Marcus Kuehne aka Huggenberg

$IBRX About the Journal of Breakthroughs in Medicine & Science and the first journal of Breaktrhoughs in Immunology-Oncology. I look forward to gaining a deeper understanding of Immunotherapy 2.0, which offers a new perspective on fighting cancer by placing immunology center stage and traditional oncology in a supporting role. See the section on the editorial advisory board for brief biographies as well. immunooncology.journalofbrea…

$IBRX The leadership is truly compelling. journalofbreakthrough.com

$IBRX The Breakthrough

Worth another read: @DrPatrick on the history and strategy of $IBRX, closely tied to the CRADA with the NCI and the collaboration with Dr. Jeffrey Schlom and Dr. James Gulley. Excerpt from the Q4 2025 earnings call: That is this complexity that I have tried since 2016 over multiple meetings, which I call breakthroughs in medicine and brought thought leaders along with me, including Dr. Jeffrey Schlom and Dr. James Gulley from the National Cancer Institute, for which we have been collaborating happily and excitingly for the last decade. We instituted what we call a CRADA, a Cooperative Research and Development Agreement. And for the last decade, between ourselves and the National Cancer Institute and academic and community doctors have gone ahead to prove this theory. So what was the seminal moment? Well, the seminal moment was in 2016 -- September 2016. I visited the FDA and was invited by Sean Khozin to present to the entire leadership of the OCE, the Oncology Center for Excellence, that had just been formed to provide this concept of quantum oncotherapeutics and the concept of a QUILT trial, constructed this wording, the QUILT trial, so that people can understand the elements of QUantum Immuno-oncology Lifelong Trial. That was what QUILT stand for. QU is quantum, Immuno-oncology Lifelong Trial. The FDA at that point said, this is exciting. We will allow you to file an IND. That was the changing moment. And by 2017, and I apologize going into this history because you now will see the development from 2017, and you will see maybe a decade from now, 2027, not only the development, but the execution of this incredible paradigm change. And I will go into that further in this call. We will show you how ANKTIVA becomes a backbone to multiple ailments, how ANKTIVA becomes a backbone to current standard of care. For example, ANKTIVA will be the backbone to chemotherapy, but chemotherapy at a lower dose. ANKTIVA could be the backbone to radiation, but radiation at a lower dose. ANKTIVA could be the backbone to BCG, but BCG even in the failure. ANKTIVA could be the backbone to checkpoint inhibitors. That we do not need to abandon the standards of care so that the current learnings of what we've learned, but enhance an adjuvate, or call as an adjuvant of the current standards of care. But we wanted to go beyond that. We want to now step back and say, okay, how do we actually use not just the standard of care, but how do we actually now generate a cancer vaccine, and that's where this becomes exciting. In order to do that, we needed to activate the dendritic cells. And therefore, the opportunity to actually use either an adenovirus or molecules that would activate the dendritic cells with antigens that the tumor would recognize and now train or create educated T lymphocytes. Now there's opportunity to combine ANKTIVA with molecules that would activate the dendritic cells. But there is yet a further opportunity. We could then harvest your NK cells. Imagine if we could harvest your NK cells from you as a person and give it to anybody as allogeneic, but stimulate those NK cells, not only with IL-15 and ANKTIVA, but IL-12 and IL-18 to make them memory-like. And now they're not only sustained, but they're active and supercharged. That combination of ANKTIVA plus m-ceNK is what we will discuss. However, we need to address the suppressors and how do we outsmart the suppressors. So what if we actually then created targeted NK cells such as PD-L1 NK, CAR-NK where we could use that off-the-shelf to go after the suppressors or we could target liquid tumors such as diffuse large B-cell lymphoma or Waldenstrom lymphoma with CD19 and so forth and even PSA. So you begin to see the ambition. So we have taken you through this mind map through January 2016. And that was the thinking as I went to the FDA. And I am forever grateful for the FDA allowing us to file the IND and approving the IND in 2017. So the next discussion is for me to reveal to the public the actual language that I put in front of the FDA as part of the IND to initiate the QUILT trials. And quite literally, I have pulled out the cover letter that I filed with the FDA under the umbrella of NantCell, and I will read to you the cover letter. The cover letter says, dated March 2017, "Initial investigational new drug submission and a request for regenerative medicine advanced therapy designation: as early as 2017, we recognized that this was what we call an RMAT opportunity. This was an opportunity for us to take combination ANKTIVA as a backbone to combine with a cell therapy, whether it be NK, whether it be CAR-T, whether it be CAR-NK, and apply as an RMAT designation." I will read the basis, the one paragraph and the intent. It says, "The Nant Cancer Vaccine is a modern approach to cancer therapy, a regenerative advanced therapy to maximize immunogenic cell death while maintaining and augmenting the patient's antitumor, adaptive, and innate responses to cancers." That's a mouthful. That is not only regulatory speak, but scientific speak on the second paragraph of the submission in 2017 to the FDA. I go on to say, "The Nant Cancer Vaccine makes use of lower metronomic doses of both cytotoxic chemotherapy and radiation therapy, with the aim of causing tumor cell death while minimizing suppression of the immune system." There, in that sentence, I was trying to explain in a very subtle way that the current standard of care maximizes the death of our lymphocytes. It maximizes what I call lymphopenia. The concept of absolute lymphocyte count was unknown, ignored, not taught, and there was a need for us to change that thinking process. The third sentence goes on to say, "These treatments are combined with immunomodulatory agents that serve to augment and stimulate patient's adaptive, innate immune responses." What I was saying there is we can use chemotherapy, for example, Abraxane. But guess what Abraxane does, it would actually go into the tumor microenvironment, it would convert M2s to M1s, it will wake up the tumor by allowing to express on its surface these what we call DAMPs and induce the ability for our T cells and NK cells to recognize it and kill it from the outside in. That is the concept of what is going on here. So if you don't mind indulging me, this is such an important cover letter. I will maybe put this cover letter together with the slides, and I want to show you -- read you the next paragraph. "The intent of the Nant Cancer Vaccine development effort," remember this is 2017 now, "is to employ this novel treatment protocol in a series of clinical trials in which the therapy was investigated across multiple oncology indications." Again, the basis of that simple sentence was to say, T cells don't have a tumor address. They know exactly where a bad cell is, regardless of its anatomy or regardless of its location, same for natural killer cells. So we were trying to indicate to the FDA by activating the immune system, it's a complete paradigm change. It's not indication by indication. If you have cancer, regardless of the location and the type, these natural killer cells and T cells, if activated, will kill them. I go on to say, "Small variations in the chemotherapies and the doses will be based upon past experiences with these therapies in a given indication." And what was I saying here? Well, there were things like FOLFOX, there's things like Gem/Abraxane, there's things like different combinations of chemotherapy. And what we did not realize as chemotherapeutic oncologists trained with a hammer of just wiping out the tumor and seeing a response rate is that these chemotherapeutic agents have novel properties that could modulate the tumor microenvironment. For example, gemcitabine I chose, because it inhibit the suppressors. So there were subtle insights that was not taken into account of generating what I call immunogenic cell death rather than what is called tolerogenic cell death. So that little sentence that says, small variations in the chemotherapies and the doses were based upon experiences, meaning past experiences, with these therapies in a given indication. So we were given the green light to go after patients who have failed all standards of care. Excitingly, this progressed to be given the greenlight to patients who failed all standard of care for lung cancer, for triple-negative breast cancer, and multitude of other cancers, which then said, I was given the greenlight to use ANKTIVA as the backbone and the entire ImmunityBio platform, which I will now show you, as part of the development program that took us a decade to complete all the way until the approval of the first indication in bladder cancer, where ANKTIVA plus BCG was just the beginning. We have already shown data on ANKTIVA plus checkpoint inhibitor, and this now is the status of where we are. And I think it puts into context the event we just had on Friday with NewsNation and Chris Cuomo and the Director of the NIH and Director of the NCI and the audience. What I discussed at that meeting was a workshop report that we just discovered recently that was published in 2007. It was really an exciting workshop report where the NCI, the NIH, the FDA, AACR, all the scientific thought leaders were asked to rank the most important molecules in your body that could cure cancer. #1 ranked was IL-15, i.e., what they called a T cell growth factor. And #2 ranked was a checkpoint inhibitor such as KEYTRUDA that took the brakes off T cells. So the revelation that the scientific community as far back as 2007 had identified, based on the science, that the IL-15s acting as a superagonist, which is today ANKTIVA, was ranked #1, and the checkpoint inhibitor, today known as KEYTRUDA, was ranked #2, was an exciting discovery. I think if you think about the biology, in order to take the brakes off T cells, which is the #2 molecule, you actually need T cells around in the tumor microenvironment, and that's what ANKTIVA provides. If you have lymphopenia induced by chemotherapy and radiation and you have no T cells, you may take the brakes off the T cells that remain and then all of a sudden, the checkpoint inhibitor fails. And that is what's happening. And I will show you another slide in 2024, how at ASCO, desperate oncologists say, "Now that we've failed in lung cancer and any other tumors, all these 40 tumor types, what we call checkpoint inhibitor failures and standard of care failures, we have nothing else to offer other than more chemotherapy, specifically docetaxel. And the docetaxel has been tested in literally thousands of patients as a single arm, again, as a control against multiple cancer trials. And regardless of the trial, it shows a median overall survival of 7 to 9 months." I want you to put that into a little memory box because we'll come back to that when we talk about QUILT-3.055 and why the Saudi FDA approved ANKTIVA for lung cancer for the first time in the world. So before I hand over to Rich Adcock to talk about the commercialization program, let me also highlight a very important discussion that occurred in the presence of the NCI and NIH Directors during that evening show. This concept of the plausible mechanism of action, which is the new policy put forth by Dr. Makary at the -- and published in the New England Journal of Medicine, speaks to a very exciting opportunity that the plausible mechanism of action is a pathway. And obviously, the mechanism of action of checkpoint inhibitors was to take the brakes off T cells. The mechanism of action of ANKTIVA is actually to grow T cells and to grow NK cells. This mechanism of action has been affirmed in 2 tests: one, by the 2007 NCI report, which affirmed that IL-15, which is basically ANKTIVA, is a T cell growth factor and ranked #1 out of over 100 molecules to be the most important molecule to cure cancer. And checkpoint inhibitor was ranked #2. So the important discussion was it is very clear that ANKTIVA falls within the plausible mechanism of action concept. And interestingly enough, as we will proceed, and I'll discuss it more further after Richard Adcock's presentation, is that the mechanism of action, not just of ANKTIVA, but the mechanism of action of the Nant Cancer Vaccine or the therapeutic vaccine, which uses ANKTIVA as a backbone, which we'll discuss later on in this call, also falls within the plausible mechanism of action of inducing both the innate and adaptive immune system for long-term memory. ….. So now let me turn my attention to the entire platform under ImmunityBio. I call this platform Immunotherapy 2.0, which combines cytokines, which is ANKTIVA; with vaccines, which is the adenovirus platform; with cell therapy platforms, which is the off-the-shelf NK-92 as well as the Apheresis Leonardo Platform. And this slide spells out this entire platform. And obviously, each of these elements of the platform are under clinical trials. So the focus of clarity will start with ANKTIVA, which is really the backbone of the 4 programs at ImmunityBio. First, ANKTIVA when combined with just standard of care, and we'll get into that; second, ANKTIVA when combined with ImmunityBio's off-the-shelf CAR-NKs, which are either PD-L1 t-haNK or CD19 t-haNK or ANKTIVA combined with ImmunityBio's apheresis program of m-ceNK. So that's ANKTIVA combined with cell therapy. Third is ANKTIVA combined with the vaccine program of adenovirus, and we'll get into that in patients with Lynch syndrome, patients with HPV, patients with colon cancer. And then finally, ANKTIVA in its own right in the treatment of lymphopenia. So these are the 4 pillars of therapies that are all in phases of clinical trials,……

$IBRX multiplylabs.com/press/serie…

IBRX finance.yahoo.com/healthcare…

$IBRX Remember: Trained Immunity

$IBRX ALC ist not just a number!

$IBRX $PDSB Something’s in the works?

$IBRX @DrPatrick Let Shyanne be part of the expanded access ResQ117EX-ALC trial.

$IBRX More info about the fundamentals of Immunotherapy 2.0 in my Substack posts: open.substack.com/pub/huggen…

$IBRX An overview of how neoepitopes operate within Immunotherapy 2.0 and the potential of Anktiva to revolutionize traditional cancer treatments. open.substack.com/pub/huggen…