Breakthrough Clinical Results
Tevogen Bio Holdings Inc. announced an update on its development of a cytotoxic T lymphocyte (CTL) therapy targeting Epstein-Barr virus (EBV)-associated lymphomas. The company is using its proprietary ExacTcell™ technology and collaborating with its AI initiative, Tevogen.AI, to select EBV peptides for a potential clinical trial. Preclinical studies are underway to validate CTL responses to the selected peptides. The approach aims to leverage the increasing understanding of EBV-induced tumorigenesis to create a highly specific and scalable CTL therapy for EBV-driven cancers.
Key Highlights
- Development update on EBV-specific CTL therapy for EBV-associated lymphomas.
- Utilizing proprietary ExacTcell™ technology for precision-engineered T cells.
- Collaboration with Tevogen.AI for AI-powered peptide selection.
- Preclinical studies underway to validate CTL responses.
Incidence and Prevalence
Epstein-Barr Virus (EBV) is linked to a variety of lymphomas, with varying degrees of association. It's crucial to differentiate between the incidence and prevalence of these lymphomas and the proportion specifically attributed to EBV. The provided text doesn't offer precise global incidence and prevalence numbers for all EBV-associated lymphomas for a single, recent year. However, it does provide some relevant information:
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Global Burden of EBV-Attributed Malignancies (2017): A study estimated the burden of EBV-attributed Burkitt lymphoma (BL), Hodgkin lymphoma (HL), nasopharyngeal carcinoma (NPC), and gastric carcinoma (GC). In 2017, the combined global incidence of these malignancies was 1.442 million cases, with over 973,000 deaths. Of these, an estimated 265,000 (18%) incident cases and 164,000 (17%) deaths were attributed to EBV. This represents an increase of 36% in incidence and 19% in mortality since 1990. It's important to note that this study only covers four EBV-associated malignancies, and the overall burden is likely higher. Additionally, the attributable fraction of each malignancy to EBV varies.
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EBV as the Leading Cause of Multiple Sclerosis (MS): While not a lymphoma, MS is a chronic inflammatory demyelinating disease. A study found a 32-fold increased risk of MS after EBV infection, suggesting EBV as the leading cause. This highlights the broad impact of EBV on human health beyond lymphomas.
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General Discussion of EBV-Associated Lymphomas: Several sources discuss the various types of EBV-associated lymphomas, including Burkitt lymphoma (BL), Hodgkin lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), and others. These sources emphasize the complex interplay between EBV infection, host immune response, and genetic factors in the development of these lymphomas. However, they don't provide specific global incidence or prevalence data.
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Focus on Specific Lymphomas: Some articles focus on specific EBV-associated lymphomas, such as Burkitt lymphoma or Hodgkin lymphoma, but again, without providing recent global incidence or prevalence figures.
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Need for Comprehensive Data: The lack of precise, up-to-date global incidence and prevalence data for all EBV-associated lymphomas highlights the need for further research and surveillance efforts. The information provided underscores the significant role of EBV in several malignancies and the importance of understanding the global burden of these diseases.
In summary, while the provided text doesn't give the exact numbers requested, it emphasizes the significant role of EBV in certain lymphomas and other malignancies. The 2017 data for four specific EBV-attributed malignancies offers a partial view, with 265,000 incident cases and 164,000 deaths globally. Further research is needed to provide a more complete picture of the global incidence and prevalence of all EBV-associated lymphomas.
Emerging Mechanism of Action
Epstein-Barr Virus (EBV) is implicated in a variety of lymphomas, and recent research highlights several key mechanisms of action (MoA) for emerging therapies:
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Activation of Lytic Viral Infection Combined with Antivirals: This approach aims to disrupt EBV latency, rendering the virus susceptible to antiviral medications. This strategy exploits the virus's own lifecycle.
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Inhibition of EBV-Induced Oncogenic Cellular Signaling Pathways: EBV infection can dysregulate cellular pathways that promote cancer development. Therapies targeting these pathways, such as B-lymphocyte-induced maturation protein 1 (BLIMP1), aim to restore normal cellular function and control malignant growth.
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Adoptive EBV-Specific T-Cell Therapies: This personalized approach involves engineering a patient's own T-cells to specifically target and eliminate EBV-infected cells. This leverages the power of the immune system to combat the virus and associated lymphomas. Specifically, T-cells targeting EBV latent membrane proteins (LMPs) have shown promise. Donor-derived LMP-specific T-cells are also being explored, particularly for patients who have undergone allogeneic hematopoietic stem-cell transplantation.
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EBV Vaccines: Preventative and therapeutic vaccines are under development to either prevent EBV infection or control established EBV-associated diseases. These vaccines aim to train the immune system to recognize and eliminate EBV-infected cells.
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Immune Checkpoint Inhibitors: These therapies block immune checkpoints like programmed death protein 1 (PD1) and its ligand (PDL1), which are often exploited by EBV-associated lymphomas to evade immune surveillance. By inhibiting these checkpoints, the immune system can be reactivated to target and destroy the malignant cells.
These emerging MoAs represent significant advancements in the treatment of EBV-associated lymphomas, offering hope for improved outcomes for patients.
Drug used in other indications
EBV-specific cytotoxic T lymphocyte (CTL) therapy has shown promise in treating EBV-associated lymphomas and is being explored for other EBV-related malignancies and conditions. Here's a summary of those applications and the intervention models used in clinical trials:
1. Nasopharyngeal Carcinoma (NPC):
- Intervention Model: A phase III trial (NCT02578641) investigated first-line gemcitabine and carboplatin (GC) chemotherapy combined with EBV-CTL versus GC alone in patients with recurrent or metastatic NPC. While the combination showed a favorable safety profile, it did not improve overall survival compared to chemotherapy alone.
- Other Studies: Other studies have explored EBV-CTL as a standalone therapy or in combination with chemotherapy in recurrent or metastatic NPC, with some showing durable responses but low overall response rates.
2. Post-transplant Lymphoproliferative Disorder (PTLD):
- Intervention Model: EBV-CTLs have been used as both prophylaxis and treatment for PTLD in solid organ transplant recipients. Studies have shown that autologous or donor-derived EBV-CTLs can increase EBV-specific killing in vivo, reduce viral load, and induce remission in some patients.
- Challenges: The efficacy of EBV-CTLs in the post-transplant setting can be limited by the need for continued immunosuppression, which can compromise CTL function. Strategies to overcome this include generating CTLs resistant to immunosuppressants or using third-party donor-derived CTL banks.
3. Hodgkin's Disease:
- Intervention Model: Studies have investigated the use of autologous and allogeneic EBV-CTLs in patients with relapsed EBV-positive Hodgkin's disease. Some patients have achieved complete remission after CTL infusion, with evidence of CTL persistence, trafficking to tumor sites, and reduction in viral load.
- Challenges: The efficacy of EBV-CTLs in Hodgkin's disease can be hampered by tumor-derived immunosuppressive factors. Strategies to address this include engineering CTLs to express immunostimulatory cytokines like IL-12.
4. Chronic Active EBV Infection (CAEBV):
- Intervention Model: Case reports have described the use of autologous CTLs and lymphokine-activated killer (LAK) cells in patients with severe CAEBV. While some improvements in symptoms and viral load have been observed, the overall efficacy of this approach appears limited.
5. Other EBV-associated malignancies:
- EBV-CTL therapy is also being explored for other EBV-associated malignancies, including Burkitt's lymphoma, gastric cancer, and NK/T-cell lymphoma. However, data on the efficacy of EBV-CTLs in these settings are limited.
Overall, EBV-CTL therapy holds promise for various EBV-related conditions beyond lymphomas. However, further research is needed to optimize treatment strategies, overcome challenges related to immunosuppression and tumor microenvironment, and determine the long-term efficacy of this approach.