Tevogen Bio, a clinical stage biotechnology company, announces Dr. Neal Flomenberg, M.D., Professor and Chairman of the Department of Medical Oncology at Thomas Jefferson University, and Chairman of Tevogen’s Scientific Advisory Board, presented data detailing immunologic escape underscoring criticality of Tevogen’s proprietary Cytotoxic T Lymphocyte (CTL) Target Tuning Technology and its investigational CTL therapeutic, TVGN-489, at the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition. ASH’s Annual Meeting convenes virtually and in-person December 11-14, 2021.
Presentation Key Points:
- Much has been written about mutations in the Spike protein. When the immune response is focused primarily on a single target (often referred to as an ‘immunodominant target’), immunologic evolutionary pressure may lead to the emergence of new variants in which that target is eliminated by mutation. This can be true for either humoral (antibody related) or cellular (T cell related) immunity.
- Having a variety of immunologic targets, knowing precisely what each target is and how much each target contributes to the overall immune response is crucial to understanding whether immunotherapies will continue to be active against new variants as they emerge.
- TVGN-489’s in vitro pattern of response illustrates the importance of these issues in cytotoxic T cell therapy. TVGN-489 is a clinical grade product consisting of highly enriched, highly potent CD8+ CTLs recognizing peptides derived from COVID-19. The peptides come from across the entire COVID-19 genome. The cells are derived from healthy donors who have recovered from a prior COVID-19 infection.
- Looking at CTLs from patients infected early in the pandemic restricted by HLA-A*01:01, one peptide target was immunodominant, being responsible for 60% or more of the CTL activity. This was seen across donors and experiments. This peptide, from ORF1ab (not Spike) is lost in 93% of the Delta variant isolates reported to the NIH-NLM database. In contrast, the other targets are preserved in 99-100% of the Delta isolates.
- Thus, the implication is that if CTLs were generated from a donor infected early in the pandemic, prior to the emergence of the Delta variant, by re-stimulation using all potential target peptides, more than half the CTLs (i.e., those recognizing this immunodominant peptide) would be ineffective in eliminating cells infected with the Delta variant.
- By eliminating this immunodominant peptide from the CTL enrichment process, the remaining targets can still be used to generate CTLs to the comparable levels of purity and potency. The resulting product can thus recognize both the older forms of the COVID-19 virus as well as the more recent Delta variant equally effectively.
- Though less information is available about the newer Omicron variant, all of TVGN-489’s targets appear preserved in this variant.
- This illustrates the importance of knowing the precise CTL peptide targets and being able to characterize their individual contributions. With this knowledge, the therapeutic products can be tuned as new variants emerge, in order to maintain high levels of effectiveness in treating infection. It also illustrates that immunodominant epitopes such as the A*01:01 epitope and other epitopes reported previously with respect to A24 are most likely to be eliminated as this provides the biggest boost to the virus’ ability to evade the immune system. The safest approach is to rely on multiple target epitopes rather than to be overly focused on a single or very small number of targets.
Tevogen Bio CEO Ryan Saadi, M.D., M.P.H. said he is encouraged by the data. “There has been recent scientific discussion about a phenomenon referred to as ‘Original Antigenic Sin’ in which the immune system focuses on what it has seen before. This can sometimes make it harder to steer the immune system in the direction we’d like it to go. We’re pleased that our ability to control the peptide mixture used to generate our T cell products allows us to avoid this issue. Simply eliminating the immunodominant peptide from the mixture altogether allowed us to refocus the immune response on the targets retained in the Delta variant,” Saadi said. “We were able to produce a high-quality product, despite the donors’ prior sensitizations with an immunodominant peptide target which we no longer wanted to be the focus of the immune response. This will allow us to continue to generate potent CTLs tailored to whatever variants may emerge as the virus continues to mutate and evolve,” he added.
Details of the presentation at the 63rd ASH Annual Meeting and Exposition are as follows:
Presentation Title: Loss of an Immunodominant HLA-Α *01:01 Restricted Epitope for CD8+ Cytotoxic T Lymphocytes (CTLs) in the Delta Variant of COVID-19: An Example of Immunologic Escape and Implications for Immunologic Treatment
Session Name: Cellular Immunotherapies: Basic and Translational
Presentation Date: Monday December 13, 2021
Presenters: Dr. Neal Flomenberg, M.D., Professor and Chairman of the Department of Medical Oncology at Thomas Jefferson University
The abstract is currently available on the ASH website: https://ashpublications.org/blood/article/138/Supplement%201/738/480005/Loss-of-an-Immunodominant-HLA-01-01-Restricted
TVGN-489 is a highly purified SARS-CoV-2 specific cytotoxic CD8+ T Lymphocyte product which detects targets spread across the entire viral genome. These targeted CTLs are expected to recognize and kill off virally infected cells, allowing the body to replace them with healthy uninfected cells. TVGN-489 has demonstrated strong antiviral activity against SARS-CoV-2 in preclinical studies and is currently undergoing proof of concept clinical trial at Thomas Jefferson University in Philadelphia.
About Tevogen Bio
Tevogen Bio is driven by a team of distinguished scientists and highly experienced biopharmaceutical leaders who have successfully developed and commercialized multiple franchises. In collaboration with key strategic partners, the company moved its lead product from discovery to clinical phase within 12 months of inception, shaving years off the industry’s standard for drug development timelines.
Tevogen leadership believes that affordable personalized immunotherapies are the next frontier of medicine and disruptive business models are required to sustain medical innovation in the post pandemic world. The company’s breakthrough technology overcomes traditional barriers to the broad application of targeted T cell therapies through revolutionary advances in speed to patient and product purity. Tevogen’s focus on organizational and manufacturing efficiency is core to its highly successful biopharma business model and goal to make personalized immunotherapies accessible to the masses for the first time. Tevogen Bio’s research pipeline includes targeted CD8+ T Lymphocyte therapeutics for the treatment of common cancers (NSCLC, Cervical Cancer) and difficult to eradicate serious viral infections (Hepatitis B).
Forward Looking Statements
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