T-Cells(Key Biologics)

A research team thinks it may be able to get better results with bispecific CAR-Ts or by combining CAR-T therapies multiple together. Mustang Bio and City of Hope’s chimeric antigen receptor T-cell (CAR-T) therapy for recurrent glioblastoma resulted in stable disease or better in half of the subjects in a phase 1 clinical trial, including one patient whose cancer has not recurred for more than five years.  The trial, described March 7 in Nature Medicine, is the largest reported so far on a CAR-T therapy in glioblastoma. It also builds the case for the feasibility and possible advantages of injecting CAR-T cells directly into a brain tumor and the cerebrospinal fluid, a method that could ultimately change how the disease is treated. “I think a lot of our findings are reshaping the field and how we’re thinking about applying cell therapy to brain tumors,” Christine Brown, Ph.D., deputy director of the T Cell Therapeutics Research Laboratories at City of Hope and creator of the therapy tested in the trial, told Fierce Biotech Research in an interview. “This paper both sets the foundation clinically, but also tries to get at some of the features of glioblastoma that make it difficult to treat, including with immunotherapy.” Into the brain    Glioblastoma, also known as glioblastoma multiforme, is the most common and most aggressive primary brain tumor. For the first occurrence, the median survival without treatment is around nine months. But that figure grows only slightly with therapy to about 12 to 14 months, as the tumors return more resistant than before. All 58 patients in the phase 1 study had experienced at least one recurrence prior to enrolling in the trial. The majority were being treated for their third, Behnam Badie, M.D., chief of neurosurgery at City of Hope and senior author on the study, told Fierce. They had previously received some combination of surgery, chemotherapy or radiation, the current standard of care for the disease. “The gliomas become more aggressive when they recur,” Badie said. “So basically, [the patients] had no other treatment options when they saw us.”  Each subject in the trial received a weekly dose of CAR-T cells aimed at the antigen interleukin-13 receptor alpha 2, or IL13Rα2, a long-established target in glioblastoma that has previously been explored preclinically and clinically for CAR-T therapy, including in a smaller phase 1 trial by Brown and Badie’s team at City of Hope. The therapy has been licensed by Mustang Bio, which is now developing the treatment. The patients received increasingly higher doses as the trial progressed, administered via different routes: direct injection into the tumor, infusion into the cerebrospinal fluid or, for the final cohort, both. The patients could continue to receive CAR-T cell infusions as long as they still met the enrollment criteria and had CAR-Ts left to use. Non-(neuro)toxic   Given that systemic administration of CAR-T therapy is linked to dangerous side effects in the brain—specifically, a set of symptoms called immune effector cell-associated neurotoxicity syndrome, or ICANS—the researchers initially worried that injecting CAR-Ts directly into the brain would go very wrong.  “When we started this study in 2015, neurotoxicity and ICANS with CAR-T cell therapy was a really hot topic,” Brown said. For that reason, the first infusion was a “very low mouse dose,” she said. “We stayed up all night, because we weren’t sure what we would see,” Brown recalled.  Surprisingly, there was no neurotoxicity in any of the patients. Some developed headaches and fevers for a few days, but that was the extent of their side effects, Badie said. That’s likely because, unlike the CD19 antigen targeted by other types of CAR-Ts, the IL13Rα2 receptor is expressed almost exclusively by the tumor and some small populations of inflammatory cells—not on neurons or cranial nerves, Badie explained. On top of that, research by Stanford and City of Hope has suggested that the adverse effects of CAR-T therapy for brain tumors might be slightly different than treating other types of tumors, Brown noted. “I don’t think we completely understand the similarities and differences,” she said. “That’s still an area to be explored.” Encouraging signs   The overall median survival duration for all patients in the trial was eight months. Twenty-nine had stable disease for at least two months after the therapy was administered. For patients who received CAR-Ts both in their tumors and their cerebrospinal fluid at a predetermined maximum feasible dose, the median survival was 10.2 months, higher than the expected six-month survival rate for patients treated for recurrent glioblastoma. The CAR-Ts given to this cohort were also manufactured with an optimized manufacturing process, Brown told Fierce in a follow-up email. One of the patients, a 58-year-old man, remains disease-free five and a half years after his treatment began. Though he has some residual complications as a result of the tumor and prior treatment—he’s paralyzed on his left side—he is able to spend time with his children and grandchild. Even for the rest of the subjects in the trial, all of whom ultimately passed away, “it was encouraging to see that [recurrence] was delayed” in so many of them, Badie said, adding that the tumor usually comes back within a month after surgery. “That means there was really good local control initially.”    Insights from outliers   Brown and Badie’s team is working to figure out what exactly made those outliers respond relatively well to treatment, a project made more robust by their ability to take samples of the tumor and its surrounding microenvironment in patients whose treatment was infused directly into the cancer. One element that stands out is that the patients who fared best had a different immune cell profile than the others, suggesting there’s something important about the interaction between host immunity and CAR-T cell therapy, Brown said.  “When we looked at their [pretreatment] tumors, we found that the immune contexture actually correlated with a better response,” she explained. Specifically, patients with higher numbers of a certain type of T cells—CD3 T cells—had better responses.  “It’s really driving this working hypothesis that in solid tumors, the design of the cell therapy and targets are important, but it’s also important to look at how it engages with host immunity,” Brown said. “We think this study provides initial insights into that.” The team has data from early-stage trials on single-target CAR-T therapies for glioblastoma that act on other antigens, too, though details on those studies haven’t yet been published. Meanwhile, based on the results of the newly published trial, the team is building bispecific CARs that go after more than one antigen at a time as well as designing a study that combines multiple CARs in a single treatment.  “We need to make an impact on this disease for these patients,” Brown said. “So we hope that this is one step in the right direction.”

MB-101 was well-tolerated and 50% of patients achieved stable disease or better with two partial responses and two complete responses lasting 7.5 and 66+ months, respectively ~70% improvement in median overall survival compared to expected survival rate in cohort with dual intratumoral (ICT)/ intraventricular (ICV) delivery and an optimized manufacturing process This is the largest reported trial to date of CAR-T therapy for solid tumors WORCESTER, Mass., March 07, 2024 (GLOBE NEWSWIRE) -- Mustang Bio, Inc. (“Mustang”) (Nasdaq: MBIO), a clinical-stage biopharmaceutical company focused on translating today’s medical breakthroughs in cell and gene therapies into potential cures for difficult-to-treat cancers and rare genetic diseases, today announced Phase 1 clinical data were published in Nature Medicine that demonstrated the promising safety and clinical activity of Mustang’s MB-101 (IL13Ra2-targeted CAR T-cells) for the treatment of patients with recurrent and refractory malignant glioma, including glioblastoma. MB-101 was developed by City of Hope, one of the largest cancer research and treatment organizations in the United States, and exclusively licensed to Mustang. Highlights from the data include: Stable disease or better was achieved in 50% (29/58) of heavily pretreated patients for at least two months, with two partial responses, one complete response (CR), and a second CR after additional CAR-T cycles under compassionate use. Patients with recurrent GBM treated in the final cohort with dual intratumoral (ICT)/ intraventricular (ICV) delivery and an optimized manufacturing process exhibited superior median overall survival of 10.2 months, compared to the expected survival rate of six months in patients with recurrent GBM. The median overall survival for all patients was eight months. Intermediate/high pre-treatment tumor T-cell levels that are indicative of a “hot” tumor microenvironment (TME) correlated with a significant survival benefit over negative/low pre-treatment tumor T-cell levels that are indicative of a “cold” TME. Overall, all routes of delivery (ICT, ICV and dual ICT + ICV) were well-tolerated at doses up to 200×106 CAR T-cells. Central nervous system (CNS) increases in inflammatory cytokines, including IFNγ, CXCL9, and CXCL10, were associated with CAR T-cell administration and bioactivity. Dr. Christine Brown, Heritage Provider Network Professor in Immunotherapy, deputy director of the T-Cell Therapeutics Research Laboratories at City of Hope, and lead author on the publication, said, “These Phase 1 clinical trial results represent a significant step forward in our understanding of the potential of MB-101 CAR T-cell therapy to treat recurrent GBM, an extremely aggressive tumor with very limited treatment options. One of the main challenges for treating brain cancer is that medications have difficulty crossing the blood-brain barrier. To overcome that barrier, the trial delivered CAR T-cells directly into the brain tumor and the cerebrospinal fluid, the fluid that protects and surrounds the brain and spinal cord. Repetitive locoregional administration of IL13Rα2-CAR T-cells was feasible and well-tolerated with no dose limiting toxicities, even at the highest dose level of 200 x 106 CAR T-cells per infusion. The safety and promising therapy-related bioactivity data pave the way for future studies of MB-101 and offer hope for a transformative treatment approach. We look forward to continuing our work with Mustang on this promising therapy.” Manuel Litchman, M.D., President and Chief Executive Officer of Mustang, said, “MB-101 has demonstrated compelling therapeutic potential, including delivering unprecedented complete responses in two high-grade glioma patients; the first patient who achieved a complete response was published in The New England Journal of Medicine. These two patients treated solely with MB-101 both had high levels of intratumoral CD3+ T-cells pre-therapy (i.e., “hot” tumors) and achieved complete responses lasting 7.5 and 66+ months, respectively. This trial has led to several other studies using MB-101, including supporting our upcoming novel combination clinical trial of MB-109 [MB-101 (IL-13Rα2 targeted CAR T-cell therapy) + MB-108 (HSV-1 oncolytic virus)] to improve treatment of recurrent GBM and high-grade astrocytoma. The combination leverages initial treatment with MB-108 to reshape the tumor microenvironment and make immunologically “cold” tumors “hot,” thereby potentially enabling the MB-101 CAR T-cell therapy to achieve efficacy equivalent to that seen in intrinsically “hot” tumors in this City of Hope Phase 1 trial.” The data reported on 65 patients with recurrent high-grade glioma, the majority being glioblastoma (GBM; 2 + recurrences); 58 patients were evaluable for disease response. Primary endpoints were safety and feasibility, with secondary endpoints measuring therapy-related cytokine dynamics, CAR T-cell persistence and clinical outcomes. Patients were treated at one of three dose schedules with three weekly infusions administered without prior lymphodepleting chemotherapy and were evaluated one week after the third cycle for dose limiting toxicities. Additional infusions were allowed, and patients were followed for toxicities, response, and survival until they progressed or required subsequent therapy. This study evaluated five treatment arms: Arm 1, intratumoral following biopsy (ICT Biopsy); Arm 2, intratumoral following maximal surgical resection (ICT Resection); Arm 3, intraventricular (ICV); and Arms 4 and 5, combined ICT and ICV delivery (Dual ICT + ICV). ICV delivery (Arm 3) was added after trial initiation based on clinical experience, in which IL13Rα2-CAR T-cells that were administered ICV mediated a complete response in a patient with multifocal recurrent GBM, and preclinical data suggested ICV was more effective against multifocal tumors. Subsequently, City of Hope transitioned to dual delivery combining both ICV and ICT (Arms 4–5) – rather than continuing with ICV alone – as preclinical data also suggested that intratumoral delivery was more effective for defined unifocal tumors in comparison to ICV-only delivery. Weekly ICT and/or ICV administration of IL13Rα2-CAR T-cells was well-tolerated, with clinically manageable adverse events. No high-grade cytokine release syndrome or immune effector cell-mediated neurotoxicity adverse events were observed, and no dose limiting toxicities (DLTs) were noted during the 28-day dose limiting toxicity period. The most common toxicities with possible or higher attribution to CAR T-cells were fatigue, headache, and hypertension. Grade 3 and above toxicities with possible or higher attribution to CAR T-cells were seen in 35% of patients, including two incidences of transient grade 4 cerebral edema with possible attribution to CAR T-cells and one grade 3 encephalopathy and one grade 3 ataxia with probable attribution to CAR T-cells. A link to the Nature Medicine publication can be found here. Dr. Brown has a financial interest in Mustang and has previously been a paid consultant for the company. Additional information on the Phase 1 study can be found on using identifier NCT02208362. About Mustang Bio Mustang Bio, Inc. is a clinical-stage biopharmaceutical company focused on translating today’s medical breakthroughs in cell and gene therapies into potential cures for difficult-to-treat cancers and rare genetic diseases. Mustang aims to acquire rights to these technologies by licensing or otherwise acquiring an ownership interest, to fund research and development, and to outlicense or bring the technologies to market. Mustang has partnered with top medical institutions to advance the development of CAR-T therapies across multiple cancers, as well as lentiviral gene therapies for severe combined immunodeficiency. Mustang’s common stock is registered under the Securities Exchange Act of 1934, as amended, and Mustang files periodic reports with the U.S. Securities and Exchange Commission (“SEC”). Mustang was founded by Fortress Biotech, Inc. (Nasdaq: FBIO). For more information, visit . Forward‐Looking Statements This press release contains “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, each as amended. Such statements, which are often indicated by terms such as “anticipate,” “believe,” “could,” “estimate,” “expect,” “goal,” “intend,” “look forward to,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “will,” “would” and similar expressions. The Company’s forward-looking statements, include, but are not limited to, any statements relating to our growth strategy and product development programs, including the timing of and our ability to make regulatory filings such as INDs and other applications and to obtain regulatory approvals for our product candidates, statements concerning the potential of therapies and product candidates and any other statements that are not historical facts. Actual events or results may differ materially from those described in this press release due to a number of risks and uncertainties. Risks and uncertainties include, among other things, risks related to the satisfaction of the conditions necessary to transfer the lease of the Company’s manufacturing facility and receive the contingent payment in connection with the Company’s sale of its manufacturing facility in the anticipated timeframe or at all; whether the purchaser of the Company’s manufacturing facility is able to successfully perform its obligation to produce the Company’s products under the manufacturing services agreement on a timely basis and to acceptable standards; disruption from the sale of the Company’s manufacturing facility making it more difficult to maintain business and operational relationships; negative effects of the announcement or the consummation of the transaction on the market price of the Company’s common stock; significant transaction costs; the development stage of the Company’s primary product candidates, our ability to obtain, perform under, and maintain financing and strategic agreements and relationships; risks relating to the results of research and development activities; risks relating to the timing of starting and completing clinical trials; uncertainties relating to preclinical and clinical testing; our dependence on third-party suppliers; our ability to attract, integrate and retain key personnel; the early stage of products under development; our need for substantial additional funds; government regulation; patent and intellectual property matters; competition; as well as other risks described in Part I, Item 1A, “Risk Factors,” in our Annual Report on Form 10-K filed on March 30, 2023, subsequent Reports on Form 10-Q, and our other filings we make with the SEC. We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in our expectations or any changes in events, conditions or circumstances on which any such statement is based, except as required by law, and we claim the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995. Company Contacts: Jaclyn Jaffe and Nicole McCloskey Mustang Bio, Inc. (781) 652-4500 ir@mustangbio.com