Editor's Note: At ICML conference, Professor Jose C. Villa Boas from Rochester, USA, was invited to present an oral report titled "EO2463 Peptide Immunotherapy in Combination with Lenalidomide and Rituximab for Patients with Follicular Lymphoma and Marginal Zone Lymphoma," detailing the latest data from the Phase 1/2 international multicenter Sydney study, bringing new treatment hope for patients with relapsed/refractory Follicular Lymphoma (FL) and Marginal Zone Lymphoma (MZL). ICML18 Focus: New Immunotherapy Strategies for Non-Hodgkin Lymphoma At the highly anticipated ICML18 conference, Professor Villa Boas, representing a multinational research team, delved into the innovative concepts and preliminary results of EO2463 peptide immunotherapy in the treatment of B-cell lymphoma. This research aims to explore a "ready-to-use" peptide immunotherapy that, through molecular mimicry, activates existing anti-bacterial immune responses in patients to target lymphoma cells. As an innovative therapy, the safety, tolerability, immunogenicity, and anti-tumor activity of EO2463 in combination therapy were the core highlights of this report, providing important references for future non-Hodgkin lymphoma treatment strategies.
19- EO2463 Peptide Immunotherapy: Innovation Based on the Oncomimics Concept
EO2463 is a “ready-to-use” peptide immunotherapy based on the “Oncomimics” concept, whose uniqueness lies in leveraging the host’s pre-existing immune memory to common bacterial antigens to attack tumor cells. Professor Villa Boas pointed out that EO2463 contains four HLA-A2 (Human Leukocyte Antigen-A2) restricted peptides, which are derived from intestinal mycobacteria but structurally exhibit molecular mimicry with B-cell antigens (including CD20, CD22, CD37, and BAFF receptor). Through this mechanism, EO2463 can utilize patients’ pre-existing CD8-positive T-cell immunity against bacterial antigens to achieve targeted clearance of B-cell malignancies. Additionally, the vaccine also includes a UCP2 (a CD4 epitope) aimed at enhancing the overall immune response. This innovative strategy is expected to open new avenues for the treatment of B-cell lymphoma.
Sydney Study Design: Assessing the Safety and Efficacy of EO2463 in Combination with R-squared
The Sydney study is an international, multicenter, Phase 1/2 clinical trial designed to enroll HLA-A2-positive patients with relapsed or refractory Follicular Lymphoma and Marginal Zone Lymphoma who have previously received at least one line of systemic therapy. The primary objective of the study is to determine the recommended Phase 2 dose of EO2463 and to evaluate the safety and tolerability of EO2463 in combination with lenalidomide and rituximab (ER²). Secondary endpoints include immunogenicity assessment and evaluation of anti-tumor activity by PET/CT (Positron Emission Tomography/Computed Tomography) according to Lugano 2014 criteria. The study protocol consists of three treatment phases: first, patients receive bi-weekly subcutaneous peptide injections four times during the induction phase; followed by a maintenance phase with injections every four weeks for up to 15 injections or approximately one year. Lenalidomide was administered starting from week 7 in Cohort 1 at a dose of 20 mg, taken for 21 days within a 28-day cycle, for a total of 12 cycles, allowing researchers to evaluate the activity of EO2463 monotherapy. In Cohort 4, lenalidomide was administered starting from week 1. Rituximab began at week 19, with a dosing schedule similar to conventional treatment regimens.
Safety and Tolerability: Combination Regimen Performed Well
As of May 5, 2025, 22 patients were evaluable for safety. The median age of patients was 60 years, with most patients having Follicular Lymphoma, predominantly advanced disease, a median of 1 prior line of therapy, and a POD24 (progression of disease within 24 months) rate of 23%. Professor Villa Boas noted that the combination treatment of EO2463 with ER² was well tolerated. The most common adverse event was local injection site reactions, occurring in 68% of patients. Hematologic toxicities were similar to those expected with the lenalidomide and rituximab combination, including any-grade neutropenia in 64% and any-grade thrombocytopenia in 32%. Grade 3/4 adverse events were primarily hematologic toxicities, with 32% being neutropenia. Notably, no Grade 5 adverse events were observed in the study, and only one patient discontinued treatment due to an adverse event. At the data cutoff, 7 patients had completed treatment, 6 patients had discontinued due to disease progression, and 6 patients were still receiving treatment.
Excellent Anti-tumor Activity: Early Efficacy of EO2463 Monotherapy and Combination Treatment
Among 20 patients evaluable for efficacy, the Sydney study demonstrated encouraging anti-tumor activity. In Cohort 1, after only 6 weeks of EO2463 monotherapy, 3 out of 9 patients achieved partial response (PR) as assessed by PET/CT. Professor Villa Boas emphasized that the addition of lenalidomide significantly improved patient response rates. At week 19 (before the introduction of rituximab), the observed overall response rate (ORR) reached 60%, with half being complete responses (CR). By week 42, with all three drugs in effect, the overall response rate further increased to 65%, with a complete response rate as high as 60% (12 out of 20 patients achieved CR). The median time to complete response was 23.1 weeks, and responses were observed across all high-risk patient groups. Professor Villa Boas specifically presented a clinical case: a patient with Follicular Lymphoma recurring after R-CHOP first-line therapy, presenting with mesenteric lymphadenopathy. After 6 weeks of EO2463 monotherapy, PET/CT showed partial response; subsequently, after the addition of lenalidomide and rituximab, the patient’s condition transformed into complete response by week 42. This strongly supports the direct anti-lymphoma activity of EO2463 and its synergistic effect when combined with ER².
In-depth Analysis of Immune Mechanisms: EO2463-Driven CD8+ T-Cell Response
To confirm and elucidate the mechanism of action of EO2463, the research team conducted extensive immune monitoring, including quantifying target-specific CD8-positive T cells using tetramer staining and flow cytometry, and further confirming T-cell activity through peptide stimulation and Interferon-gamma ELISpot (Enzyme-Linked ImmunoSpot assay). Results showed that target-specific CD8-positive T cells were detected in the peripheral blood of 70% of patients, with over half of these patients detectable after a single EO2463 injection (i.e., by week 3). Importantly, a significant correlation was observed between the degree of immune response and complete response. Professor Villa Boas pointed out that patients achieving complete response showed significantly higher immune responses to B-cell target antigens than other patients, confirming that the anti-tumor activity of EO2463 is indeed mediated by the expansion of CD8-positive T cells. The study also detailed a patient’s dynamic immune response: target-specific T cells rapidly and robustly expanded after a single EO2463 injection. This robust immune response was durable, with high levels of target-specific CD8-positive T cells still detectable 94 weeks (approximately 10.5 months) after the last EO2463 injection.
Expert Summary and Clinical Application Outlook: Potential of EO2463 in B-cell Lymphoma
Professor Villa Boas concluded that EO2463 in combination with ER² was well tolerated in patients with Follicular Lymphoma and Marginal Zone Lymphoma, and induced rapid, robust, and durable target-specific CD8-positive T-cell responses. EO2463 monotherapy demonstrated direct anti-lymphoma activity in just 6 weeks (after only three peptide injections). Compared to ER² alone, EO2463 combined with ER² may lead to higher complete response rates. There is a strong correlation between EO2463-driven target-specific CD8-positive T-cell expansion and complete response. During the Q&A session, Dr. Noyer inquired about the details of the peptides. Professor Villa Boas explained: “These HLA-A2-restricted peptides are derived from intestinal mycobacteria, and they mimic antigens on the surface of B cells, including CD20, CD22, CD37, and BAFF receptor. We are utilizing pre-existing CD8-positive memory T-cell populations to ‘cross-react’ with B-cell antigens.” Dr. Zelenetz focused on the frequency of HLA-A2, to which Professor Villa Boas responded: “In Caucasian populations, the frequency of HLA-A2 is expected to be between 50% and 60%, which is why this HLA subtype was chosen for initial studies. Theoretically, after proof of concept and further expansion, additional peptides could be developed for other HLA subtypes.” Regarding future development plans, Professor Villa Boas revealed that the research team is completing enrollment for Cohort 4 (a total of 15 patients) and plans to expand Cohort 4 to a total of 40 patients to further evaluate safety and determine the durability of response. Currently, a feasibility study exploring an optimized ER² dosing regimen with earlier rituximab administration starting at week 7 is also underway. Immune response is expected to become a predictive biomarker for patients treated with EO2463. Based on the safety, early efficacy, and mechanistic data demonstrated by the Sydney study, further development of EO2463 in B-cell lymphoid malignancies is well warranted. This research by Professor Villa Boas and his team not only brings new treatment options for patients with relapsed/refractory Follicular Lymphoma and Marginal Zone Lymphoma but also highlights the global oncology immunotherapy field’s unremitting efforts in exploring innovative therapies, instilling new hope in clinical practice. Contribution/Interview Source: Oncology Outlook – Oncology News — END OF FILE 092中文摘要.txt —
