PDL1 x IFNα2

Investigators at Sanford Burnham Prebys found that inhibiting a key metabolic enzyme kills melanoma cells and halts tumor growth, opening the door for a new class of drugs to treat melanoma. "Rarely do we find tumor-specific pathways that signify a tumor type," Ze'ev Ronai, Ph.D., professor and director of the National Cancer Institute (NCI)-designated Cancer Center at Sanford Burnham Prebys, told BioSpace. "Here, the finding of GCDH as a melanoma-specific gene to which the cancer is dedicated to offers novel paths for understanding what makes melanoma unique compared with other tumors, and how this can be exploited therapeutically." The authors write that melanoma has an “addiction to the mitochondrial protein glutaryl-CoA dehydrogenase (GCDH), which functions in lysine metabolism and controls protein glutarylation.” When they inhibited the enzyme, it led to changes in a key protein, called NRF2, which acquires its ability to suppress cancer. GCDH plays a key role in metabolizing lysine and tryptophan, which are essential amino acids. The Ronai laboratory assayed melanoma cells to determine how they generate energy from lysine. They found that GCDH was crucial. “Melanoma cells ‘eat’ lysine and tryptophan to produce energy,” said Sachin Verma, Ph.D., a postdoctoral researcher in the Ronai lab and first author of the study. But using energy from the pathway demands that cancer cells control toxic waste produced during the process. There are six steps in the process, and Verma noted, “We thought the cells would need all six enzymes. But it turns out only one of these enzymes is crucial, GCDH. Melanoma cells cannot survive without the GCDH portion of the pathway.” By inhibiting GCDH in laboratory animals, they were able to suppress the progression of melanoma. Earlier research demonstrated that NRF2 could drive and repress cancer, but they didn’t know how to shift NRF2 from driving cancer to stopping cancer. “Our current study identifies the answer,” Ronai noted. In their research, the animals who did not have GCDH were essentially normal but could not tolerate a high-protein diet. Melanoma patients’ tumors are typically low in GCDH. Because GCDH plays a role in protein processing, the researchers think GCDH-poor tumors might be susceptible to high-protein foods. This suggests the possibility of dietary treatment. Also, decreasing GCDH tumor levels with drugs may be enhanced by specific protein diets. They note that because normal cells that lack GCDH are mostly unaffected, drugs that inhibit GCDH would likely be specific to melanoma cells. Ronai’s laboratory is now collaborating with the Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys to identify potential small molecule GCDH inhibitors. “In the study, we used genetic approaches to inhibit GCDH, which provide the proof of concept to search for small molecules inhibitors,” Verma said. “Indeed, we are actively searching for potential drugs that could inhibit GCDH, which would be candidates for novel melanoma therapies.” Ronai told BioSpace, "We will identify small molecules that can selectively target GCDH, an effort we undertake with our drug discovery center (The Prebys Center) at Sanford Burnham Prebys. The possible use of specific diets or immune checkpoint therapy with GCDH inhibition will also be examined." The research was published in Nature Cell Biology. Meanwhile, other companies are conducting clinical studies with other compounds to treat melanoma. AIM ImmunoTech and Roswell Park Comprehensive Cancer Center announced on Aug. 30 that they had initiated patient enrollment in a Phase II trial in patients with primary PD-1/PD-L1 resistant melanoma. The study will evaluate a type-1 polarized dendritic cell vaccine in combination with a tumor-selective chemokine modulation made up of interferon-alpha 2b, Ampligen (rintatolimod) and Celecoxib. Ampligen is AIM’s dsRNA product candidate. On Aug. 23, Immatics treated the first patient in its Phase Ib expansion cohort C of IMA203CD8, its second-generation TCR-T monotherapy where a proprietary CD8aß co-receptor is added to PRAME-specific IMA203 T cells. PRAME refers to a melanoma antigen preferentially expressed in tumors. Interim data from the company’s Phase Ia trial demonstrated a 50% objective response rate in various solid tumors, including melanoma, head and neck cancer, uveal melanoma and synovial sarcoma.

Phase 2 to evaluate polarized dendritic cell vaccine, interferon alpha-2b, Ampligen and celecoxib for the treatment of HLA-A2+ refractory melanoma First patient dosing is expected in Q4, 2022 OCALA, Fla., Aug. 30, 2022 (GLOBE NEWSWIRE) -- AIM ImmunoTech Inc. (NYSE: American AIM) (“AIM” or the “Company”), an immuno-pharma company focused on the research and development of therapeutics to treat multiple types of cancers, immune disorders, and viral diseases, including COVID-19, the disease caused by the SARS-CoV-2 virus, today announced its clinical development collaborator, Roswell Park Comprehensive Cancer Center (“Roswell Park”), in a clinical trial fully funded by the National Cancer Institute (NCI), has commenced patient enrollment in its Phase 2 study in subjects with primary PD-1/PD-L1 resistant melanoma. The Phase 2 study will evaluate type-1 polarized dendritic cell (αDC1) vaccine in combination with tumor-selective chemokine modulation (“CKM”) comprised of Interferon alpha 2b, Ampligen (rintatolimod) and Celecoxib. “The start of this NCI-funded clinical trial marks an important milestone for our Melanoma R&D program. Despite recent successes of immune checkpoint inhibitors in advanced-stage disease, only a minority of treated melanoma patients have a durable benefit, reinforcing the need to develop second-line therapies that are effective against checkpoint-refractory disease. Based on the data seen to-date, we believe Ampligen, in combination with Roswell’s polarized dendritic cell vaccine plus interferon, has an opportunity to fill this gap and potentially provide clinical benefit to melanoma patients in need,” commented AIM Chief Executive Officer Thomas K. Equels. Ampligen (rintatolimod) is AIM’s dsRNA product candidate being developed for globally important cancers, viral diseases and disorders of the immune system. Ampligen is being evaluated as a combinational therapy for the treatment of a variety of solid tumor types in multiple clinical trials – both underway and planned – at major cancer research centers around the country. The single-arm Phase 2 study plans to enroll up to 24 subjects. Subjects will be on active experimental treatment for 12 weeks. In the absence of disease progression, patients will be followed for progression-free survival (PFS) and overall survival (OS) within routine care. Patients with progressive disease at 12 months can, at the physician’s discretion, begin CTLA-4± PD-1/PDL1 inhibitor treatment and will be followed as per standard of care for this disease group. Patients will continue to be monitored for PFS and OS within standard care visits (every 3 months for up to 2 years). The primary endpoint of the study is objective response rate (ORR) at 12 weeks (only in participants who have completed the first 3 treatment cycles), which will be evaluated using RECIST 1.1 criteria. The trial will be conducted at Roswell Park under the clinical leadership of Igor Puzanov, MD, MSCI, FACP, Chief of Melanoma at Roswell Park, and the overall scientific leadership of Pawel Kalinski, MD, PhD, Roswell Park Chair of Immunology. Enrollment of patients is underway. “We are interested in further exploring the potential of rintatolimod for the treatment of refractory melanoma and appreciate AIM’s participation and collaboration in this study,” said Dr. Kalinski. “Based on the pre-clinical data demonstrated, we believe that combining our vaccine approach with the rintatolimod-based modulation of the tumor microenvironment in a first-in-human trial has potential for converting checkpoint (PD1)-resistant ‘cold’ melanomas into PD1-sensitive ones. We look forward to getting this study underway and remain dedicated to evaluating the potential effectiveness of rintatolimod for this application.” For more information about the Phase 2 study, visit ClinicalTrials.gov: NCT04093323 About Roswell Park Comprehensive Cancer Center Roswell Park Comprehensive Cancer Center is a community united by the drive to eliminate cancer's grip on humanity by unlocking its secrets through personalized approaches and unleashing the healing power of hope. Founded by Dr. Roswell Park in 1898, it is the only National Cancer Institute-designated comprehensive cancer center in Upstate New York. Learn more at , or contact us at 1-800-ROSWELL (1-800-767-9355) or ASKRoswell@RoswellPark.org. About Ampligen Ampligen is AIM’s dsRNA product candidate being developed for globally important cancers, viral diseases and disorders of the immune system. Ampligen has demonstrated in the clinic the potential for standalone efficacy in a number of solid tumors. Additionally, Ampligen has shown success in increasing survival rates and efficacy in the treatment of animal tumors when used in combination with checkpoint blockade therapies. Ampligen is currently being evaluated as a combinational therapy for the treatment of a variety of solid tumor types in multiple clinical trials – both underway and planned – at major cancer research centers around the country. Ampligen is being used to treat pancreatic cancer patients in an Early Access Program approved by the Inspectorate of Healthcare in the Netherlands at Erasmus Medical Center. Additionally, Ampligen is also approved in Argentina for the treatment of severe chronic fatigue syndrome and is currently being evaluated in SARS-CoV-2/COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Post COVID Conditions. About AIM ImmunoTech Inc. AIM ImmunoTech Inc. is an immuno-pharma company focused on the research and development of therapeutics to treat multiple types of cancers, immune disorders, and viral diseases, including COVID-19. The Company’s lead product, Ampligen® (rintatolimod) is an immuno-modulator with broad spectrum activity being developed for globally important cancers, viral diseases and disorders of the immune system. For more information, please visit aimimmuno.com and connect with the Company on Twitter, LinkedIn, and Facebook. Cautionary Statement This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 (the “PSLRA”). Words such as “may,” “will,” “expect,” “plan,” “anticipate” and similar expressions (as well as other words or expressions referencing future events or circumstances) are intended to identify forward-looking statements. Many of these forward-looking statements involve a number of risks and uncertainties. The Phase 2 Clinical Trial discussed above is subject to a number of unknowns including, but not limited to, whether the trial will yield favorable results, and that significant additional testing and trials will be required to determine whether Ampligen, as part of a CKM when combined with a type-1 polarized dendritic Cell (αDC1) vaccine, will be effective in treating melanoma patients with Primary PD-1/PD-L1 Resistance. Among other things, for those statements, the Company claims the protection of safe harbor for forward-looking statements contained in the PSLRA. The Company does not undertake to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof. Investor Relations Contact JTC Team, LLC Jenene Thomas 833-475-8247 AIM@jtcir.com