An epitope-specific DerG-PG70 LEAPS vaccine modulates T cell responses and suppresses arthritis progression in two related murine models of rheumatoid arthritis

3区 · 医学

Article

作者: Kurko, Julia ; Cress, Steve ; Glant, Tibor T ; Mikecz, Katalin ; Markovics, Adrienn ; Zimmerman, Daniel H ; Steiner, Harold L ; Rosenthal, Kenneth S ; Carambula, Roy E

Rheumatoid arthritis (RA) is an autoimmune joint disease maintained by aberrant immune responses involving CD4+ T helper (Th)1 and Th17 cells. In this study, we tested the therapeutic efficacy of Ligand Epitope Antigen Presentation System (LEAPS™) vaccines in two Th1 cell-driven mouse models of RA, cartilage proteoglycan (PG)-induced arthritis (PGIA) and PG G1-domain-induced arthritis (GIA). The immunodominant PG peptide PG70 was attached to a DerG or J immune cell binding peptide, and the DerG-PG70 and J-PG70 LEAPS vaccines were administered to the mice after the onset of PGIA or GIA symptoms. As indicated by significant decreases in visual and histopathological scores of arthritis, the DerG-PG70 vaccine inhibited disease progression in both PGIA and GIA, while the J-PG70 vaccine was ineffective. Splenic CD4+ cells from DerG-PG70-treated mice were diminished in Th1 and Th17 populations but enriched in Th2 and regulatory T (Treg) cells. In vitro spleen cell-secreted and serum cytokines from DerG-PG70-treated mice demonstrated a shift from a pro-inflammatory to an anti-inflammatory/regulatory profile. DerG-PG70 peptide tetramers preferentially bound to CD4+ T-cells of GIA spleen cells. We conclude that the DerG-PG70 vaccine (now designated CEL-4000) exerts its therapeutic effect by interacting with CD4+ cells, which results in an antigen-specific down-modulation of pathogenic T-cell responses in both the PGIA and GIA models of RA. Future studies will need to determine the potential of LEAPS vaccination to provide disease suppression in patients with RA.

Frontiers in immunology

Current status of immunological therapies for rheumatoid arthritis with a focus on antigen-specific therapeutic vaccines

Review

作者: Zimmerman, Daniel H ; Markovics, Adrienn ; Mikecz, Katalin ; Szekanecz, Zoltan ; Rosenthal, Kenneth S ; Carambula, Roy E

Rheumatoid arthritis (RA) is recognized as an autoimmune joint disease driven by T cell responses to self (or modified self or microbial mimic) antigens that trigger and aggravate the inflammatory condition. Newer treatments of RA employ monoclonal antibodies or recombinant receptors against cytokines or immune cell receptors as well as small-molecule Janus kinase (JAK) inhibitors to systemically ablate the cytokine or cellular responses that fuel inflammation. Unlike these treatments, a therapeutic vaccine, such as CEL-4000, helps balance adaptive immune homeostasis by promoting antigen-specific regulatory rather than inflammatory responses, and hence modulates the immunopathological course of RA. In this review, we discuss the current and proposed therapeutic products for RA, with an emphasis on antigen-specific therapeutic vaccine approaches to the treatment of the disease. As an example, we describe published results of the beneficial effects of CEL-4000 vaccine on animal models of RA. We also make a recommendation for the design of appropriate clinical studies for these newest therapeutic approaches, using the CEL-4000 vaccine as an example. Unlike vaccines that create or boost a new immune response, the clinical success of an immunomodulatory therapeutic vaccine for RA lies in its ability to redirect autoreactive pro-inflammatory memory T cells towards rebalancing the “runaway” immune/inflammatory responses that characterize the disease. Human trials of such a therapy will require alternative approaches in clinical trial design and implementation for determining safety, toxicity, and efficacy. These approaches include adaptive design (such as the Bayesian optimal design (BOIN), currently employed in oncological clinical studies), and the use of disease-related biomarkers as indicators of treatment success.

项与 CEL-4000 相关的新闻（医药）

2024-05-16

·BioSpace

CEL-SCI Corporation Reports Second Quarter Fiscal 2024 Financial Results

VIENNA, Va.--(BUSINESS WIRE)--CEL-SCI Corporation (NYSE American: CVM) today reported financial results for the quarter ended March 31, 2024, as well as key recent clinical and corporate developments. Clinical and Corporate Developments include: In May 2024, CEL-SCI received the go-ahead from the U.S. Food and Drug Administration (FDA) for its confirmatory Registration Study of Multikine* in the treatment of head and neck cancer based on very strong safety and efficacy data from the completed Phase 3 study which enrolled 928 patients. The survival benefit for the target population treated with Multikine vs standard of care alone was so strong and clear that the confirmatory study only needs to enroll 212 people. The FDA agreed with the pre-surgical selection of patients most likely to benefit from Multikine—those with newly diagnosed advanced primary head and neck cancer with no lymph node involvement (determined via PET scan) and with low PD-L1 tumor expression (determined via biopsy). According to statisticians, the Registration Study is highly likely to succeed because it aims to confirm prior findings and to show a 10% absolute survival benefit vs control at 5 years following treatment. In the Phase 3 study, Multikine demonstrated the following in the target population: 28% absolute survival benefit vs control at 5 years Risk of death cut in half compared to control at 5 years 73% survival for Multikine vs 45% in the control at 5 years No safety signals or toxicities vs standard of care More detailed results may be viewed here: LINK In February 2024, CEL-SCI’s cGMP state-of-the-art dedicated manufacturing facility commissioning was completed, a significant milestone toward a regulatory approval of Multikine. In January 2024, the European Medicines Agency’s Paediatric Committee granted CEL-SCI a product-specific waiver of strict requirements for commercialization of cancer drugs in the European Union. The waiver is a significant step forward for Multikine, as it removes a major hurdle on the path towards commercialization in Europe. CEL-4000, CEL-SCI’s LEAPS vaccine technology, was featured in an article titled "Current status of immunological therapies for rheumatoid arthritis with a focus on antigen-specific therapeutic vaccines" published in the peer reviewed journal Frontiers in Immunology. The article articulates how CEL-4000 may deliver a safe and effective therapy for rheumatoid arthritis by rebalancing inflammatory response, without weakening important immune defense mechanisms, risking infections or cancer, as current treatments may. “We are eager to commence our FDA Registration Study to confirm the remarkable overall survival benefits Multikine delivered for patients in our target population. The FDA has acknowledged the great unmet need in this patient population. Through the wealth of data produced in our Phase 3 trial, we were able to identify the precise selection criteria for patients and the corresponding diagnostics to identify these patients prior to surgery. This achievement paved the way for us to get FDA agreement to conduct a study on what could become a pre-surgical standard of care in head and neck cancer,” stated CEL-SCI CEO, Geert Kersten. “We believe the Registration Study is de-risked, thereby building even more confidence in CEL-SCI and our prospects for Multikine in other solid-tumor cancers.” Financial Results Research and development expenses decreased by $2.5 million, or 22%, to approximately $9 million during the six months ended March 31, 2024, compared to $11.5 million for the six months ended March 31, 2023. General and administrative expenses in the six months ended March 31, 2024 were $4.6 million compared to $4.4 million in the six months ended March 31, 2023. During the six months ended March 31, 2024, net loss narrowed by $2.2 million or 14% to $14.0 million, approximately $5.3 million of which are non-cash expenses, from $16.4 million in the prior year period. CEL-SCI raised gross proceeds of approximately $7.75 million through a public offering of common stock during the second fiscal quarter. About CEL-SCI Corporation CEL-SCI believes that boosting a patient’s immune system while it is still intact should provide the greatest possible impact on survival. Multikine is designed to help the immune system "target" the tumor at a time when the immune system is still relatively intact and thereby thought to be better able to mount an attack on the tumor. In the completed Phase 3 study, CEL-SCI studied patients who were newly diagnosed with locally advanced primary squamous cell carcinoma of the head and neck with the investigational product Multikine administered first, before they received the standard of care, which involved surgery followed by either radiation or chemoradiation. The Phase 3 study enrolled 928 patients. Our approach is unique because most other cancer immunotherapies are administered only after conventional therapies have been tried and/or failed. After analyzing data from the Phase 3 study, we have better defined the target population for Multikine, which is locally advanced primary head and neck cancer patients with no lymph node involvement and with low PD-L1 tumor expression. In the Phase 3 study, we observed statistically significant survival in this target population, showing that Multikine cut the risk of death in half at five years vs control. Multikine (Leukocyte Interleukin, Injection) received Orphan Drug designation from the FDA for neoadjuvant therapy in patients with squamous cell carcinoma (cancer) of the head and neck. The Company has operations in Vienna, Virginia, and near/in Baltimore, Maryland. Forward-Looking Statements This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. When used in this press release, the words "intends," "believes," "anticipated," "plans" and "expects," and similar expressions, are intended to identify forward-looking statements. Such statements are subject to risks and uncertainties that could cause actual results to differ materially from those projected. Such statements include, but are not limited to, statements about the terms, expected proceeds, use of proceeds and closing of the offering. Factors that could cause or contribute to such differences include an inability to duplicate the clinical results demonstrated in clinical studies, timely development of any potential products that can be shown to be safe and effective, receiving necessary regulatory approvals, difficulties in manufacturing any of the Company's potential products, inability to raise the necessary capital and the risk factors set forth from time to time in CEL-SCI's filings with the Securities and Exchange Commission, including but not limited to its report on Form 10-K for the year ended September 30, 2023. The Company undertakes no obligation to publicly release the result of any revision to these forward-looking statements which may be made to reflect the events or circumstances after the date hereof or to reflect the occurrence of unanticipated events. * Multikine (Leukocyte Interleukin, Injection) is the trademark that CEL-SCI has registered for this investigational therapy. This proprietary name is subject to FDA review in connection with the Company's future anticipated regulatory submission for approval. Multikine has not been licensed or approved for sale, barter or exchange by the FDA or any other regulatory agency. Similarly, its safety or efficacy has not been established for any use. CEL-SCI CORPORATION CONDENSED STATEMENTS OF OPERATIONS SIX MONTHS ENDED MARCH 31, 2024 AND 2023 (UNAUDITED) 2024 2023 Operating expenses: Research and development $ 8,981,044 $ 11,476,034 General and administrative 4,580,791 4,350,761 Total operating expenses 13,561,835 15,826,795 Operating loss (13,561,835 ) (15,826,795 ) Interest expense, net (380,397 ) (311,852 ) Other expense (12,183 ) (57,671 ) Net loss (13,954,415 ) (16,196,318 ) Modification of warrants - (171,552 ) Net loss available to common shareholders $ (13,954,415 ) $ (16,367,870 ) Net loss per common share – basic and diluted $ (0.28 ) $ (0.38 ) Weighted average common shares outstanding – basic and diluted 50,228,860 43,513,571 CEL-SCI CORPORATION CONDENSED STATEMENTS OF OPERATIONS THREE MONTHS ENDED MARCH 31, 2024 AND 2023 (UNAUDITED) 2024 2023 Operating expenses: Research and development $ 4,628,535 $ 6,083,488 General and administrative 2,447,413 2,092,758 Total operating expenses 7,075,948 8,176,246 Operating loss (7,075,948 ) (8,176,246 ) Interest expense, net (182,701 ) (159,063 ) Other income (expense) 13,758 (7,500 ) Net loss (7,244,891 ) (8,342,809 ) Net loss available to common shareholders $ (7,244,891 ) $ (8,342,809 ) Net loss per common share – basic and diluted $ (0.14 ) $ (0.19 ) Weighted average common shares outstanding – basic and diluted 52,006,442 43,588,381

临床结果临床3期免疫疗法疫苗财报

2024-03-19

·BioSpace

CEL-SCI’s LEAPS Vaccine Offers Promising New Paradigm to Treat Rheumatoid Arthritis: Published in Frontiers in Immunology

CEL-4000 may deliver safe and effective therapy for RA by rebalancing the inflammatory response, without weakening important immune defense mechanisms, risking infections or cancer, as current treatments may VIENNA, Va.--(BUSINESS WIRE)-- CEL-SCI Corporation (NYSE American: CVM) today announced the peer reviewed scientific journal Frontiers in Immunology published an article regarding CEL-SCI’s Ligand Epitope Antigen Presentation System (LEAPS) technology in the treatment of rheumatoid arthritis (RA) titled: “Current status of immunological therapies for rheumatoid arthritis with a focus on antigen-specific therapeutic vaccines”. CEL-SCI’s LEAPS team, along with outside collaborators from U.S. and Europe, reviewed published/presented results from pre-clinical animal model of antigen-specific LEAPS therapeutic vaccines, such as CEL-4000 and CEL-5000, made specific for the treatment of RA, and compared these findings with published results of other RA-therapies that either suppress or alter the immune response in order to treat RA. In the article, the authors note that the currently available therapeutic arsenal for the treatment of RA consists mainly of immunosuppressive or ablative drugs, which may carry the potential risk of facilitating recurrent or primary infectious diseases or cancer. They also underscore that a therapeutic vaccine that can rebalance the inflammatory disease process, promoting antigen-specific disease-directed T cell immune responses, is highly desirable. CEL-4000, an antigen specific immunomodulating vaccine, is provided as a new treatment paradigm that should deliver therapy for RA without weakening important immune defense mechanisms against microbial infections or cancer. The authors also emphasized that the most appropriate way to advance the LEAPS vaccines to the clinic would be an adaptive study design for clinical trials, enrollment of patients with early-stage RA, and using the Bayesian optimal design model, currently used in oncology studies, as well as the use of disease-related biomarkers to ascertain responsiveness to treatment and introduce additional tools to assess outcome at the disease level. “At CEL-SCI, we focus on utilizing a healthy immune system to overcome disease safely and with minimal side effects. Our LEAPS platform, and CEL-4000 specifically approaches the treatment of auto immune diseases like rheumatoid arthritis in a completely different way. By rebalancing the immune system to its original healthy state, CEL-4000 could protect patients from the risk of cancer and infection,” stated CEL-SCI CEO, Geert Kersten. “The growing body of preclinical data on LEAPS supports the advancement of this asset into human studies.” About CEL-SCI Corporation CEL-SCI believes that boosting a patient’s immune system while it is still intact should provide the greatest possible impact on survival. Multikine* (Leukocyte Interleukin, Injection) is designed to help the immune system "target" the tumor at a time when the immune system is still relatively intact and thereby thought to be better able to mount an attack on the tumor. In a Phase 3 study, CEL-SCI studied patients who were newly diagnosed with locally advanced primary squamous cell carcinoma of the head and neck (oral cavity and soft-palate) with the investigational product Multikine administered first, before they received the standard of care, which involved surgery followed by either radiation or chemoradiation. The Phase 3 study enrolled 928 patients. Our approach is unique because most other cancer immunotherapies are administered only after conventional therapies have been tried and/or failed. After analyzing data from the Phase 3 study, we have better defined the target head and neck cancer population for Multikine, which is advanced primary head and neck cancer patients with no lymph node involvement and with low PD-L1 tumor expression. In the Phase 3 study, we observed statistically significant survival data in the final target population, showing that Multikine cut the risk of death in half at five years vs control. We plan to submit the proposed study protocol to the FDA in Q1 2024, with the goal to get FDA buy-in for a confirmatory clinical trial, and also to discuss potential accelerated approval pathways. Multikine (Leukocyte Interleukin, Injection) received Orphan Drug designation from the FDA for neoadjuvant therapy in patients with squamous cell carcinoma (cancer) of the head and neck. The Company has operations in Vienna, Virginia, and near/in Baltimore, Maryland. Forward-Looking Statements This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. When used in this press release, the words "intends," "believes," "anticipated," "plans" and "expects," and similar expressions, are intended to identify forward-looking statements. Such statements are subject to risks and uncertainties that could cause actual results to differ materially from those projected. Such statements include, but are not limited to, statements about the terms, expected proceeds, use of proceeds and closing of the offering. Factors that could cause or contribute to such differences include an inability to duplicate the clinical results demonstrated in clinical studies, timely development of any potential products that can be shown to be safe and effective, receiving necessary regulatory approvals, difficulties in manufacturing any of the Company's potential products, inability to raise the necessary capital and the risk factors set forth from time to time in CEL-SCI's filings with the Securities and Exchange Commission, including but not limited to its report on Form 10-K for the year ended September 30, 2023. The Company undertakes no obligation to publicly release the result of any revision to these forward-looking statements which may be made to reflect the events or circumstances after the date hereof or to reflect the occurrence of unanticipated events. * Multikine (Leukocyte Interleukin, Injection) is the trademark that CEL-SCI has registered for this investigational therapy. This proprietary name is subject to FDA review in connection with the Company's future anticipated regulatory submission for approval. Multikine has not been licensed or approved for sale, barter or exchange by the FDA or any other regulatory agency. Similarly, its safety or efficacy has not been established for any use.

免疫疗法临床结果临床3期孤儿药疫苗

100 项与 CEL-4000 相关的药物交易

登录后查看更多信息