Cancer Research Institute

Published in the Journal for ImmunoTherapy of Cancer (JITC), Intravenous Dosing Shows Strong Evidence of Tumor Delivery, Viral Replication and Transgene Expression CAMBRIDGE, Mass.--(BUSINESS WIRE)--Akamis Bio, a clinical-stage oncology company using a proprietary Tumor-Specific Immuno-Gene Therapy (T-SIGn®) platform to deliver novel immunotherapeutic proteins, biomolecules and transgene combinations to treat solid tumors, today announced the publication of data supporting the continued clinical development and intravenous route of administration of NG-350A, its lead program for the treatment of advanced metastatic cancers. NG-350A is a next-generation transgene-armed tumor gene therapy designed to drive intratumoral expression of a CD40 agonist monoclonal antibody resulting from selective replication in both primary and metastatic epithelial-derived solid tumors. Data from the first-in-human dose escalation FORTITUDE study in patients with metastatic/advanced epithelial tumors supports proof-of-mechanism for NG-350A, with strong evidence of tumor-selective delivery, replication and transgene expression. Additionally, this study demonstrates that intravenous delivery of NG-350A results in a superior overall pharmacokinetic and pharmacodynamic profile, with no apparent disadvantages versus intratumoral injection. Blood sample analysis from patients showed sustained persistence of NG-350A up to seven weeks after intravenous dosing was completed (maximum follow up), particularly at higher dose levels. Further, a dose-dependent pattern was also seen with systemic delivery, resulting in four patients remaining positive for vector DNA in biopsies nearly two months after receiving the treatment. Transgene messenger RNA from replicating NG-350A was detected in nearly half the patients with intravenous treatment but only in one patient that had received intratumoral injection. Sustained increases in inflammatory cytokines were also observed following dosing, particularly with higher intravenous dose levels. “These findings are highly supportive of our ongoing focus on intravenous administration of NG-350A to safely drive sustained transgene expression within the tumor microenvironment. Systemic delivery offers considerable advantages over current intratumoral approaches, particularly with transgene-containing viral vectors where the cargo needs to reach both the primary tumor and metastases throughout the body – an application for which direct injection or dependence on an abscopal effect is not viable,” said Oliver Rosen, M.D., Chief Medical Officer at Akamis. Dr. Rosen continued: “This study demonstrated that a T-SIGn therapeutic armed with targeted immunostimulatory proteins such as CD-40 agonists can be successfully delivered intravenously, resulting in a superior overall pharmacokinetic and pharmacodynamic pro to intratumoral administration. Our preliminary data suggest that the local expression of immunostimulatory therapies following intravenous administration can overcome toxicity that limits non-targeted systemic administration. We look forward to continuing to understand the potential of this treatment in upcoming proof-of-concept studies.” NG-350A will now be studied in combination with chemoradiotherapy in FORTRESS, a multicenter open-label non-randomized Phase 1b trial of patients with locally advanced rectal cancer. A link to the publication “First-in-human clinical outcomes with NG-350A, an anti-CD40 expressing tumor-selective vector designed to remodel immunosuppressive tumor microenvironments” can be found here. About T-SIGn Akamis Bio’s T-SIGn® therapeutics are based on a replication competent, chimeric group B adenovirus backbone which has been adapted via directed evolution to home specifically to both primary and metastatic epithelial-derived solid tumor tissue following intravenous delivery. Once at the tumor site, T-SIGn therapeutics can drive the intratumoral expression of multiple transgene payloads, turning solid tumor cells into “drug factories” while leaving healthy tissue unaltered and intact. The intratumoral expression of immunologically active biomolecules and therapeutic proteins can result in the remodeling of the solid tumor microenvironment, triggering robust antitumor immune responses. T-SIGn therapeutics have the potential to be used in the monotherapy setting, as well as in combination with other immuno-oncology agents to target the key mechanisms that tumors use to evade the immune system. About Akamis Bio Akamis Bio is a clinical-stage oncology company using a proprietary Tumor-Specific Immuno-Gene Therapy (T-SIGn®) platform to deliver novel immunotherapeutic proteins, biomolecules and transgene combinations to treat solid tumors. The company is developing a portfolio of solid tumor-targeted T-SIGn therapeutics which aim to enable a patient’s own immune system to recognize, attack, and clear their cancer. Akamis Bio has a growing pipeline of T-SIGn therapeutics anchored by its lead clinical-stage program, NG-350A (an immuno-stimulatory tumor gene therapy driving intratumoral expression of a CD40 agonist monoclonal antibody) being investigated in ongoing Phase 1 clinical studies in patients with metastatic or advanced epithelial tumors. In addition to internal pipeline development efforts, Akamis Bio has a number of T-SIGn platform-focused collaborations with leaders in the immuno-oncology field including Merck and the Cancer Research Institute (CRI). To learn more, please visit . Contacts Media: Jason Glashow Glashow Strategic Communications Jason.Glashow@akamisbio.com

Research scientists found that a 'one-two punch' of combining the immunosuppressive drug ruxolitinib with existing checkpoint inhibitor therapies may be a more effective way to fight some cancers, including Hodgkin lymphoma. Checkpoint inhibitor therapies can be thought of as the molecular 'brake release' for the immune system. These drugs eliminate the protein barriers that impede the immune system from recognizing and targeting cancer cells in the body. Checkpoint inhibitor therapies can be thought of as the molecular "brake release" for the immune system. These drugs eliminate the protein barriers that impede the immune system from recognizing and targeting cancer cells in the body. While there are multiple checkpoint inhibitors approved to treat different types of cancer, many patients don't respond or develop resistance to available regiments. A Scripps Research team has now found that ruxolitinib, an approved immunosuppressive drug, supercharged T-cell responses when used alongside checkpoint inhibitors -- boosting their effectiveness in fighting cancer. These findings, published in Science on June 21, are supported by a phase I clinical trial of patients with Hodgkin lymphoma, as well as preclinical models. "There's a lot of activity in developing the next generation of immunotherapies, and we're looking beyond therapeutics that target T cells directly," says co-senior author John Teijaro, PhD, a professor in the Department of Immunology and Microbiology at Scripps Research. T cells are produced by the immune system to fight off infections, as well as cancer. Patients often stop responding to checkpoint immunotherapy when their T cells begin to wane. This phenomenon, called T-cell exhaustion, happens as T cells become chronically exposed to cancer cells. But based on the results of previous work, Teijaro and his research team wondered whether a JAK inhibitor -- like ruxolitinib -- could increase T-cell production, while also improving checkpoint inhibitors and their "brake release" effects. JAK enzymes are important parts of the JAK/signal transducer and activator of transcription (STAT) pathway -- a chain of interactions between cells and proteins that are essential for immune cell development. Dysregulation of the pathway is associated with both inflammation and cancer. JAK inhibitors restrict signals believed to cause inflammation, resulting in the immune system "calming down." "A lot of this started about 11 years ago, when we originally found that blocking a cytokine that signals through the JAK/STAT pathway, type 1 interferon, can promote immune responses and hasten virus clearance," says Teijaro. Although JAK inhibitors are typically used to treat inflammatory diseases, there's a known genetic link between JAK mutations and cancer, he adds. To determine which existing JAK inhibitors could restore the function of exhausted T cells, Teijaro and his team turned to ReFRAME, a drug repurposing library built by Calibr-Skaggs, the drug discovery and development arm of Scripps Research. ReFRAME permits researchers to rapidly sort through thousands of existing FDA-approved drugs and determine if they could treat any other major illnesses. Using ReFRAME, the researchers identified ruxolitinib as a contender. Through a range of preclinical models in which mice had various forms of cancer and persistent viral infections, the researchers found that compared with checkpoint therapy alone, combining the treatment with ruxolitinib increased both the number of T cells and natural killer (NK) cells -- another type of immune cell that limits the spread of cancer. With this preclinical data in hand, the team partnered with Veronika Bachanova, MD, PhD, at the University of Minnesota who had initiated a phase I clinical trial of 19 patients with Hodgkin lymphoma who failed to respond to checkpoint inhibitors or relapsed following an initial response. "Among patients with all types of cancer, fewer than 20% respond to checkpoint inhibitors. Even in cancer types that typically respond well such as Hodgkin lymphoma, about 10% to 20% of patients don't respond to checkpoint inhibitors, and they have to be treated with a chemotherapy that is fairly nonspecific and is not curative," explains first author Jaroslav Zak, a postdoctoral fellow at Scripps Research. "It's very difficult to treat these patients." But two years after starting a treatment regimen that combined ruxolitinib with the checkpoint inhibitor nivolumab -- a current standard of care -- 87% of patients were still alive, and 46% stopped exhibiting signs of cancer progression altogether. "Anecdotally, we know for sure that at least one patient had a very good response that lasted beyond the two years of the clinical trial," says Zak. "Unlike chemotherapy, this treatment didn't just slow down the disease but actually reversed it." Myeloid cells, a type of immune cell from the bone marrow, are among the body's most important lines of defense against infection. But cancer cells often hijack myeloid cells, which leads to tumor growth and metastasis. A high number of myeloid suppressor cells -- which are found in many types of tumors and cause weak responses to immune checkpoint inhibitors -- as well as a high ratio of neutrophil-to-lymphocyte cells are tied to poor prognosis of several cancers, including Hodgkin lymphoma. But using the ruxolitinib combination therapy resulted in a reduction of both indicators, while also promoting functional T cells. "We're now enlisting myeloid cells as helpers for immunotherapy, as it seems that in order for T cells to increase in number and functionality, ruxolitinib needs to modulate the myeloid cells," explains Teijaro. These findings, however, were unexpected. For one, past research showed that ruxolitinib didn't work on its own to treat cancer. "Ruxolitinib is actually an immunosuppressive drug that's clinically approved for chronic graft-versus-host disease, so the fact that we saw immune-enhancing effects in patients treated with this drug using combination therapy was definitely surprising," continues Zak. "This suggests that some drugs can actually have immune-enhancing effects, even if their primary indication is to relieve inflammatory disease pathology." Building on their success, the researchers plan to examine whether other JAK inhibitors are even more effective than ruxolitinib at treating cancer. They're also designing clinical trials to test the efficacy of ruxolitinib combined with checkpoint inhibitors in other forms of cancer, including those with solid tumors. "It's very rare to have supporting evidence with preclinical data and a clinical trial in one paper," says Teijaro. "I've been doing this for decades, and I've never had that happen in my career." He continues, "our results are particularly exciting because we are already seeing patients benefit from the combination and we believe this could be applied to several immunotherapy resistant cancers." This work and the researchers involved were supported by funding from Bristol- Myers Squibb (grant CA209-9EF), the Cancer Research Institute/Irvington Postdoctoral Fellowship, Incyte Corporation (grant IST-USA-000382), and the National Institutes of Health (grants R01AI123210, R01AI164744, R21AI141842, and UL1TR002550 Pilot Award).

Scientists uncover why cancer patients with ARID1A gene mutations are more likely to respond to immunotherapy, discovering ARID1A mutations invite cancer-fighting immune cells into tumors by triggering an antiviral-like response. Their findings could help improve cancer care and drug development for many cancer types, including endometrial, ovarian, colon, gastric, liver, and pancreatic cancers. Immunotherapy has revolutionized the way we treat cancer in recent years. Instead of targeting the tumor itself, immunotherapies work by directing patients' immune systems to attack their tumors more effectively. This has been especially impactful in improving outcomes for certain difficult-to-treat cancers. Still, fewer than half of all cancer patients respond to current immunotherapies, creating an urgent need to identify biomarkers that can predict which patients are most likely to benefit. Recently, scientists have noticed that patients whose tumors have a mutation in a gene called ARID1A are more likely to respond positively to immune checkpoint blockade, a type of immunotherapy that works by keeping cancer-fighting immune cells called T cells turned "on" when they'd otherwise be turned "off." Since this ARID1A gene mutation is present in many cancers -- including endometrial, ovarian, colon, gastric, liver, and pancreatic cancers -- researchers at the Salk Institute wondered how it contributes to treatment sensitivity, and how clinicians can use this information to customize cancer treatments to each patient. The new study, published in Cell on May 15, 2024, reveals that ARID1A mutation renders tumors sensitive to immunotherapy by inviting cancer-fighting immune cells into the tumor through an antiviral-like immune response. The researchers suggest this mutation and antiviral immune response could be used as a biomarker to better select patients for specific immunotherapies, like immune checkpoint blockade. The findings also encourage the development of drugs that target ARID1A and related proteins as a way of sensitizing other tumors to immunotherapy. "This could really make a difference in patient outcomes from cancer treatment," says Associate Professor Diana Hargreaves, senior author of the study. "These ARID1A mutation cancer patients are already having an immune response, so all we need to do is upregulate that response using immune checkpoint blockade to help them destroy their tumors from the inside." While it was reported that people with ARID1A mutations responded well to immune checkpoint blockade, the exact relationship between the two remained unclear. To elucidate the mechanism behind this, Salk scientists turned to mouse models of melanoma and colon cancer with either mutated ARID1A or functional ARID1A. The team observed a powerful immune response in all animal models with mutated ARID1A tumors but not those with functional ARID1A tumors, supporting the idea that the ARID1A mutation was, indeed, driving the response. But how did this work on a molecular level? "We found that ARID1A plays an important role in the nucleus of keeping DNA properly arranged," says Matthew Maxwell, first author of the study and a graduate student in Hargreaves' lab. "Without functional ARID1A, loose DNA can be excised and escape into the cytosol, which activates a coincidentally desirable antiviral immune response that can be further enhanced by immune checkpoint blockade." The ARID1A gene codes for a protein that helps regulate the shape of our DNA and maintain genome stability. When ARID1A is mutated, a microscopic chain of events analogous to a Rube Goldberg machine is set off in the cancer cell. First, the lack of functional ARID1A leads to escape of DNA into the cytosol. Next, the cytosolic DNA activates an antiviral alarm system -- the cGAS-STING pathway -- since our cells are adapted to flag any DNA in the cytosol as foreign to protect us against viral infections. Finally, the cGAS-STING pathway calls on the immune system to recruit T cells into the tumor and activates them into specialized cancer-killing T cells. With each step relying on the last, this chain of events -- ARID1A mutation, DNA escape, cGAS-STING alarm, T cell recruitment -- results in more cancer-fighting T cells in the tumor. Immune checkpoint blockade can then be used to ensure these T cells stay "on," supercharging them to defeat the cancer. "Our findings provide a novel molecular mechanism by which ARID1A mutation can promote an anti-tumor immune response," says Hargreaves. "What's most exciting about these results is their translational potential. Not only can we use ARID1A mutations to help select patients for immune checkpoint blockade, but we now also see a mechanism by which drugs that inhibit ARID1A or its protein complex could be used to further enhance immunotherapy in other patients." By outlining the mechanism by which immune checkpoint blockade is more effective for ARID1A mutant cancers, the researchers have provided cause for clinicians to prioritize the immunotherapy for patients with mutated ARID1A. The findings are a major step in personalizing cancer treatment and inspiring novel therapies that target and inhibit ARID1A and its protein complex. In the future, the Salk team hopes its findings can improve patient outcomes across the many cancer types associated with ARID1A mutations and is set to explore this clinical translation with collaborators at UC San Diego. Other authors include Jawoon Yi, Shitian Li, Samuel Rivera, Jingting Yu, Mannix Burns, Helen McRae, Braden Stevenson, Josephine Ho, Kameneff Bojorquez Gastelum, Joshua Bell, Alexander Jones, Gerald Shadel, and Susan Kaech of Salk; Marianne Hom-Tedla and Katherine Coakley of Salk and UC San Diego; Ramez Eskander of UC San Diego; and Emily Dykhuizen of Purdue University. The work was supported by the National Institutes of Health (NCI CCSG P30 014195, T32DK007541, R01 CA228211, R01 CA285867, R01 CA216101, R01 CA240909, R01 AI066232, R21 MH128678, S10-OD023689), National Science Foundation, Howard Hughes Medical Institute, Cancer Research Institute, Pew-Stewart Scholars for Cancer Research, American Cancer Society, and Padres Pedal the Cause.