became a “hard endpoint” for the P3 as the trial spanned so many years.

“OS is the "gold standard" for measuring the clinical benefits of a cancer drug. The global trial has also reached the secondary endpoint of OS in recurrent GBM with statistical significance.”

“The ultimate goal of all oncology drugs is to improve patient-centered endpoints. These 'hard' endpoints, which are intrinsically valuable to patients, are increased overall survival (OS), improved quality of life (QoL), or both. However, by many drugs are approved or used based solely on their ability to improve surrogate endpoints; outcomes that are not inherently meaningful, but aim to predict hard outcomes.”

“In oncology, the most commonly used surrogates are response rate; a set of criteria characterizing tumor shrinkage; and time to event endpoints, such as progression-free survival (PFS)”

Overall survival is the gold standard and remains the definitive end point in cancer clinical trials.

Quite simply:

You cannot mistake
the dead for the living.
That is why OS is the
gold standard.

Most recent news and events:

https://m.youtube.com/watch?v=h_tev1qm1ZE&feature=youtu.be
Dr. Ashkan, a world-renowned clinical trial expert and an advisor to the U.K. government, presents DCVax P3 data.

https://soc-neuro-onc.org/
Autologous tumor lysate-loaded dendritic cell vaccination improves survival in patients with newly diagnosed and recurrent glioblastoma: survival results from a phase 3 trial Plenary Abstract Presenter: Linda M. M. Liau, MD PhD
- University of California, Los Angeles

https://nwbio.com/press-releases/
On August 17, the Company received final approval of the Pediatric Investigation Plan (PIP) from the MHRA. The final regulatory approval of the PIP must be obtained before a sponsor may submit a Marketing Authorization Application (MAA) for approval to commercialize the new medicine for adult patients. The Company’s approved PIP includes a deferral under which the pediatric trials are anticipated to be undertaken after an MAA application has been submitted. Patients will be treated with DCVax-L on the same treatment schedule as in the Company’s Phase III trial in adult glioblastoma patients.

The primary endpoint for each of the 2 pediatric trials will be overall survival, determined by comparing the survival of DCVax-L treated patients to matched contemporaneous external controls. The external controls will be identified using the same methodology as was used to pre-specify the external controls in the Statistical Analysis Plan for the Company’s Phase III trial in adult patients.

https://youtu.be/Oq39FFUwKug
UCLA Presentaion
DCVax is discussed beginning at minute 40, to focus on Keytruda (pembrolizumab) plus DCVax in combo at UCLA, skip to minute 45:40

Yes, you are correct that the FDA is crucial and I certainly would agree with that. The U.S. government (FDA-NIH NCI) is largely responsible for the development of the DCVax platform technology as they have always supported and funded Liau’s work. The 20 consecutive years of NIH funding of Dr. Liau have played a direct and crucial role in DCVax. Together with Merck, NIH is funding the DCVax doses going into arms TODAY in a study investigating its efficacy in combo with Keytruda.

FDA has approved multiple DCVax trials and their design including the ongoing Keytruda trial.

September 14, 2022 Update of NIH NCI Funding of Dr. Liau

https://connect.uclahealth.org/2022/09/14/brain-cancer-discovery-clinical-trials/

https://www.fda.gov/science-research/advancing-regulatory-science/fda-nih-joint-leadership-council-charter

https://www.bentley.edu/news/nih-funded-research-related-every-new-cancer-drug-approved-2010-2016

9/14/2022
In a trial now underway, a dendritic cell vaccine is made from a participant's own tumor tissue and combined with an anti-PD1 immune checkpoint inhibitor to counter resistance when either treatment is used alone. The checkpoint drugs work by blocking the proteins that stop the immune system from attacking cancer cells.

"What I'm excited about is that we're seeing a growing number of long-term survivors in our patients treated with immunotherapy combinations," Dr. Liau says. "We're seeing some patients with certain combination immunotherapies that are living for many more years than would be expected. Currently, we're trying to find out what combination works best and for which patients."

https://cancer.ucla.edu/research/ucla-brain-spore

https://www.merck.com/stories/fighting-cancer-requires-an-open-mind/

Merck: “Personalized cancer vaccines which are therapeutic vaccines based on patients’ specific cancer that could potentially prime the immune system to recognize certain characteristics and attack the cancer cells”

https://m.youtube.com/watch?v=Oq39FFUwKug

DCVax is discussed beginning at minute 40, to focus on Keytruda (pembrolizumab) plus DCVax in combo at UCLA, skip to minute 45:40

NCI, Merck, & PHASE ONE are today supporting collaborators on the UCLA Keytruda trial—100% of patients in both the experimental group AND the placebo group receive DCVax. Only Keytruda in combo is being investigated—everyone receives DCVax as if it were SOC.

Group A (pembrolizumab, ATL-DC, poly ICLC)
Beginning 14 days prior to scheduled surgery, patients receive pembrolizumab IV over 30 minutes. After surgery, patients receive pembrolizumab IV over 30 minutes on day 1. Cycle repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive ATL-DC ID with poly ICLC IM every 2 weeks for up to 3 doses in the absence of disease progression or unacceptable toxicity.

Group B (placebo, ATL-DC, poly ICLC)
Beginning 14 days prior to scheduled surgery, patients receive placebo IV. After surgery, patients receive placebo IV on day 1. Cycle repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive ATL-DC ID with poly ICLC IM every 2 weeks for up to 3 doses in the absence of disease progression or unacceptable toxicity.

https://clinicaltrials.gov/ct2/show/NCT04201873

Dr. Linda Liau is a world-renowned neuro-oncologist, surgeon, and educator at UCLA where she is also the chair of the department of neurosurgery. As her paper on DCVax moves through the independent peer review process, it is interesting to note that she was once the editor-in-chief of a neuro-oncology medical journal.

https://www.uclahealth.org/providers/linda-liau

https://doi.org/10.3171/2020.12.FOCUS20954

https://soc-neuro-onc.org/

Across the pond from Dr. Liau, Dr. Ashkan was the chief investigator of the DCVax trial for patients in Europe. At King’s College in London, Ashkan is the lead clinician for neuro-oncology and the chair of the King’s Neurosciences Clinical Trial Unit. He is a world-renowned cancer trial expert. A few years ago, Professor Ashkan was named the UK Clinician of the Year by The Brain Tumour Charity. Additionally, Ashkan serves as an advisor to the U.K. government.

https://www.kcl.ac.uk/people/keyoumars-ashkan

https://m.youtube.com/watch?v=h_tev1qm1ZE&feature=youtu.be

https://virtualtrials.org/dcvax.cfm

Richard Pazdur, M.D. is the director of the FDA's Oncology Center of Excellence (OCE), which leverages the combined skills of the FDA's regulatory scientists and reviewers with expertise in drugs, biologics and devices to expedite the development of novel cancer products. In his role as director of the OCE, Pazdur is responsible for leading the effort to develop and execute an integrated regulatory approach to enhance the cross-center coordination of oncology product clinical review.

Pazdur has published more than 400 articles, book chapters and abstracts. In 2015, Fortune magazine named Pazdur as one of the 50 World’s Greatest Leaders. The American Association for Cancer Research recognized Pazdur with its Distinguished Public Service Award (2015) and the American Society of Clinical Oncology recognized him with the Service Recognition Award (2009) and the Public Service Award (2013). In 2015, Pazdur also received the Public Service Leadership Award from the National Coalition for Cancer Survivorship and also the Face of Hope Award from the LUNGevity Foundation. Most recently, in 2016, Pazdur was named to Massachusetts General Hospital Cancer Center’s “The One Hundred” list.

"Now we are in the era of immunotherapy"
-Richard Pazdur, MD

"Often, novel agents are so obviously superior to standard of care that no patient would participate in a randomized trial knowing that somebody else might get the experimental drug
-Richard Pazdur, MD

"There's also been a revolution in tumor immunology. Before, in my early career, tumor immunology was looked at kind of as black magic, as witchcraft. Now it's accepted."
-Richard Pazdur, MD

"When we make a decision about approving a drug, it has to be patient centered. It can't be about the regulations"
-Richard Pazdur, MD

https://www.annalsofoncology.org/article/S0923-7534(22)00006-0/fulltext

https://www.fda.gov/drugs/news-events-human-drugs/50-years-progress-treating-patients-cancer

https://www.webmd.com/cancer/cancer-in-context/video/richard-pazdur

https://www.onclive.com/view/pazdur-followed-the-pathway-of-greatest-resistance-to-the-fda

So many of these survivor stories are old news— research 2022 updates—some are GBM patients surpassing a decade or multiple decades—miraculous …

https://www.hawaii.edu/news/2017/03/30/newirth-laker-for-a-day/

https://m.youtube.com/watch?v=K9azZaIwOH8&feature=youtu.be

Other Relevant Links:

https://www.kcl.ac.uk/people/keyoumars-ashkan

https://www.liverpool.ac.uk/systems-molecular-and-integrative-biology/staff/michael-jenkinson/

https://www.fda.gov/science-research/advancing-regulatory-science/fda-nih-joint-leadership-council-charter

https://connect.uclahealth.org/2021/03/22/ucla-received-590-million-in-nih-funding-second-highest-total-for-academic-medical-centers-in-2020/

https://virtualtrials.org/dcvax.cfm

https://www.annalsofoncology.org/article/S0923-7534(22)00006-0/fulltext


Search in video
0:03
[Music]
0:13
this lecture is being brought to you in part by the generous gifts of these sponsors
0:22
good evening thank you for the kind introduction dr ford and colleagues for the invitation to visit
0:28
this lovely facility and also spend some time with you this evening talking about immunotherapeutic approaches to
0:34
treating cancer in general and specifically some of the efforts in trying to tackle one of the most aggressive and challenging malignancies
0:41
that we deal with in oncology which is brain cancer so this is my first visit
0:47
to the ihmc here in pensacola and you guys have a lovely lovely town it's really been a pleasure to
0:52
spend the day here and hopefully we'll have an engaging presentation and more importantly discussion afterwards i try to fill you
0:59
in on some of the highlights of the field of cancer immunotherapy and some of the challenges
1:05
and and efforts that we have in research to try to make this treatment approach
1:10
for refractory cancers applicable to more patients in general make sure i have this
1:17
all right first in wave disclosures i do have technologies in the human oncology space
1:23
that have been patented and licensed by pharmaceutical companies they are not going to be the major focus of this
1:28
overview presentation this evening but i will touch on some experimental therapeutics which are intellectual property of the
1:34
university of florida and co-inventors so outline i'll discuss a little bit of
1:39
history of cancer immunotherapy this is a field that has received a lot of attention uh particularly over the last
1:45
five to ten years most people if you watch any television you've probably seen commercials uh advertising uh
1:51
cancer immunotherapeutic treatments for lung cancer and in particular melanoma and others but this has really been a
1:57
field that has evolved for over a century of efforts to try to figure out how to
2:03
use the immune system to actually recognize cancer as a foreign invader in the body and effectively eliminate
2:09
malignant cells i'll talk about the really conventional approaches to targeting tumors using
2:15
immunotherapy particularly those that have already received fda approval for one or more cancers and while there's a
2:21
lot of investigational approaches still under development you'll probably see that this has been a field that just in the last 10 years has
2:28
actually moved from a research effort to now one of the most dominant forms and effective forms
2:35
for treating a wide variety of malignancies today and then i'll talk about our efforts in brain tumor
2:40
immunotherapy which is a disease that is not yet seen as a whole the tremendous benefits of immunotherapy
2:47
that have been realized in other cancers and our efforts to try to understand why where where are some of the challenges
2:53
and opportunities for breakthrough in treating malignant brain tumors so cancer immunotherapy how do we get
2:58
here i um as was mentioned in my bio i studied for my phd immunology at duke university
3:04
starting 1995 and at that time i was interested in cancer immunology i ended
3:09
up doing my dissertation work and trying to understand how the antigen presenting
3:14
cells of the immune system recognized and presented antigens from cancer to the t cells of the immune system and i
3:21
ran into an undergraduate student not too long ago who had been interested and had become recently interested in cancer
3:26
immunotherapy when she asked me how long i had been studying the field i mentioned her that i you know got into
3:31
it in 1995 she said wow you've been at it since the very beginning
3:37
uh not really the the history of cancer rental therapy predates uh my graduate studies but it just highlighted really
3:43
that um you know how long does it take for an overnight success to really become uh publicly aware uh it's about
3:50
100 years and so if you if you really look historically the the concept that the immune system might recognize in
3:56
fight cancer uh dates back at least to the late 1800s dr coley observed
4:02
actually read about a patient who had had a surgical resection for cancer and an incomplete resection but
4:10
subsequently a post-operative infection where the wound had become infected with a bacterial infection and the patient
4:16
subsequently had spontaneous remission of the remaining cancer and so he reasoned that the immune system must
4:22
have been awakened by the actual infection and then recognized the remaining cancer cells
4:28
and led to an effective rejection and began a series of actually experiments of trying to purposefully induce cancer
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regression by infecting patients initially with live bacteria and then some of the
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heat killed components of mycobacteria known as coley's toxins to try to induce whatever this uh inflammatory or
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immunologic response that could hopefully spread and awaken to recognize cancer cells while this
4:53
approach wasn't largely effective in the majority of patients some actual lessons that were learned
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even from the late 1800s in this approach are still used today and in fact
5:05
a treatment of superficial bladder cancers is actually used as a form of derived
5:10
mycobacterial products to induce an effect inflammatory response that can in the case of bladder cancer actually
5:17
mediate effective rejection so the underlying principles have been around for a long time and subsequently
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our understanding of the basic components of the immune system and the steps that are required for effective
5:28
immune engagement have really led to an evolution now of understanding at least in some cases how to either induce an
5:35
appropriate response or overcome the obstacles that cancer presents to the immune system in recognizing
5:41
these tumor cells as foreign invaders one of the seminal breakthroughs in the field and understanding of immunology in
5:47
general and in cancer immunology has been the recognition that the immune system itself really responds to
5:55
cues and signals from really commanders or sentinels of the immune system that tell our bodies what really is a foreign
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invader what's something that's dangerous versus what this is something that we perhaps should ignore or even repair so the
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concepts of the immune system really recognizing self from non-self has really evolved to
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understanding that our immune systems really recognize antigens or challenges in the
6:19
environment in a certain context and so you can imagine if you have an injury
6:24
where you need to both defend against infection but also repair a wound these
6:30
are signals where the body can either be feeding that environment with nutrients blood vessels angiogenesis in the form
6:37
of wound healing and repair or in the setting of an infection really
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being cued to destroy and kill infected cells and other foreign invaders in that environment
6:48
cancer in some ways in a simplistic sense sends the body mixed signals there are abnormalities in a cancer a growing
6:54
cancer that the body definitely can recognize as abnormal there are also foreign proteins
7:00
or mutations or changes in cancer cells that that do elicit proteins that are different
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than what the immune system normally encounters in healthy tissues and yet at the same time many of the signals around
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injury and repair are actually also triggered by cancer cells and so the overriding
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physiological response can sometimes be to feed and grow and try to repair that injury as opposed to recognizing this as
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a something that should be rejected ralph steiman and dr cohen and colleagues uh discovered the sentinels
7:30
of the immune system called dendritic cells are antigen presenting cells that really provide context to the immune
7:36
system and say that this is either a protein or an abnormality that's dangerous and should be attacked by the
7:42
immune system or in fact this is self or a non-dangerous signal and really should
7:48
either be ignored or repaired and so dendritic cells ultimately are somewhat like the generals of the immune system
7:55
army that are either telling the the overall immune system to attack or to ignore or retreat and so with
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recognition of this of the really important role of dendritic cells and antigen presentation for triggering
8:07
an effective immune response much of our understanding of both vaccine development and therapeutic
8:13
cancer immunology really centers on having these antigen presenting cells send the appropriate signals to the
8:19
soldiers of the immune system the first real breakthrough in the cancer immunotherapy
8:25
field in terms of an fda approval is actually taking advantage of this understanding of the role of antigen
8:30
presenting cells it was actually a cell-based dendritic cell-based therapeutic treatment for
8:36
castrate-resistant prostate cancer in this treatment the actual
8:42
antigen presenting cells are collected from the blood of patients in a large volume leukopheresis
8:48
white cells that contain these dendritic cells are actually enriched from this peripheral blood draw or large really
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extraction of white cells from the body they are actually mixed in a ex vivo culture system with a over expressed
9:03
protein that's expressed in many prostate cancers tumor cells called pap and along with a signal from gmcsf a
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cytokine that really activates these antigen presenting cells and then they are infused back intravenously into a
9:16
patient uh receiving back their own cells that have now been loaded if you will with this tumor tumor-associated
9:22
antigen this was actually shown in in a randomized clinical trial to actually
9:28
improve survival compared to chemotherapeutic treatment was not a overwhelming miraculous cure
9:34
of advanced prostate cancer but did was heralded the first fda approved immunotherapeutic treatment in the field
9:41
it also highlighted some of the challenges this has not been widely adopted in terms of a standardized treatment and in fact many of the
9:47
challenges of this manufacturing workflow limited its adoption and its ability to turn these
9:53
cells back around and deliver them back to patients in a timely fashion
9:58
after the approval of the cell-based therapeutics for prostate
10:03
cancer the real breakthroughs in the field came in 2011 and really over the last 10 to 12 years and that's been with
10:10
the understanding that the immune system actually has both activating signals and importantly regulatory signals or breaks
10:17
on the immune system that we call checkpoints that actually tell the body not to respond or not to attack and these
10:24
immune checkpoints are oftentimes overexpressed in cancer patients
10:30
and upregulated on cancer cells such that any signals that are alerting the immune system that there may be an
10:36
abnormality here are being overridden by these immune checkpoint signals that are telling the immune system this is self
10:42
not to attack these are very important in preventing autoimmune disease very important in limiting the duration
10:48
of an immune response where we don't want a chronic immunologic response that is not turned off but in the setting of
10:54
cancer these signals really essentially a function as a stoplight that's always on
11:00
the development of immune checkpoint inhibitors or the ability to block these negative regulatory signals has actually
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been the largest shift in our understanding of the balance between immune rejection or ignorance when it
11:14
comes to cancer and these monoclonal antibodies the first anti-ctla iv are called epilimumab and anti-pd1 called
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nivolumab and now there's also pembrolizumab these antibodies do not directly attack
11:28
cancer cells or directly stimulate the immune system but instead simply remove
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the breaks that the ho the patient has on their own immune response and unleashes essentially a more unchecked
11:40
immunologic response against cancer these have had dramatic effects in patients with metastatic melanoma
11:48
non-small cell lung cancer and actually now over 15 different cancers and over
11:53
32 fda approved indications in which immune checkpoint inhibitors are used to treat
11:59
advanced disease in 2013 cancer immunotherapy was heralded as the breakthrough of the year
12:04
by science magazine in the subsequent next four years both the american society of clinical oncology
12:10
as well as the american association of sciences had highlighted breakthroughs and advances in cancer immunotherapy
12:18
as the most significant or certainly in the top five to 10 breakthroughs in the cancer field during those subsequent
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years and so this has really been a revolution of 100 years ago the concept of trying to activate the immune system
12:30
to now we actually have metastatic cancers such as lung cancer where immunotherapy may be the first
12:37
recommended treatment for patients that are diagnosed with certain forms of advanced lung cancer
12:42
and so that's been quite a dramatic shift this is a list of the cancers with fda approved immunotherapies
12:48
to date it's an expanding list that quite honestly every six to eight months either a new type of cancer or another
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indication within these systemic cancers are approved by the fda
13:01
number 15 is actually a really interesting approval because it represents the first
13:07
pan cancer fda approval for a treatment to treat any cancer that
13:13
actually has a certain type of genetic alteration and so these are called microsatellite and stable
13:19
or mismatched repair deficient cancers msi or mmr dmmr cancers what this really
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are patients who have an abnormality in their cancer cells where they do are not able to repair the dna
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effectively it turns out that these cancers because the dna repair
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or the stability of the genome is very unstable in those cancers they accumulate very large numbers of
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mutations and it turns out that these mutate some of these mutations end up changing the
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proteins of the cancer cell in such a way that the immune system can actually recognize those mutated proteins as
13:57
foreign and so you can use checkpoint inhibitors for these cancers that have these very
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high levels of mutations we in the immunologic field call them neo antigens they basically translate into new
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proteins that have not been seen by the immune system before and in many cases regardless of the
14:17
cancer type you can achieve effective immunologic responses and clinical responses using uh checkpoint inhibitors
14:25
for those patients so this is the first time a fda has approved a treatment essentially for any cancer based on
14:32
simply the underlying genetics of those cancers and i think it it heralds really two huge areas of advance obviously our
14:39
understanding of the underlying genetics and genomic biology of cancers and how important that has become and how we
14:45
treat them today but then also a real signals a huge advance in the use of the
14:50
immune system to recognize cancers in our own field of brain cancer you know this is not on this list yet
14:57
these are cancers that don't typically have the the large numbers of mutations that lead to
15:02
this immune recognition and so we look at other strategies to try to induce effective immunologic responses but a
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small percentage of patients with brain cancer actually do have these underlying genomic disorders and those patients
15:15
actually do respond to immunotherapy and so this has been a real significant advance so this is a simple
15:21
understanding of how does the immune system really recognize and kill a tumor cell your t cells uh of your immune system uh
15:28
carrier each has a carries a unique receptor that can recognize uh
15:33
your antigen presenting machinery called mhc molecules and what they present are over here they present the proteins that
15:40
are made inside of any cell in your body any nucleated cell in your body presents little pieces of the protein on their
15:46
surface if these are normal proteins uh um and and are sampled all the time uh
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this can lead to either being ignored by the immune system or even tolerance because the signals tell the immune
15:57
system these are the normal proteins of the cell but when you have an abnormal protein such as a mutated uh
16:03
protein within a tumor cell or a protein that isn't normally expressed being turned back on in those cells and
16:09
importantly the appropriate cues that tell the immune system that there is a dangerous presentation occurring in this
16:14
context now these t cells can recognize antigen and elicit a program where they
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essentially lead to the specific killing of this target cell through recognition of this antigen
16:26
this involves poking holes in the surface of the cell using molecules called perforins and then injecting
16:31
enzymatic proteins called granzymes that actually lead to the degradation and apoptosis of the of that cell this works
16:38
very effectively against infected cells uh and the goal of cancer immunotherapy is to try to get this to work as
16:44
effectively against tumor cells one of the real powerful and always attractive features of the
16:50
immune system is that this is a very specific interaction you can see it's almost like a lock and key type recognition
16:57
which makes the immune attack very specific and it also can lead to what we call immunologic memory this t cell or a
17:03
certain subset of these t cells can remember that they have been activated and essentially if they see these same
17:10
antigens again can become engaged to even more rapidly kill so the ability to specifically kill cells to remember what
17:17
those cells look like or what the at least foreign components of those cells look like and potentially have long-lived immune protection has always
17:24
been one of the really attractive features or the potential for cancer immunotherapy this is an actual picture
17:30
of tumor cells i'm sorry of a tumor cell in the center being uh probed by t cells
17:37
and what are highlighted in in red are these perforins uh that you can see are being pulled sorry these are
17:43
the granzymes that are being polarized this cell you can tell has actually recognized something on the surface of
17:48
this tumor cell that is leading it to attack and it is now polarizing those granzymes to be injected directly into
17:55
that tumor cell to lead to its killing and so if there were normal cells sitting right adjacent to it these uh
18:00
immune cells could kill this tumor cell ignore a normal cell next to it and look again for another tumor cell to mediate
18:06
its specific attack so this is something that has always attracted people in the field
18:11
to try to harness that that capability to treat invasive tumor cells
18:19
our understanding of why this goes wrong and where we can intervene to try to make the immune system more effective in
18:26
treating cancer has really led to the breakthroughs in the field to date and certainly to ones that we'll have in the
18:31
future we understand now that for an effective immunologic response there are several steps that all must occur
18:37
with the appropriate engagement of specific signals first you have to have tumor cells that are expressing tumor
18:43
antigens we believe that most cancers that we have looked at do express one or more protein that can be recognized by
18:50
the immune system as foreign at least potentially but these antigens have to be released typically from dying tumor
18:56
cells and reach antigen presenting cells called dendritic cells in a context where these dendritic cells recognize
19:03
that there is a abnormality that i want to signal immune attack against and so if there's the
19:09
appropriate cues these dendritic cells pick up these cancer antigens they migrate to lymph
19:14
nodes where the t cells of the immune system are circulating and when that appropriate engagement that i showed in
19:21
the in the prior diagram occurs they can activate these t cells which then clonally expand into very large numbers
19:28
leave the lymph nodes and have to traffic back into the tumor microenvironment looking for the proteins that they were activated
19:34
against in the lymph nodes if they find cells that are expressing those same proteins they will then lead to that
19:39
very specific killing that i described and that will lead to the release of more antigens and again a feed forward
19:46
mechanism for this cycle to be amplified and to continue until the burden of anagen
19:51
is decreased or gone and then this cycle will cease so in the course of an infection
19:57
this proceeds and typically through to resolution of that infection but obviously in the course of a growing
20:02
cancer one or more of these steps is interrupted so that we do not complete this cancer immunity cycle and really
20:08
the goals of the different forms of immunotherapy are to intervene at one or more of these steps to try to complete
20:14
this wheel if you will of a physiologic host response if we look at the forms of immunotherapy
20:21
that have actually at least in one or more cancers been shown to be effective and have reached fda approval we really
20:26
have three whatever called classical approaches at a fourth uh which has become recognized as a form of
20:32
immunotherapy that still embody uh the fda approved treatment approaches that we have today
20:39
sorry let me come back that's a pretty impressive immunotherapy response so cancer vaccines
20:45
this is trying to stimulate the immunologic response where we present the antigens
20:50
that are expressed inside of tumor cells to the immune system in a more effective manner this can be done by actually
20:56
loading dendritic cells directly with anagen i'll show you some studies where we have done that in patients or delivering
21:03
the actual antigen directly into the patient so that their own dendritic cells can pick up those antigens and
21:10
ideally more effectively engage the immune system adoptive cellular therapy bypasses those steps of activating the
21:16
immune system in the body and says let's extract these killer t cells or in some cases other immune cells that can kill
21:22
cancer grow them to very large numbers outside of the body activate it in a way that they recognize
21:28
the patient's own tumor and then deliver these killer t cells or other natural killer cells back to the patient in the
21:34
hopes that now they can go find tumor cells and kill them i mentioned to you the immune checkpoint inhibitors think
21:40
of that as taking the breaks off the immune system sort of like when you're sitting at a red light and it hasn't changed for a
21:45
long time you just kind of blow right through it right that's what that's what an immune checkpoint inhibitor does um and it and
21:51
it really allows uh the the patient's own response if there are antigens that are being engaged to proceed in a more
21:58
unchecked fashion and then the last form of therapy which has at least been approved for the treatment of melanomas
22:03
actually uses viruses that have been modified to kill tumor cells uh so that they don't infect the normal cells but
22:09
they replicate inside the tumor they were originally designed and still have as a goal the ability to spread through
22:16
the tumor and kill the tumor cells as they lyse the tumor and spread to other tumor cells but what they found is that
22:22
the immune response against these oncolytic viruses usually shuts the actual viral infection down pretty
22:28
quickly however the antigens that have been released from the tumor cells during the course of this response and the fact
22:35
that these viruses signal a very strong immunologic context can now lead to a
22:40
awakening of an immune response against the cancer and at least in the case of metastatic melanoma has been also a form of
22:47
effective treatment this is just a a pretty visual demonstration of the of the power of uh
22:54
cancer immunotherapy um one of the pioneers in the field dr stephen rosenberg who is the director of the
23:01
surgery uh surgical oncology branch at the national cancer institute he has been working for many years in
23:09
trying to treat aggressive melanomas using the immune system and particularly approach where they harvest the t cells
23:16
that are actually at the tumor site he and others had hypothesized that the reason those immune cells are probably
23:22
found inside the tumor is they are attempting to fight the cancer but they're obviously not doing it effectively he has taken those cells out
23:29
grown them to very large numbers in an activated fashion and then returned them to patients with metastatic melanoma
23:36
along with cytokines to help those t cells grow in vivo this is showing a patient that has a huge
23:42
involved metastatic probably lymph node in this case or subcutaneous growth that's just
23:49
tremendous in size and you can see after 12 days 12 days after the infusion of these tumor infiltrating lymphocytes or
23:56
till therapy this patient had a complete response that's been durable for many many years
24:01
and so i actually read stephen rosenberg's book in 1993 before starting graduate school he even back then had a
24:07
few examples of patients with melanoma that have responded like this to immunotherapy and was one of the key
24:14
influences in my interest in in pursuing this field was this really dramatic demonstration that the immune system
24:19
really can if appropriately engaged treat cancers but if we look at with all of these fda approved indications now
24:27
and the real advance of immunotherapy as a standard treatment for many malignancies we still recognize that
24:33
there's a large fraction of patients that are not deriving benefit from these treatment approaches even in
24:39
the diseases where immunotherapy has been approved and this graph really kind of shows is a
24:44
simplistic picture of what really the current status of the cancer immunotherapy field looks like for many
24:51
refractory and metastatic cancers in the past let's take melanoma or non-small cell lung cancer
24:57
if you treated these advanced cancers at stage four or after they've spread from their local site of growth we could
25:03
sometimes extend survival for months but very rarely cure or have durable
25:10
cures of these advanced diseases what immunotherapy has really done is is is create an extension of survival for some
25:17
patients and actually a significant increase in the proportion of patients that have
25:22
long term durable or even curative treatments but you can see from this curve which shows it's supposed to
25:28
represent about a third of patients who are actually deriving this long-term benefit we still have patients who are
25:33
receiving immunotherapeutic treatment and either not deriving this really effective deep cures or if they
25:41
are having responses are short-lived and so the field is still really focused in trying to understand
25:47
what differentiates these patients who do have long-term responses and durable responses from those that that fail to
25:53
receive benefit one of our understandings is that while
25:59
we may have shifted from standard treatment to a short-term
26:04
survival benefit we're seeing this fraction of patients with long-term cures studying really what are the
26:09
factors either of those patients cancers and or their own immune systems or other host factors we
26:17
know that many other things influence how the immune system actually responds to cancer treatments
26:23
such as many of you may have heard of the microbiome which is a very
26:29
relatively new uh field in terms of trying to understand how the micro bacteria and bacterial and in some
26:36
cases even viruses within our own host influence immunologic response the
26:41
microbiome has actually has a significant influence on response to cancer immunotherapy
26:46
and we're really just beginning to understand some of the host factors and tumor derived factors that predict who
26:52
are these patients who have long-term durable benefit from those that don't through through trying to then combine
26:58
approaches either of immunotherapy approaches or even integration with standard therapy approaches the hope is
27:03
that we'll continue to increase the proportion of patients that have these long-term durable benefits
27:09
and really start to speak about cures and settings where we really previously hadn't discussed the potential uh for
27:15
curative treatment and we're seeing some of this um in in perhaps some unpredictable uh or unanticipated ways
27:21
so chemotherapy which has been a long stay in the treatment of cancer and we know
27:27
does have negative effects on immune on the immune system uh typically there's certain cycles of chemotherapy people's
27:33
white cell counts oftentimes drop they can can become more susceptible to infections
27:38
and then the body does seem to recover between these cycles we're finding that
27:43
combining chemotherapy and immunotherapy in integrated fashions can actually have
27:48
additive or even sometimes synergistic benefits and so we're trying to understand
27:53
why we may have predicted that chemotherapy might limit some immunologic responses in some cases
27:59
in lung cancer as an example the combination and even in triple negative breast cancers of immunotherapy and
28:05
standard treatments is actually looking quite effective and and so this is an active area of
28:11
research within our own field as many others the other thing that people have um had
28:17
concerns about is what about the side effects of immunotherapy so if you if you take the host's immune system i
28:23
mentioned to you many of these regulatory signals are there to prevent us from attacking our own excuse me
28:29
bodies with the autoimmune disease or long-term inflammation it turns out that some of these treatments particularly
28:35
the ones that block those negative regulatory signals can have side effects that we call immune associated adverse
28:41
events and so there's been a lot of study in looking at what are what is the side effect profile of standard
28:48
immunotherapeutic treatments most of this although not all of this data comes from the use of immune checkpoint inhibitors or a form of t
28:55
cell therapy where the t cells are expanded outside the body and genetically engineered to recognize
29:01
cancer cells more effectively they can lead to a spectrum of side effects that are actually shown in this diagram from
29:06
the national cancer institute the size of the blue dot actually indicates how how frequent
29:12
overall these side effects are actually seen and then the red dot uh determines the severity in terms of where do we see
29:18
uh more uh severe symptomology and so you can see uh side effects really that
29:24
impact almost any system within the body but there are some classically
29:29
classic groupings of areas where we see either inflammatory responses or even autoimmune disease
29:35
that can be induced by the treatment that is being delivered to these patients fortunately in the majority of
29:40
patients these are mild to moderate and reversible symptoms that can be managed with vigilance and
29:46
also sometimes a break in treatment therapy and also the use of corticosteroids and
29:53
oftentimes these patients can actually resume with treatment once those immuniverse events are controlled
29:59
and there have been now a large scale studies of comparing well how does immunotherapy compare to conventional treatments and so some meta-analysis
30:06
that have looked at tens of thousands of patients particularly from randomized clinical trials where they were
30:11
receiving either immunotherapy or chemotherapies have shown that the cumulative side effect profile of
30:18
patients that have significant side effects that at least require medical management is about 16 and a half
30:23
percent that's a broad range i mean there's a broad range with those numbers but that was the average from one of the
30:29
larger meta-analyses by comparison if you look at chemotherapy treatments um from those same studies
30:35
the incidence of side effects that at least required some medical management was actually 40
30:40
so while these are new a new spectrum of side effects that the field has had to
30:45
learn to recognize and treat comparatively speaking immunotherapy has actually been a well tolerated and
30:52
effective treatment regimen to integrate into cancer care so for the last few minutes i will touch
30:58
on efforts in brain tumor immunotherapy so brain cancer
31:03
although not the most common uh of malignancies are actually one of the most challenging uh cancers in oncology
31:10
due to the fact that of course all of our organ systems and the essence of our memories personalities communication
31:17
skills etc are all housed within the central nervous system in adults the most common malignant brain tumor is
31:23
glioblastoma which is a stage four glioma meaning that unfortunately the
31:29
majority of patients present with a disease stage that has already advanced
31:34
and can't be cured with standard therapies standard treatment for this disease
31:39
involves as much of a what we call gross total resection to try to remove with surgery
31:44
as much of the tumor as possible even though the tumor has spread beyond that site we know that removing a lot of the
31:50
tumor burden can reduce can one extend survival but also reduce
31:56
the symptoms that some of the tumor pressures and swelling can uh inflict on patients and also improve
32:02
their quality of life then they typically have a radiation and chemotherapy combination that extends
32:08
for anywhere from six months to a year post-surgical resection and a more recently approved fda
32:14
approved therapy is also using alternating electric fields that can actually slow tumor progression
32:21
despite this very aggressive treatment and duration most patients unfortunately
32:27
spend the rest of their lives uh going through this treatment with immediate survival of only 15 to 18 months
32:34
so there's a real significant need to try to improve care options for patients with glioblastoma
32:40
pediatric brain tumors are actually less common than adult tumors but have
32:45
actually become now the leading cause of cancer-related deaths in children and that's really because of the remarkable
32:52
advances that we've made in treating more common childhood malignancies such as leukemias
32:58
standard treatment also we do cure more children with malignant brain tumors than we see in adults on average
33:04
but because of the developing nervous system and the sensitivity to some of the standard treatments particularly
33:09
radiation but even chemotherapy on on the systemic and developing organ systems the treatment uh for those
33:16
children that do survive is very harsh on the developing nervous system
33:21
as well as other organ systems and then for those that do suffer relapse about a third children that have
33:27
relapse after radiation these tumors are almost uniformly incurable at that stage and so our
33:33
center has focused and the field is focused on trying to determine whether immunotherapy can be
33:38
an effective and safe treatment for both childhood and adult brain tumors
33:43
so this is a snap a current snapshot of the university of florida's brain tumor immunotherapy program clinical trials
33:51
these are actual treatment approaches that have been developed through laboratory investigations by our faculty
33:58
and have progressed through the stages of pre-clinical evaluation what we call fda
34:03
investigational new drug enabling studies and then have received fda approval to move into first in human
34:08
clinical trials so these are discovery two intervention immunotherapeutic approaches and you can see that our
34:14
stunner is really pursuing a wide variety of approaches to treating malignant brain tumors including cancer
34:21
vaccine approaches adoptive t-cell therapy approaches this year we'll open a new form of therapy using actually
34:28
stem cells from the bone marrow to actually reprogram the immune response against malignant brain tumors and have
34:34
several trials that are looking at how to make immune checkpoint inhibitors more effective in the treatment of brain
34:39
tumors these actually approaches open the blood-brain barrier to allow these checkpoint inhibitors to actually get
34:45
into the tumor microenvironment and also increase the release of tumor antigens
34:51
and in some cases have been shown to be effective for these patients so
34:56
one of the earliest approaches that we've developed in our center was actually based on this understanding of
35:01
the role of dendritic cells and their importance for activating the immune system and our lab has been
35:07
studying rna based vaccines long before covid and everyone became very familiar with rna
35:13
based approaches but using messenger rnas that encode for tumor antigens and then either loading them into dendritic
35:20
cells that have been harvested from a cancer patient so that the rna is then converted into the tumor protein the
35:26
dendritic cell processes that protein to present it to the t cells of the immune system and then we return these loaded
35:32
and activated dendritic cells back to patients that are bearing cancer with the hope that they will migrate to the lymph nodes and induce that program that
35:38
i showed you in the cancer immunity cycle we've also recently and just started a first in human clinical trial where the
35:45
rna is directly direct injected into patients uh similar to in a formulation
35:51
to what the covet mrna vaccines uh work and then these are taken up by dendritic cells in the patient's body and used to
35:58
stimulate immunologic responses that trial just opened a few weeks ago and has treated its first patient with glioblastoma and then the other approach
36:05
that we have used is using this same paradigm to use these dendritic cells to activate the t cells outside the
36:11
patient's body expand those t cells to very large numbers larger than what could be achieved inside the patient's
36:17
body and then return the activated t cells as an adoptive t cell therapy approach so our group has centered on
36:24
the use of rna-loaded dendritic cell vaccines for either vaccine priming or
36:29
t-cell therapies for many years now for well over a decade and a half this is actually the results of the
36:35
first phase one study that ran with her colleagues at duke where we looked at patients with glioblastoma
36:41
who received standard of care treatment so all of them went through surgery radiation combined with chemotherapy but
36:47
then we integrated a dendritic cell vaccine made from their own taken from their own white blood cells loaded with
36:54
rna expressing a tumor-derived a tumor-associated protein and then returned back to those patients
37:00
during each intervening cycle of chemotherapy and these patients were actually randomized to receive one of
37:05
two dendritic cell vaccines the first was combined with a tetanus booster shot
37:12
and the second were actually did not receive the tetanus booster and what we were studying at the time was whether or
37:18
not if you induced a strong immune response against something the body had seen already like tetanus would that
37:24
actually make the dendritic cell vaccine have a more effective response because the body would see it
37:31
in the context of a memory recall response or immunologic response and so patients were randomized to receive one
37:37
of two of the dendritic cell formulations we also studied where those dendritic cells go
37:43
but in the interesting part of the study was that those that had received the combination
37:48
tetanus toxoid booster along with their dendritic cell vaccines actually had more than double the overall survival of
37:54
the other patient cohort group and we actually had 50 it was a small study but
38:00
three of those patients uh that were randomized on this arm actually had survivals that are now out past five
38:05
years and so this was a small but significant response that had a very interesting
38:11
underlying mechanism of action that we also discovered during this treatment and this has now moved on to a large
38:17
randomized phase 2 trial of 150 patients that's uh recently we'll actually will
38:24
complete enrollment at the university of florida in that study in the coming months so this year we will hopefully
38:29
determine whether or not this has been replicated in a much larger scale now with a large number of patients
38:35
this is actually an mri from a patient that's on this phase two it's called the attack ii clinical trial this was a
38:40
gentleman who was diagnosed with a midline glioblastoma the area
38:46
of white that you see on this scan is actually the the normal brain appears gray this is actually
38:52
brain glioblastoma tumor and because of the location of where this tumor grew
38:57
this patient could not have a complete resection so post-surgery he still had quite a significant amount of disease
39:04
and so what you're looking at are slices in the mri is the images moving through and every area of white enhancement uh
39:10
is an area of glioblastoma that was left behind this is a pretty poor what we call poor prognosis prognosis when you can't
39:16
resect the tumor and also based on its location uh this patient did have standard treatment along with these
39:22
integrated dendritic cell vaccines and after his fifth vaccine actually had a complete radiographic response to
39:27
treatment and it's been actually now this july will be four years
39:34
that he's been tumor free and so we're excited about the potential uh for for
39:39
patients and this is obviously a pretty significant and dramatic response and we'll find out when the study is
39:45
completed in a large population cohort whether it has had a meaningful benefit to the patients who have received these
39:51
vaccines this is a picture actually of the second patient that was enrolled on the phase one study that was started in
39:57
2006. uh her name is sandy she's been featured on television a couple of times
40:03
she was 61 years old when she was diagnosed with a glioblastoma and told that she had
40:08
about nine months to live this is a picture i think taken in 2015 which was nine years post diagnosis
40:17
and she is uh currently now approaching 16 years tumor free
40:22
from the phase one study um so there certainly are some patients that we believe have a meaningful benefit from
40:29
cancer immunotherapy treatment even with advanced brain cancers however we don't see complete responses in all
40:36
patients that are treated and we'll find out whether on a population level we've had a meaningful benefit to a large
40:42
cohort but we are still actively trying to understand just like others in the field what differentiates these
40:47
remarkable responders from patients who don't respond another form of therapy that we've
40:52
worked on is this adoptive cell therapy platform i described to you where instead of activating the t cells in the
40:57
patient's body we actually do this in a basically in a pharmaceutical grade clinical laboratory called a gmp
41:03
facility and then return these activated t cells back to patients this is example of a child with
41:09
metastatic meds excuse me mental blastoma that also had a complete response to adoptive t-cell therapy uh the two
41:16
figures here are showing the tumor and the cerebellum as well as in the cortex's brain where all the areas of
41:22
white that you see are actually tumor cells that have spread essentially throughout the entire cns of this
41:27
patient he also unfortunately had metastatic disease that had spread outside of the brain and even to this thoracic cavity
41:34
and bone marrow he received adoptive cell therapy after salvaged chemotherapies where the tumor
41:39
had progressed during chemotherapy and actually had a complete response to treatment you can see all these areas of
41:45
white were are completely eradicated um unlike sandy hillburn who's 15 years out
41:51
however disease-free this patient did not have a long-term durable response and so we are studying and trying to
41:57
understand again in a case where an immune system becomes activated but doesn't maintain
42:02
this disease remission either what is the cancer done to adapt or what has happened with the immune response that
42:07
has made it short-lived compared to these patients that have these long and durable complete remissions
42:13
so in the last part i'll talk about our efforts to build better t cells and enhance the function of the immune
42:19
system so that we can hopefully increase the proportion of patients who can derive benefit from cancer immunotherapy
42:26
so one of the things that i mentioned to you is the is this concept of memory and having long-lived immune responses and
42:32
this is something that i think has been really highlighted properly to the public awareness by the coveted vaccines i mean how many of you all thought when
42:38
we had the first vaccines come out you were like oh thank god we can finally get this behind us and then you were told you needed boosters and you're like
42:44
okay i'll get a booster and you were told maybe a third one you're like well wait a minute how come i you know i've had
42:49
measles mumps and rubella shots when i was a kid and you know never never had them uh after
42:54
that and so we kind of this concept of how durable even when you've boosted an immune response is really
43:00
an important conceptual framework that obviously virologists and people working in the infectious disease setting have
43:05
been tackling for many years but in our understanding of what establishes memory against cancer and
43:11
how the immune response can be re-engaged if those tumor cells either remain or continue to grow is really at
43:18
very early stages of understanding so we have worked on increasing the proportion of these t
43:23
cells that actually have the phenotype of memory cells and these long-lived immune cells and that has been shown
43:30
certainly in pre-clinical studies uh and in some studies of adoptive t-cell therapy the more memory uh like immune
43:37
cells that you can give to a patient for at least in the case of melanoma the better responses they can have and the
43:42
more durable those responses are so that's an area of ongoing effort we have a new fda approved license to
43:48
investigate a new product where we've enhanced the memory t cells over what i showed you in the prior mris
43:54
another area of major research in our center is understanding what are the unique components of a patient's own
44:00
tumor that are actually being recognized by their immune system and so we're using computer-based algorithms some machine
44:06
learning techniques and also functional testing to actually identify
44:12
the antigens that are expressed in a patient's own cancer and then stimulate their immune response
44:18
with a patient-specific cocktail if you will of antigens that are specific for their own
44:25
cancer it's important you can activate these immune cells but if they don't get to
44:30
the tumor or don't infiltrate the tumor they obviously can't mediate their killing functions and so using both
44:36
nanoparticle-based treatment approaches and genetic engineering approaches we're looking at how you can both follow where
44:41
these immune cells go in vivo after you give them and can you engineer these cells to
44:47
actually traffic better to the to the tumor microenvironment and then finally uh in an area where we're
44:52
collaborating with engineers at our university to really understand what
44:58
happens to these t cells when they enter this hostile tumor micro environment and can we through studying how t cells
45:04
interact with the immune cells improve their function so that they can get there and mediate more effective killing
45:10
and for this we're actually using um uh we're collaborating with an aerospace engineer named um greg sawyer who's
45:15
pictured here he actually uh um has worked on and still and and for many
45:22
years uh space exploration and other aspects but he also uses uh soft matter
45:27
tissue what we call 3d printing of live tissues or soft tissues to actually study in three-dimensional spaces
45:34
how these complex microenvironments can be dissected to its individual components and so we've been working
45:39
with greg's laboratory to 3d print tumor cells 3d print immune cells and actually
45:45
study their interactions under high resolution microscopy and then compare if you manipulate either the
45:52
micro environment or the immune cells in certain ways how can you make them more effective in killing cancer cells so
45:58
this is an example of a 3d printed uh glioblastoma from gregg's laboratory this really highlights the challenge of
46:05
treating this cancer it was printed in started off as a spherical ball but this is just over a period of
46:11
48 hours you can see these tumor cells that are migrating away from the cancer
46:16
mass and so when someone's diagnosed with this brain tumor the surgeon can take out this central mass here but
46:22
there are these tumor cells that in many cases have migrated all the way to the other side of the brain that we have to figure out how to really
46:28
get rid of this is actually 3d printing of t cells that have been engineered to recognize
46:35
the glioblastoma so the t cells are in green the glioblastoma tumor cells are in red and these are what are called car
46:40
t cells or chimeric antigen receptor t cells so they have been modified with a receptor that has very high affinity and
46:47
recognition of a protein that's expressed in these tumors and you can see they once they start to recognize
46:52
the tumor they just sort of swarm it and you can even see they start to dissolve you can look at the center of this tumor mass as being completely obliterated as
46:59
the as the tumor is being chewed up by the t cells what we're able to do in uh greg's laboratory is actually you can go
47:06
in and sample some of these t cells you can see don't seem to really engage and so what's the difference in these t
47:11
cells that are sitting out here versus the ones that really are trafficking and begin to understand what are the components of the biology that really
47:19
generates an effective t cell and can we either change the way we generate these cells or modify them in a certain way
47:25
that they are much more effective at killing tumor cells so what does the future really look like for this field
47:31
one i think we're encouraged by the advances in the in the field of cancer immunotherapy in general
47:36
that there are approaches that can be effective even for challenging tumors like brain cancer we are using a lot of integration of
47:43
large data sets that are coming from other fields to understand some of the factors that predict responsiveness or
47:49
resistance and then using that to actually guide our immuno oncology approaches
47:54
the precision immunotherapy platform is really what i mentioned which is understanding that each patient's tumor is still unique even patients with the
48:01
same diagnosis and how can we use the underlying genetics and biology of their tumor to really design
48:08
personalized immunotherapeutic treatments either the right combination of treatment drugs and or the right
48:14
engineered cell therapies that are recognizing that patient specific cancer and then really combining these
48:20
approaches most of these uh therapies right now are being tested for their safety and their effectiveness in
48:25
isolation or maybe integrated with standard treatments but we haven't uh we're approaching what we are really
48:30
doing are now rationally developed combination approaches based on some of the underlying biology
48:35
where we can combine these treatments for hopefully more effective uh approaches so in summary i think you
48:41
know cancer immunotherapy is certainly a paradigm shifting approach to treating advanced malignancies uh it's been shown
48:47
to be a feasible well tolerated and and certainly shows promise in some
48:53
patients with malignant brain tumors our future efforts really in overcoming resistance and evaluating combination
49:00
treatments are warranted and are underway at our center and many others and i'd like to thank the members of the
49:06
brain tumor immunotherapy program this is a big team effort uh and many of them aren't pictured here but this is a
49:12
pre-coveted snapshot obviously of the of the team we're working on getting a postcode uh get-together picture uh
49:18
pretty shortly this is our um clinical and translational science institute where many of our patients
49:23
actually receive their vaccines in our clinical research center um this is another center site in in the on our
49:29
orlando campus um obviously our funding agencies that have supported this work uh and most importantly the patients and
49:35
families who've actually participated in these clinical studies and really entrust us with their care and oftentimes know that they're
49:41
participating in studies that may not benefit them but will hopefully benefit patients in the future
49:46
so thank you for your attention
49:55
and hopefully we have a question in the back there dr mitchell welcome to pensacola thank you
50:00
in 1938 dr otto warburg said that one of the cancer's main
50:06
functions was to protect the pancreas do all do your glioblastoma patients have a
50:11
elevated a1c as a rule um that's a really good question in terms of uh so so the alt you know as
50:18
you know the alter the metabolism and understanding um really cancer cells dependence really on
50:24
glycolysis and whether we can exploit that to to inhibit tumor growth has been an active area of investigation a1c is as
50:32
oftentimes not elevated in patients with glioblastoma as a characteristic of their profiles
50:37
but both due to standard treatments steroid uh treatments we do see significant
50:45
metabolic alterations in patients with glioblastoma and other brain tumors and actually glucose restriction and
50:51
exploiting metabolic vulnerabilities is an area of active research i didn't touch on that and i talk here
50:56
but it's an area that actually is under rigorous exploration at our center as you can imagine the interface between
51:02
metabolism of the immunes of how immune cells and what nutrients they're dependent on and the competition for those nutrients
51:09
in the tumor microenvironment plays a big role in how effective and long-lived immune cells can actually be once they
51:15
enter the hypoxic and metabolically restricted environment of tumor cells so this is something that's a real active area of
51:21
research but but we don't necessarily see that the gbms are altering the systemic
51:26
metabolic profile in patients sure we have i think back here and then up front yep that's
51:32
the shadow hand raised yes with regard to brain cancer
51:38
diagnosis is there any noted direct correlation between the diagnosis and a compromised
51:45
blood brain barrier and are there presently any reliable tests in our symptoms that physicians or patients can
51:51
figure this out at an earlier stage yeah it's a really great question we had a good discussion about this earlier so
51:58
let me touch on the on the second part first which is you know early detection and possibilities for early stage
52:04
diagnosis so it's it's there's a lot of active research being done particularly to see if there are there's
52:10
some evidence that there are peripheral biomarkers that may uh be detectable with proteomic approach basically
52:16
looking for peptides or protein signatures in the blood excuse me that are indicative of a
52:22
disruptive blood-brain barrier and or disease pathology within the central nervous system
52:27
and quite a bit of research to determine whether or not these are picked up much earlier than we typically diagnose
52:34
patients with glioblastoma based on symptoms um so some studies that have shown there are altered proteins that
52:41
can be detected in these patients in the periphery and a few that actually had retrospective uh samples that have shown
52:48
that that some of these altered signatures were detectable in patients with glioma months and even years before
52:53
diagnosis whether this is a broad biomarker is is that can be used for
52:58
early detection is still being investigated but it's an area of great interest but
53:04
when these tumors grow the chances are that the breakdown of the blood-brain barrier
53:09
itself is probably at a point at which the tumor has either invaded and reached a
53:15
certain size and or often what has happened is is the tumor has induced angiogenesis and
53:21
neovasculature new blood blood supply into a growing tumor mass and that irregular vasculature is
53:28
actually the leakiest part of of the of the tumor so what we end up seeing in the mri in that central mass is often
53:35
vasculature that has really been developed to feed the tumor itself and it is more leaky than the classical
53:41
physiologic blood-brain barrier so it's not clear how early at the stage of development we may
53:48
be able to pick up bbb permeability whether that would be an early stage or late presentation in
53:55
some of these tumors but there's great interest in seeing if either brain specific proteins or even and
54:01
perhaps more likely alterations of other peripheral biomarkers that are being affected by
54:09
the the alterations that are occurring in the brain may be detectable in the periphery we have time for one more question all
54:15
right that was going to be my question so
54:21
since you already answered it i'll ask you this are there any symptoms of early
54:26
a brain tumor yeah so the so so brain tumors do present with a spectrum of
54:32
symptoms that unfortunately are not uh always very specific for
54:37
brain cancer in fact as you can imagine depending on the part of the brain in which these tumors arise and they essentially can arise in
54:44
any area of the brain headaches can be a common presentation which is most often not a brain tumor
54:50
but is a common spectrum of symptomatology associated brain tumors seizures can can also
54:56
so focal signs of either cognitive motor deficits or seizures
55:02
that can lead to imaging much more rapidly in an earlier diagnosis in children because of increased
55:07
intracranial pressure oftentimes nausea and vomiting particularly projectile vomiting can be again a a particular
55:13
symptomology unfortunately because we don't have direct pain receptors in the central
55:19
nervous system uh the majority of these tumors when they lead to symptoms that actually result in imaging in the
55:25
diagnosis of a brain tumor they've either arisen in a very critical area so they're detected still early or they've
55:31
gotten to a size where they're a little bit late stage in development so we don't have great
55:36
early diagnosis or early symptom presentations for brain tumors at this point
55:43
on that note let's thank our speakers
55:56
you

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