Full Press Release Details
INKmune: An Interview With INmune Bio (INMB)'s
TW Research (TW): Dr. Lowdell, thanks for speaking with us today.
I know you've been involved with INKmune since the very beginning and was hoping that we could start with the origins of the program.
Where did the idea behind activating NK cells originate?
Dr. Mark Lowdell (ML): Okay. So back in 1995, clinically in
our transplant program in London, we had a lady who was too old for transplant and had a disease that couldn't be cured by chemotherapy
alone. So, palliatively, she was given chemotherapy, and really surprisingly, her disease went away. When she'd first presented with leukaemia
she had a huge amount of disease in her bone marrow, so we were able to freeze down her leukemic for storage and later testing. After
chemotherapy she went into remission, which we weren't expecting; we took her blood and we tested to see if she had any cells in her blood
that were killing her leukemia, because that was the only explanation we had, that she'd made an immune response against the leukemia.
And we discovered that she had, and we found it was mediated by a particular
type of cell in her blood, called a natural killer cell.
Now we all have natural killer cells, they're the oldest part of our
immune system. We share them with earthworms, sponges; every invertebrate on the planet has an NK cell. And we started to look at why
the NK cells in her blood were killing her leukemia but, six months later, they stopped killing her leukemia and she relapsed and was
needing more chemotherapy. My boss said to me, "How can we make her NK cells work better?" and I said, "Well, there's a
drug called Interferon Alpha which activates NK cells". We could give her Interferon Alpha because it's given for other leukemias,
so there's good safety data on it She was treated with alpha interferon, her NK cells activated, and she went back into remission.
That was in 1995 and she finally came to see me in 2011 to say she
had breast cancer and she didn't want to be treated. She was in her 80s and happy with her life but she asked to be tested again to see
if her NK cells were still working. So, we tested her again, and she still had her NK cells in her blood able to kill her original leukemia,
all those years later. Then she went back to Spain, where she'd emigrated to and I finally got an email a few months later from her husband
saying that she'd passed away.
Her response back in 1995 made me start to think, why is it that some
leukemias, some cancers, trigger NK cells and others evade this NK response? We've all got cancers popping up all the time, and they are
normally being cleared by our NK cells, but sometimes that fails. So, we started to look at patients who were cured of leukemia with chemotherapy
alone and found that they too, made an NK cell response to their disease. That's the paper containing the image that we show in our slide
We looked at patients with acute myeloid leukemia (AML). We knew from
big, big, big international studies that if you pitched up in a hospital, my hospital, with AML today, you would be treated with chemotherapy
immediately, and you would have a 40 percent chance of being cured. And if you weren't cured, the only cure that is possible is to have
a bone marrow transplant from somebody else, a so-called "allogeneic bone marrow transplant".
We know that allogeneic transplant only because you get the donor's
immune response, and that's what really cures you after the chemotherapy has reduced the amount of leukemia to a level able to be cleared
by the immune system
So, I had this big idea that maybe the 40 percent of patients who were
cured by chemotherapy alone weren't really cured by chemotherapy. All the chemotherapy did was reduce the bulk of disease to allow their
immune response to get rid of it.
And that was really this sort of... A seminal moment, and we found
that was true. And we found that in those patients who were cured by chemotherapy, those were the patients who made the natural killer
cell mediated response against their own leukemia, and we could predict them. So, we tested them and found that if they were above a certain
level, they would stay in remission for beyond five years and therefore be cured, and those who were below a certain level, they all relapsed
within two years and all went on to a bone marrow transplant.
And more recently, we've done it in another type of leukemia called
myelodysplastic syndrome and a related group. I was just a co-author, but it was one of my ex-PhD students who's in charge of the malignant
hematology program in Athens. She did the same thing in a different leukemic group. And we published two years ago exactly the same data;
if you've got NK cell activity above this certain level, you stay in remission. And if you're below it, you will relapse, and without
a transplant You will die of the disease.
That's what led me to start to find out how you could make NK cells
better. And we discovered this tumor cell line, which was able to activate NK cells to the point where they're almost ready to kill, but
So, I see you're wearing a Tottenham Hotspur shirt there [Dr. Lowdell
and I were on a Zoom call for this interview]. I used to be a Tottenham fan back in the day. And back in the 1990s, we had big problems
with football hooliganism in the UK. And, basically, if you turned up outside a football stadium wearing the wrong shirt, you were likely
to get beaten up because you would be recognized as not being part of the local team.
The immunology world tends to think of natural killer cells, really,
as football hooligans. They attack anything that's not wearing the right molecules on the surface to make them look like your own "local"
cells. And if they're not part of the same team, if your cell isn't regarded as normal, then the NK cells just randomly attack it. And
what we showed is they're a bit more subtle than that, and they need this multi-step activation pathway. They're like a nuclear warhead,
you need multiple turns of the key at the same time.
And what we found was that you could take a tumor cell line that isn't
killed by NK cells (called CTV-1), but it does give them enough signals to get the NK cells really, really, really activated and really
close to triggering. The highly activated NK cells can then kill other tumor cells that were otherwise NK resistant. And we did a trial
using that in the UK. We took CTV-1 cells and made a tumor membrane preparation from them which we incubated with healthy donor NK cells,
activated them, and gave them to patients to treat their leukemia.
That technology was bought by a US company that RJ was a medical director
of, which is how I met RJ. They did a much bigger trial in the US and had the same results as our academic UK trial. And then the company
put it on the back burner while they decided to invest in CAR T therapies because they were raising an awful lot of money in the marketplace
and NK cells weren't, this was 2009, 2011. A little later RJ said to me, "Why are we activating the NK cells outside the body and
having to make an NK product with all the complexity and time and expense of that, because the majority of our patients actually relapsed
before they got the product because they had such acute disease. Why can't we use the cell line to activate the NK cells inside the patient."
And I said, "Well, I wouldn't want to be injected with a leukemic
cell line, frankly. And the FDA don't let you do it because they have a maximum amount of tumor DNA which can be administered to a patient."
Then the FDA changed their rules, you have probably heard of a company called NantKwest which is using an NK cell tumor cell line to treat
patients, which they make that replication incompetent by irradiating it. They stop it dividing so it can't engraft in the patient and
become an NK cancer.
And so we spoke to the drug regulatory agencies, and they said yes,
if you can take your cell line, make it into a pharmaceutical grade cell line and make it replication incompetent, show that it's replication
incompetent, you could inject it straight into the patient. So that's what INKmune is. We took my original cell line, which I had found,
which is a commercial cell line; it's available from a cell bank, and we discovered that it wasn't one cell line. It had obviously
been a mixture of cell lines over the years.
We cloned out cells from that cell line. We found the ones that were
the best at activating NK cells. And when we did the DNA fingerprint, it was a different DNA fingerprint than the one that was published
for the cell line that we'd been using.
Then we went to the American Type Cell Collection (ATCC) and said,
"This is our DNA fingerprint from our cell line. This is the parent cell line that we cloned it from, and that's the DNA fingerprint.
Do you agree that this is a unique cell line that is ours?" And they said yes, so we were able to patent it. So, we own the IMB16
cell line, which when made replication incompetent in the manufacturing process, is called INKmune, and that's the drug that we treat
patients with. And we've just treated our first patient.
TW: You mentioned that you're activating NK cells in vitro as
opposed to removing the NK cells and altering them, similar to a CAR-T program, which is what I think the other companies do. Can you
talk a little bit more about your method of action and how you compare vis-a-vis what the other NK companies that are out there are doing?
ML: Every NK company that is out there injects NK cells. They
have to manufacture those from something, so they can either manufacture them from the IPS cell line, with all of the costs of manufacture;
with my academic background of making IPS cell lines, I know how complex and how expensive that is, even in an academic setting where
we obviously don't have the overheads that a company has.
So that's one way of doing it. Or you can derive them from cord blood
stem cells, which is what a company like Glycostem does. You can isolate them directly from cord blood and then genetically modify
them to express a CAR like the Takeda product. In fact the Takeda cord blood CAR-NK cells also secrete IL15, and IL15 is a critical cytokine
for NK survival. And, if you look at the latest Fate Therapeutics (FATE) data, they're giving IL15 as a constituent. Other NK companies,
including Fate in their original trials, had to give low dose IL2 to sustain the NK cells.
The truth is that NK cells don't like just being NK cells. You need