Emerging research shows that targeting initial mutations expressed on a tumor cell surface, called clonal mutations, is critical in achieving a durable clinical benefitFor example, lung cancer patients with high levels of clonal neoantigens treated with checkpoint inhibitors experienced significantly better clinical outcomes as shown in multiple retrospective analysesMost immunotherapies have not been designed explicitly to directly target clonal neoantigens which may explain their limitations in solid tumorsIn a Phase 2b clinical study, Gradalis demonstrated that its clonal neoantigen targeting immunotherapy, Vigil®, works best when used in patients with a high level of clonal neoantigen rich tumorsA biomarker for measuring clonal neoantigens may expand the use of certain immunotherapies and support a pan-cancer application DALLAS, Dec. 05, 2023 (GLOBE NEWSWIRE) -- Gradalis, Inc., a clinical-stage biotechnology company developing a personalized anti-cancer therapy for patients with ovarian and other cancers, announced a peer-reviewed publication in Cancers, highlighting the newly discovered critical clinical role of clonal neoantigens in the durable efficacy of immunotherapies in oncology and the potential to use clonal neoantigens as a new biomarker to better identify patients who will best respond to certain immunotherapies. The publication, entitled “Clonal Neoantigen: Emerging ‘Mechanism Based’ Biomarker of Immunotherapy Response”, provides insight into the science and implications of this key discovery. It reviews the potential limitations of certain immunotherapies designed without explicit consideration of clonal neoantigens. This may also explain why clonal neoantigen targeting immunotherapies like Gradalis’ Vigil have shown longer-term overall survival benefits in a randomized controlled trial of patients with solid tumors. The full text of the article can be found here. “It is now possible to identify the external structures, or neoantigens, found on the surface of millions of cells of a patient’s tumor. Using this information and proprietary algorithms, we can identify the neoantigens related to initiating tumor mutations. These are called clonal neoantigens. These clonal neoantigens can be targets for guiding new therapies to eliminate tumor cells. Since these targets can vary in structure and number from patient to patient, targeting them needs to be custom designed, or personalized, for each patient to have the most durable clinical effect. Research shows the more personalized, the better for ensuring long-lasting efficacy,” Gradalis’ Chief Executive Officer Steven Engle stated. “The human immune system has evolved to eliminate errant cells like tumor cells if it can identify them. Vigil is the only therapy in late-stage clinical testing that has been shown in clinical studies to safely enable the immune system to identify tumor cells, and as a result, to generate customized effector cells, which include T cells, and as many types and number as needed, to target the clonal neoantigens. This allows us for the first time go after the root cause of cancer, specifically the mutations that cause it,” Mr. Engle continued. A few of the key findings in this area include: A meta-analysis in 1008 patients across 12 landmark trials of factors associated with Overall Survival response to Checkpoint Inhibitors (CPIs) showed that clonal Tumor Mutational Burden (clonal TMB) was the leading biomarker of clinical benefit with high clinical significance (p = 2.9x10-7)1 when compared to subclonal TMB and other factors.Levels of clonal neoantigens have been shown to predict disease free survival in untreated early-stage lung cancer patients (p ≤ 0.025), not subclonal neoantigens (p = n. s.)2Greater numbers of clonal TMB and clonal neoantigens have been found in tumor cells with stable DNA repair capacity, the homologous recombination proficient (HRP) genetic profile.3 Clonal TMB is a likely surrogate for clonal neoantigen expression on the surface of the tumor cell. “Immunotherapy has improved the outlook for many cancer patients, but its benefit has been limited to a fraction of the total patients in each tumor type. Targeting clonal neoantigens may be key to improving this situation. Clonal neoantigens are tumor initiating mutations and therefore found on the surface of all cells of a patient’s tumor. Clonal mutations expressed on the cancer surface provide a distinguishing difference between cancer cells and normal non-cancer cells. Emerging research shows that targeting clonal mutations may be critical in achieving a durable clinical benefit,” stated John Nemunaitis, MD, Chief Scientific Officer of Gradalis and co-author of the paper. “For example, cancers displaying high levels of clonal neoantigens have been shown to be more responsive to checkpoint inhibitors, a type of immunotherapy used in several tumor types. In multiple retrospective analyses of studies of lung cancer patients treated with CPIs, higher levels of clonal neoantigens are highly correlated with better patient outcomes.” As described in the paper, Vigil is a personalized neoantigen immunotherapy that is designed to enable the immune system to recognize each patient’s unique tumor clonal neoantigens and generate effector cells, including T-cells, to target the clonal neoantigens and thereby provide durable clinical benefit. In a Phase 2b trial, the benefit seen as measured by Recurrence Free Survival (RFS) and Overall Survival (OS) was highest in patients of the HRP type. Patients with the HRP genetic profile have an enhanced ability to maintain their DNA sequences which research indicates results in a higher level of clonal neoantigens. These patients represent approximately 50% of ovarian cancer patients and up to 80% of other cancer types. “There is a major unmet medical need for new therapies in HRP ovarian cancer patients because they do not respond well to standard-of-care therapies like chemotherapy and PARP inhibitors. This represents a major gap in treatment, especially in recurrent ovarian patients of the HRP type where multiple PARPi therapies were withdrawn in 2022,” observed Dr. Nemunaitis. “In its study, Gradalis discovered that Vigil works best when used in clonal neoantigen rich tumors as identified by the HRP genetic test. One of Vigil’s main strengths as a therapy is that it enables the immune systems to “see” the tumor cells and decide on the most effective targets. Vigil’s ability to increase clonal neoantigen targeting effector cells may represent a major breakthrough in achieving more consistent clinical benefit not only with Vigil as monotherapy, but also in combination with other immune therapeutic approaches like checkpoint inhibitors. The company is preparing to initiate a Phase 2 clinical study designed for potential accelerated approval opportunity to evaluate Vigil in platinum-sensitive recurrent ovarian cancer patients with the HRP profile.” David Willoughby, PhD, VP of Genomic Services of Frontage Laboratories Inc. and a co-author, stated “Molecular genomic assessment utilizing next generation and whole exome sequencing is now being increasingly applied to biomarker determination to refine use of targeted immune therapies. Recent research discussed in the article provided several case examples followed by retrospective study assessment that have convincingly demonstrated clonal neoantigens are relevant predictors of response to checkpoint inhibitor therapy. A meta-analysis of over 1000 cancer patients from 12 landmark trials referred to in the publication showed no clinical benefit to CPI therapy in targeting patients with a high level of subclonal TMB, whereas targeting patients with a high level of clonal TMB was found to be highly correlated with better overall survival. The publication summarizes these findings and describes advantages of immunotherapy treatment utilizing clonal neoantigens as a biomarker to define the likelihood of cancer response to immunotherapy.” Rodney Rocconi, MD, Director of Cancer Center and Research Institute at the University of Mississippi Medical Center, co-author and lead Principal Investigator in Gradalis’ Phase 2b study, commented, “There are multiple biomarkers used to predict potential patient response to immunotherapies, but they are not currently focused on the level of clonal neoantigen expression. It may be that use of immunotherapies that help the immune system identify clonal neoantigens will broaden the clinical application of immunotherapies such as checkpoint inhibitors. Work outlined in our review article support characterization of clonal neoantigen as an advancement in defining checkpoint inhibitor activity and logically suggest combination of Vigil with checkpoint inhibitor as a fruitful direction in further clinical testing.” About VigilVigil® is a novel, triple function immunotherapy platform that modifies a patient’s tumor by using bi-shRNA to reduce furin, an enzyme which facilitates immunosuppressive TGF beta protein production, and to maximize DNA expression of GM-CSF, which stimulates the immune system and attracts key immune system effector cells, including T-cells. By utilizing the patient's own tumor as the antigen source, Vigil is designed to elicit an immune response that is specifically targeted and broadly relevant to each patient's unique “clonal” tumor neoantigens. Vigil therapy has been well tolerated in Phase 1, 2a and 2b clinical studies. The company is preparing to initiate a Phase 2 clinical study in platinum-sensitive recurrent ovarian cancer patients with the HRP profile. In VITAL, a multicenter, randomized, double-blind, placebo-controlled Phase 2b trial in Stage III/IV newly diagnosed, frontline ovarian cancer patients, Vigil showed a positive trend in the primary endpoint of recurrence free survival (RFS) in the overall population and a statistically significant improvement in the secondary endpoint of recurrence free survival and overall survival (OS), with a median survival time of three years to date, in patients with the BRCAwt molecular profile. Most importantly in patients with tumors of the HRP type, where there is a high unmet medical need, a greater statistically significant improvement was seen in RFS and OS. Additionally, Phase 1 results in an “all-comer” clinical trial have shown positive signals of activity in 19 different tumor types and some patients treated with Vigil remain in the study 48 months later. Vigil has also demonstrated safety and benefit in two separate pilot studies when administered concurrently or in sequence prior to treatment with check point inhibitor therapy. The sequential treatment results support the hypothesis that Vigil administration prior to starting checkpoint inhibitor therapy may focus the immune effector population to the cancer, potentially enhancing activity and limiting off target side effects. The Vigil manufacturing process takes two days. It does not require the bioreactors and other time consuming and costly processes required by other cell therapies. Following the initial removal of the tumor, a small amount of tumor tissue is shipped to the company’s manufacturing plant in Dallas, Texas where its genetics are modified to produce the immune system enhancing effects. It is then put in vials and stored for in-office intradermal administration by the patient’s physician every three to four weeks for an average four to six month course of treatment. About Gradalis, Inc.Founded in 2006, Gradalis is a privately held, clinical-stage biotechnology company developing a new category of personalized immunotherapy called Vigil, that has been tested in multiple studies in ovarian and other cancer tumor types. Vigil is the first cellular immunotherapy to demonstrate longer-term survival benefits in a randomized controlled trial of patients with solid tumors. The results of the company’s Phase 2b study have been published in Lancet Oncology and presented at the American Society of Clinical Oncology. Vigil is being studied in other women’s cancer types and has shown positive results in combination with checkpoint inhibitors. Gradalis’ Vigil platform uses the patient’s immune system to target the entire tumor. Based on multiple clinical studies, Gradalis has developed a pioneering oncology platform that is designed to decloak the full repertoire of a patient’s tumor antigens, including all clonal neoantigens, reactivate the immune system, and summon key effector cells to deliver a durable clinical response. When combined, these are a powerful Trifecta of anti-cancer activities, potentially eliminating even the elusive metastatic cells, and as shown in Phase 2 clinical studies in ovarian cancer, a potential gamechanger in oncology. Our clinical trials have also demonstrated that Gradalis’ platform is better tolerated compared to standard cancer treatments since Vigil uses the patient’s immune system operating within its natural state of balance rather than in an artificial overdrive as with some technologies. Vigil utilizes proprietary bi-shRNA technology that has been proven to silence multiple genes in a variety of cancers and has the potential to be used in other diseases. Forward-Looking Statements This press release contains forward-looking statements, including, without limitation, statements regarding the success, cost, and timing of our product development activities and clinical trials, our plans to research, develop, and commercialize our product candidates, and our plans to submit regulatory filings and obtain regulatory approval of our product candidates. These forward-looking statements are based on Gradalis’ current expectations and assumptions. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks, and changes in circumstances that may differ materially from those contemplated by the forward-looking statements, which are neither statements of historical fact nor guarantees or assurances of future performance. Important factors that could cause actual results to differ materially from those in the forward-looking statements include but are not limited to: (a) the timing, costs, and outcomes of our clinical trials and preclinical studies, (b) the timing and likelihood of regulatory filings and approvals for our product candidates, and (c) the potential market size for our product candidates. These forward-looking statements speak only as of the date made and, other than as required by law, we undertake no obligation to publicly update or revise any forward-looking statements. This press release does not constitute an offer to sell, or a solicitation of an offer to buy, any securities. Gradalis ContactMark Early(214) 442-8161mearly@gradalisinc.com LifeSci Advisors ContactJoyce Allaire+1 (617) 435-6602jallaire@lifesciadvisors.com 1 Litchfield et al Cell 20212 Russo et al Science 20193 Wu et al Seminars in Cancer Biology 2022; Wolf et al Cell 2019
