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Umoja Biopharma’s technology is designed to overcome the key limitations of CAR-T therapy, eventually making it possible to have “off-the-shelf” CAR-Ts that are more accessible to patients. Umoja Biopharma’s VivoVec platform has generated in vivo chimeric antigen receptor T cells, or CAR-T cells, in nonhuman primates, according to new data presented by the company Sept. 1 during the annual CAR-TCR Summit in Boston. The CAR-Ts also appeared to have activity against target cells and continued proliferating for more than a month in one of the animals. "Our hope is that the replication of these data in our early clinical trials will lead to a new class of in vivo CAR-T cell therapeutics that expand the breadth of reach of CAR-T cell therapies by reducing costs and logistical complexity of delivery and by offering an immediate, off-the-shelf, product that generates autologous, patient-specific CAR-T cells," Andy Scharenberg, M.D., Umoja's co-founder and CEO, told Fierce Biotech Research via email. Umoja’s technology programs a patient's T cells against their cancer in vivo—that is, without ever having to remove the T cells from their body, as currently approved therapies require, or transferring them from donors as occurs with next-generation allogeneic therapies like Allogene's. Instead, Umoja uses lipid nanoparticles it's dubbed VivoVec particles to activate, integrate and express the CAR in a patient’s own T cells. This replaces the expensive, time-consuming process of extracting and transducing the cells with CARs using viral vectors before re-implanting them back into the patient, steps that can be marred by vector shortages and the possibility of manufacturing failure or low yields. The platform also negates the need for chemotherapy to clear out a patient’s blood cells. Back in May at the American Society of Gene & Cell Therapy’s annual conference, Umoja reported preclinical data on VivoVec in mice. In the new studies, the researchers injected four male and female pigtail macaque monkeys in the groin-area lymph nodes with a single, clinically relevant dose of the VivoVec particles designed to generate anti-CD20 CARs, the type used to target B-cell lymphoma. The team then monitored the animals for CAR-T cell activation and expansion as well as toxicity. None of the monkeys received chemotherapy beforehand. In three of the primates, CD20 CAR-T cells peaked at about 40% to 60% of total circulating T cells at their peak. The same three monkeys also had persistent B-cell aplasia, a sign that the CAR-Ts were working. The numbers for most of the animals exceeded the benchmark for ex vivo CAR-T therapies in a similar primate model, Scharenberg told Fierce. In a 2018 study on rhesus macaque monkeys that underwent chemotherapy followed by CAR-T infusion, the engineered cells proliferated to a peak of 272 to 4,450 CAR-T cells per microliter; their B-cell aplasia lasted between 35 and 42 days.  In Umoja's latest study, the CAR-T cells in two of the monkeys peaked at between 5,000 and 10,000 cells per microliter and their B-cell aplasia lasted beyond 42 days. In another, the researchers detected a large secondary CAR-T cell expansion around Day 49 or 50, "suggesting that VivoVec may capture aspects of memory T cell biology that are difficult or impossible to capture with ex vivo CAR-T cell manufacturing processes," Scharenberg wrote. While the therapy was largely well tolerated, there were a few side effects in two of the animals—though none out of the ordinary for CAR-T therapy, and less serious than what was seen in the 2018 study on an ex vivo treatment. The most serious was a mild cytokine release syndrome and neurotoxicity event that culminated in a single seizure, to which the monkey responded to single doses of the appropriate medications. The primate experiments are ongoing; more data from them will be presented at medical conferences in the fall, Umoja said in the release. The company currently has a piece of its technology in clinical trials at Seattle Children’s Hospital and plans to submit a request to the FDA in the first half of 2024 to take its first VivoVec-based therapy into human studies. Editor's note: This story has been updated to clarify the technology in clinical trials at Seattle Children's Hospital and the timeline for submitting a request for its first VivoVec-based therapy. 

Looking at mice with xenografts of folate receptor-expressing tumor cells, researchers saw that UB-VV200 controlled solid tumor growth in a dose dependent manner—the more TagCAR T cells that were generated, the smaller the tumor volume. It’s a statistic that haunts David Fontana, Ph.D., chief operating officer of Umoja Biopharma: At a time when manufacturing space is hard to come by, as many patients die waiting for CAR-T cell therapy as are actually treated. “Physicians … are having to choose which patient [gets the therapy]. Do we go with the sick elderly one that has no hope, or the healthy one that can probably survive?” Fontana told Fierce Biotech at the American Society for Gene and Cell Therapy’s (ASGCT's) annual meeting. “I’ve started calling them the ‘Goldilocks patients’: The ones who aren’t too sick, not too well. You’re narrowly defining these patients simply because of these supply chain issues.” Umoja wants to offer a solution. The biotech is working on ways to confront all the major limitations of CAR T-cell therapy—the lengthy, pricey manufacturing process and the poor efficacy against solid tumors—with therapies that reengineer a patient’s T cells within their own body, rather than removing and redelivering them the way current autologous CAR T-cell therapy is administered today. It’s also in the process of establishing partnerships with Big Pharma companies that want to take their ex vivo therapies in vivo by pairing them with Umoja’s VivoVec gene delivery system, which the company is aiming to manufacture end-to-end at its forthcoming plant in Colorado. “We know we can manufacture 100% of our own supply chain, so that’s attractive to partners,” Fontana said, especially in light of the ongoing shortage of lentiviral vectors. Though no deals have been announced yet, Umoja is “actively pursuing” partnerships, he added. What the company has announced is new preclinical data validating its therapeutic approach in solid tumors. On May 17 at ASGCT, researcher Alyssa Sheih, Ph.D., showed how Umoja’s gene delivery platform UB-VV200, which uses the company’s VivoVec technology, combined with UB-TT170, a folate receptor-targeting version of its small-molecule adapter TumorTag technology, was able to generate CAR T cells in vivo and successfully control solid tumor growth in mice. A brief overview of how all the pieces work together: The scientists administer UB-VV200, an engineered lentiviral vector that encodes a universal CAR called a TagCAR along with the company’s synthetic cytokine system, RACR, which helps the CAR T cells expand and persist without the need for pre-treatment chemotherapy. UB-VV200 selectively binds, activates and transduces the T cells, resulting in TagCAR expression on their surface. The TagCAR-T cells will bind to the TumorTag coated folate receptor-expressing tumors—in this instance, the TumorTag UB-TT170, which binds to folate receptors. Looking at mice with xenografts of folate receptor-expressing tumor cells, the researchers saw that UB-VV200 controlled solid tumor growth in a dose-dependent manner. The more TagCAR T cells that were generated, the smaller the tumor volume. Umoja is conducting ongoing nonhuman primate studies, which the company described as “encouraging” so far. Details are to be presented at an upcoming medical conference, though Umoja declined to disclose which one.  The Seattle Children's Research Institute is currently testing Umoja's UB-TT170 in pediatric osteosarcoma, a folate receptor-expressing tumor type, with plans to expand into gynecological tumors. The company also intends to submit an investigational new drug application for human testing with the FDA for UB-VV200 by the second half of 2024. Other preclinical assets include UB-VV111, a CD-19 CAR T-cell therapy for hematological cancer. Meanwhile, the company is busy finishing up the manufacturing plant in Louisville, Colorado, dubbed The Colorado Laboratory & Innovative Manufacturing Building, or The CLIMB. The $70 million plant will span 77,000 square feet and is expected to open later this year. Producing an off-the-shelf, in vivo CAR T therapy rather than an ex vivo one allows the company to make more efficient use of its manufacturing space, Senior Vice President of Translational Sciences Ryan Larson explained. Autologous ex vivo CAR T cell therapies are produced for each individual patient, so each batch of CAR T cells must be produced one at a time. In contrast, “we can scale up—we don’t have to scale out,” Larson said. As demand for Umoja's therapies grows, along with the number of partners that want to use the VivoVec platform to convert their own CAR T cell therapies to in vivo products, “we can just increase the volume of our bioreactors.” Given the manufacturing challenges and other accessibility issues associated with autologous CAR T-cell therapies, it’s likely that the field more broadly is headed toward an in vivo approach, Larson said. There’s a precedent for this already in the gene therapy space. Gene therapies started out with genes being transduced into cells outside a patient’s body, then over time began to move in-patient as the technology improved. The same thing is happening with CAR T-cell therapies: As the treatment’s power has become clear, researchers are looking for ways to make it more accessible. “Now, to me, it’s an obvious next step if you can make a truly off-the-shelf product that engineers the patient’s own cells in vivo essentially an autologous product—it’s your T cells—and you bypass all the complexity of the ex vivo approach by going directly in vivo,” Larson said. “I would say yeah, it’s definitely the way of the future.”