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Scientists have solved a cellular murder mystery nearly 25 years after the case went cold. Following a trail of evidence from fruit flies to mice to humans revealed that cannibalistic cells likely cause a rare human immunodeficiency. Now the discovery shows promise for enhancing an up-and-coming cancer treatment. Scientists have solved a cellular murder mystery nearly 25 years after the case went cold. Following a trail of evidence from fruit flies to mice to humans revealed that cannibalistic cells likely cause a rare human immunodeficiency. Now the discovery shows promise for enhancing an up-and-coming cancer treatment. "This paper takes us from very fundamental cell biology in a fly, to explaining a human disease and harnessing that knowledge for a cancer therapy," said UC Santa Barbara's Denise Montell. "Each one of those steps feels like a major discovery, but here they are, all in one paper." Researchers in Montell's lab published their findings in the Proceedings of the National Academy of Sciences and are now investigating the mechanisms and implications. An ancient gene The primary character in this story is a gene, Rac2, and the protein it encodes. Rac2 is one of three Rac genes in humans. "Rac is very ancient in evolution, so it must serve a fundamental function," said senior author Montell, Duggan Professor and Distinguished Professor of Molecular, Cellular, and Developmental Biology. Rac proteins help build a cell's scaffolding, called the cytoskeleton. The cytoskeleton is made of dynamic filaments that allow cells to maintain their shape or deform, as needed. In 1996, while studying a small group of cells in the fruit fly ovary, Montell determined that Rac proteins are instrumental in cell movement. Since then, it has become clear that Rac is a nearly universal regulator of cell motility in animal cells. Back in the '90s, she noticed that a hyperactive form of the Rac1 protein, expressed in only a few cells in a fly's egg chamber, destroyed the whole tissue. "Just expressing this active Rac in six to eight cells kills the entire tissue, which is composed of about 900 cells," explained lead author Abhinava Mishra, a project scientist in Montell's lab. Why did this happen? How does it work? "This was our 25-year-old cold case," Montell said. A few years ago, evidence began to mount implicating cell eating, also known as cannibalism, in tissue destruction. There's a step in normal fly egg development where certain cells similar to the border cells consume their neighbors because they are no longer needed. Indeed, cellular cannibalism is not as rare as you might expect: Millions of old red blood cells are eliminated from the human body this way every second. Rac2 is one component of the complex eating process. Rac helps the eating cell to envelop its target. The team was curious if a hyperactive form of the protein was causing border cells to prematurely consume their neighbors. For this to occur, the border cells need to recognize their targets, which requires a particular receptor. Indeed, when Mishra blocked this receptor, the border cells expressing activated Rac didn't consume their neighbors, and the egg chamber remained alive and healthy. "Our 25-year-old cold case was solved, and that was very satisfying for us," Montell exclaimed. "But this is a fairly niche area of Drosophila egg development." The implications would soon grow, though. A mysterious immune condition Around the time that her lab made their breakthrough, Montell caught wind of an intriguing study in the journal Blood. This paper found that three unrelated people suffering from recurrent infections had the exact same mutation, which hyperactivates Rac2, a Rac protein produced in blood cells. She suspected her lab's recent revelation in fruit flies might shed light on this enigma. The patients' mutation was just mildly activating, and yet it was enough that they all suffered from multiple infections and ultimately needed bone marrow transplants. Blood tests revealed that these patients had nearly no T cells, a specialized kind of white blood cells crucial to the immune system. The team at the National Institutes of Health inserted the Rac2 mutation into mice and found the same mysterious loss of T cells. They also found that the T cells with hyperactive Rac developed normally in the animals' bone marrow, and migrated to the thymus, where they continued to mature without incident. But then they just seemed to disappear. So, the paper ended with a mystery: what was causing the T cells to disappear? The authors of that journal study had noticed that many of the patients' neutrophils -- another type of white blood cell -- were enlarged. They seemed to be consuming quite a lot of material, unusual behavior in an otherwise healthy person. Montell wondered if the patients' T cells were disappearing because their innate immune cells like neutrophils with active Rac2 were eating them, much like the fruit fly border cells with active Rac were eating the egg chamber. Her team turned their attention to macrophages -- the neutrophil's more voracious counterpart -- to investigate. Mishra cultured human macrophages with and without hyperactive Rac2 together with T cells. He observed that macrophages with hyperactive Rac consumed more cells, confirming the group's hypothesis from their work with fruit flies. To test whether this might cause the observed immunodeficiency, co-author Melanie Rodriguez (a graduate student in Montell's lab) took bone marrow samples from mice with the same hyperactive Rac2 mutation found in the patients. She then grew the marrow stem cells into macrophages, and performed a similar experiment to Mishra, but this time mixing both macrophages and T cells with and without the Rac2 mutation. She found that macrophages with active Rac2 consumed significantly more T-cells than their normal counterparts. However, T-cells with active Rac2 were also more vulnerable to consumption from either kind of macrophage. So the most likely explanation for the patients' missing T cells was a combination of increased consumption by macrophages as well as increased vulnerability of the T cells themselves. A human medical mystery was solved based on fundamental observations in fruit flies. Harnessing haywire cells The implications of these insights expanded in January 2020, when co-author Meghan Morrissey interviewed for a faculty position at UCSB. In her talk she described programming macrophages to eat cancer cells as a novel treatment for the disease, an approach called CAR-M. Morrissey had found that adding a CAR receptor to macrophages promoted this behavior. But it was also clear that inducing the macrophages to eat more would make the approach more effective -- especially if they would specifically consume, and kill, entire cancer cells . Well, if there was one thing that Montell and her lab had learned, it was how to make macrophages eat and kill whole, living cells. So they collaborated with Morrissey, now an assistant professor of molecular, cellular and developmental biology, to determine if adding activated Rac2 would increase the effectiveness of the CAR-M approach. Rodriguez grew macrophages from the bone marrow of normal and mutant mice with activated Rac2. In each of these groups, Morrissey expressed either a dummy receptor or the CAR receptor, which recognizes B cells (another type of white blood cell). They found that the normal and hyperactive Rac cells with the dummy receptors did not eat many B cell targets. The normal macrophages with CAR receptors consumed far more B cells, as Morrissey had previously shown. However the macrophages with both hyperactive Rac and the CAR receptors ate twice-again as many B cells as the CAR-only group. Activated Rac2 also seemed to increase the number of so-called "super eaters" -- ravenous macrophages that eat and kill multiple cancer cells. The results made it clear that activated Rac and the receptor were both necessary for the enhanced effect. "If you add active Rac without the right receptor, it doesn't do anything," Montell explained. This level of control is good news for any potential treatments, because it would give doctors a way to focus the modified macrophages' attack on cancerous cells. Clinicians hopefully won't need to worry about the engineered cells eating the patient's T-cells either, because the T-cells wouldn't have the active Rac2 mutation making them more vulnerable to this, as Rodriguez had previously discovered. There is a current cancer treatment called CAR-T, which uses the CAR receptor and a patient's own T-cells to attack and destroy cancers. It is highly effective against some cancers, but there are many that do not respond. CAR-M,a newer cousin to CAR-T, has recently entered into clinical trials in humans and so far seems safe. Montell and her group are interested in harnessing Rac-enhanced CAR macrophages to increase the efficacy of CAR-M treatments. They've filed a provisional patent for the technique -- which they call RaceCAR-M -- and are inviting biotech companies to partner in further developing the approach. This new multifaceted paper raises both basic science and practical questions, which the lab has begun to tackle. They're investigating whether the technique, which is so effective in the lab, will also work in freshly collected human immune cells and in animal cancer models, in mice and zebrafish. The team is also exploring how Rac2 is making this all happen at the molecular level, deep inside the cells. Further down the line, Montell wants to know how many kinds of cancer the RaceCAR-M treatment might successfully target. For comparison, CAR-T has been effective against cancers like leukemia and lymphoma, but not against solid-tumor cancers like breast, lung or colon. The results have amazed Montell, an esteemed cell biologist with well over 100 papers to her name. "This is my favorite paper so far," she said. "We had this 25-year-old cold case in fruit flies, and we solved it," Montell added. "And that helped us solve the mystery of an unexplained human immunodeficiency. And then we harnessed that knowledge to enhance a potential cancer immunotherapy. "It was just one mystery after another, and Rac turned out to be the answer to each of them." You can hear more about the path from fruit flies to potential cancer treatment in Montell's SNPets interview with the Genetics Society of America, episodes 4-6 ( ).

Foundational technology developed by UCLA for the Company’s Universal Cancer Vaccine can be adapted to function as an in-vivo CAR-T cell platform to dramatically lower the cost of CAR-T cell cancer therapiesLEHI, Utah, Sept. 12, 2023 (GLOBE NEWSWIRE) -- CancerVAX, Inc., a pre-clinical biotechnology company working with UCLA to develop breakthrough immunotherapy cancer treatments that use the body’s immune system to fight cancer, today announced an expansion of its development pipeline to include a Universal CAR-T Cell Platform that can dramatically lower the cost of CAR-T cell cancer therapies. CAR-T cell therapy is a type of immunotherapy treatment in which a patient’s T-cells are genetically modified in the laboratory, then reinjected back into the patient, so they will bind to specific proteins (antigens) found on cancer cells and kill them. These modified T-cells are called Chimeric Antigen Receptor (CAR) T Cells. Conventional CAR-T Cell therapy can cost more than $500,000 per dose due to complicated and expensive lab processes. We believe we can dramatically lower the cost to a few thousand dollars per dose by simply helping the body make its own CAR-T cells. During a remarkable meeting with Company executives recently, the UCLA research team reported significant project progress. Based on their recent findings, it is now clear that the foundational nanoparticle technology developed for the current Universal Cancer Vaccine project, can be easily adapted to target T-cells and carry genetic instructions to reprogram T-cells into CAR-T cells inside the body (in-vivo). Depending on the specific genetic instructions provided, different cancers can be targeted by the new CAR-T cells. Preliminary lab test suggests that this is easy to do. As a result, the Company has decided to expand its development pipeline to include a “Universal CAR-T Platform”. Conventional CAR-T Cell Therapy Steps: A patient’s T cells are removed from their blood.The gene for a special receptor called chimeric antigen receptor (CAR) is inserted into the T cells in the laboratory by gene editing. The gene forces the T cell to express a protein (receptor) on its surface that binds to the cancer cell’s surface protein (antigen).Millions of CAR-T cells are grown in the laboratory.They are then given to the patient by intravenous infusion.The CAR protein on the surface of the CAR-T cells bind to antigens on the cancer cells and kill them. CancerVAX Envisioned CAR-T Cell Steps: Genetic codes for targeting specific proteins on cancer cells are loaded into a smart nanoparticle using an innovative high-speed, low-cost manufacturing process.Millions of nanoparticles are injected into the patient as a shot. The nanoparticles attach to the patient’s natural T-cells inside the body, unload the genetic code, and reprogram the T-cells to target specific cancer cells and kill them. The Company’s pipeline of three projects with UCLA now includes: Children’s Cancer – Immunotherapy treatments for Ewing sarcoma, a children’s bone and tissue cancer with 100% death rate for recurrence.Universal Cancer Vaccine​ Platform – A novel and customizable Universal Cancer Vaccine (UCV), to be delivered as a shot, that can uniquely detect, mark and kill only cancer cells.Universal CAR-T Cell Platform – A novel and customizable low-cost treatment, to be delivered as a shot, that can reprogram natural immune T-cells inside the body to seek and destroy targeted cancer cells. Ryan Davies, CEO of CancerVAX commented, “CAR-T cell therapy is one of the more promising immunotherapies entering the mainstream of cancer treatment. There are currently six FDA approved CAR-T cell therapies, and they all cost around $500,000 per dose. While no amount of money is too much to save a single human life, we hope to dramatically lower the cost of CAR-T cell therapy by several orders of magnitude and help save many lives. The extreme low cost of the COVID vaccine, which uses similar technology and concepts, leads us to believe that this major cost reduction is possible with our Universal CAR-T Cell platform.” For more information about CancerVAX, please visit http://www.cancervax.com/. About Us CancerVAX, Inc., a pre-clinical biotechnology company working with UCLA to develop breakthrough immunotherapy cancer treatments that use the body’s immune system to fight cancer. Working with a team of experienced cancer researchers and physicians at UCLA, we are developing a pipeline that includes three innovative projects: (1) treating Ewing sarcoma, a deadly children’s cancer, (2) a Universal Cancer Vaccine that will detect, mark, and destroy only cancer cells while leaving healthy cells in-tact, and (3) a low cost Universal CAR-T Cell Platform that can reprogram natural immune T-cells inside the body to seek and destroy targeted cancer cells. All of our immunotherapy technologies are designed to be delivered as injections. We look forward to the day when treating cancer will be as simple as getting a flu shot – a better way to treat cancer. Forward-Looking Statements This press release may contain “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based only on our current beliefs, expectations, and assumptions regarding the future of our business, plans and strategies, projections, anticipated events and trends, the economy, and other future conditions. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks, and changes in circumstances that are difficult to predict, many of which are outside our control. Our actual results and financial condition may differ materially from those in the forward-looking statements. Therefore, you should not rely on any of these forward-looking statements. Any forward-looking statement made by us in this release is based only on information currently available to us and speaks only as of the date it is made. We undertake no obligation to publicly update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments, or otherwise. Press Contact:CancerVAX, Inc.Tel: (805) 356-1810communications@CancerVAX.com

Kyverna will utilize Verily's Immune Profiler to advance biomarker discovery and longitudinal data collection strategies to drive efficient, enhanced clinical trials SOUTH SAN FRANCISCO, Calif. and EMERYVILLE, Calif., Sept. 7, 2023 /PRNewswire/ -- Verily, an Alphabet precision health technology company, and Kyverna Therapeutics ("Kyverna"), a clinical-stage cell therapy company engineering a new class of therapies for autoimmune diseases, today announced a multi-year collaboration to identify novel biomarkers and innovate clinical trial design and execution. The initial phase of the collaboration focuses on deploying Verily's state-of-the-art immune mapping platform (Immune Profiler) to elucidate biomarkers of treatment response in autoimmune patients treated with Kyverna's KYV-101, an autologous Chimeric Antigen Receptor (CAR) T-cell therapy currently in Phase 1 clinical trials in the US and Europe. "B cell depletion using CAR T-cells represents a new frontier with curative potential for autoimmune patients, and together we will be uncovering the biological basis of the immune reset that confers durable therapeutic response in these patients," said Charlie Kim, head of molecular science at Verily. Immune Profiler's high-resolution molecular phenotyping and advanced computational analytics enables interrogation of a broad range of immune functions over the time course of CAR T-cell therapy, providing an unparalleled view of biological activity. Kyverna brings a network of research-ready participants and a growing sample library from treating autoimmune patients in multiple indications and geographies with KYV-101, its fully human anti-CD19 CAR T-cell therapy. "We are excited to explore our emerging patient data set, which will enable us to generate a first look into the biology underlying immune reset after administration of CAR T-cell therapy," said James Chung, chief medical officer at Kyverna. Additionally, as part of the collaboration, Verily and Kyverna will implement digital tools and technology solutions to reframe evidence generation, using a participant-centered study design that draws conclusions from data collected in real-world settings in addition to data collected directly from study sites. The companies will also develop solutions specifically designed for the needs of autoimmune patients treated with CAR T-cell therapy. "We are pleased to partner with Verily based on our shared vision to create the future landscape of clinical research, and to enable broader data collection from real-world settings that may contribute to regulatory decision-making," said Peter Maag, chief executive officer of Kyverna. "This collaboration links Verily's deep molecular capabilities with its extensive suite of tools for real-world evidence generation, providing a comprehensive and detailed understanding of the biology and participant experience with this new therapeutic modality in autoimmune disease," said Amy Abernethy, president of product development and chief medical officer at Verily. About Verily Verily is an Alphabet health technology company focused on research, care, and health financing to deliver on the promise of precision health and help people live healthier lives. We are uniquely positioned at the intersection of technology, data science, and healthcare to create tools to accelerate evidence generation, products to enable more personalized care, and approaches to make costs more predictable. For more information, please visit: verily.com or contact [email protected]. About Verily's Immune Profiler Immune Profiler is a next generation discovery tool leveraging high-resolution immune measurements and advanced analytics to accelerate and enhance biomarker and target discovery. By combining cytometry, whole genome sequencing, genetics, transcriptomics, epigenomics, and proteomics workflows and integrating high-resolution molecular phenotypes in powerful and efficient analytical workflows, the platform yields a deep and broad view of immune function with valuable translational insights. About Kyverna Therapeutics Kyverna Therapeutics is a clinical-stage cell therapy company with the mission of engineering a new class of therapies for autoimmune and inflammatory diseases. The Kyverna therapeutic platform combines advanced T-cell engineering and synthetic biology technologies to suppress and eliminate the autoreactive immune cells at the origin of autoimmune and inflammatory diseases. Kyverna's pipeline includes next-generation chimeric antigen receptor T-cell therapies in both autologous and allogeneic formats with properties well suited for use in B cell-driven autoimmune diseases. By offering more than one mechanism for taming autoimmunity, Kyverna is positioned to act on its mission of transforming how autoimmune diseases are treated. For more information, please visit . About KYV-101 KYV-101 is an autologous version of a novel, fully human clinical-stage anti-CD19 chimeric antigen receptor (CAR) T-cell construct with properties well suited for use in B cell-driven autoimmune diseases such as lupus nephritis and other B-cell driven autoimmune diseases. In a 20-patient Phase 1/2 study in oncology, expected anti-lymphoma activity was associated with a significant reduction of cytokines released that translated into a strong reduction of cytokine-driven side effects such as the rate of immune effector cell-associated neurotoxicity syndrome (ICANS)1. The fully human anti-CD19 CAR also translated into reduced immunogenicity that favorably impacted cell persistence at one month. Kyverna recognized that these properties singled out KYV-101 as a product ideally poised for use in autoimmune disease patients, and the company obtained exclusive, worldwide licenses from the National Institutes of Health (NIH) to use this CD19 construct in both autologous and allogeneic CAR T-cell therapies. References: 1 Brudno et al., Nature Medicine 2020; 26:270-280. Contacts Verily Steven Cooper +1 (646) 358-2765 sjcoop@verily.com Kyverna Christian Pflaumer +1 (917) 841-4525 [email protected] SOURCE Kyverna Therapeutics