B-cell Immunotherapy Research Articles

Abstract CT215: Frontline vaccination with the B-cell peptide compound HER-Vaxx (IMU-131), combined with standard-of-care chemotherapy induces high levels of HER2-specific antibodies mediating ADCC and intracellular phosphorylation inhibition resulting in overall survival benefit in patients with HER2+ metastatic or advanced gastric/GEJ adenocarcinoma - Final results from Phase II/HERIZON study

Abstract Background: HER2, a member of the epidermal growth factor receptor (EGFR) family, is overexpressed in approximately 30% of gastric cancers. HER-Vaxx is a B cell peptide-based anti-HER2 vaccine (IMU-131) comprising trastuzumab’s binding site. Here, we present the results of the randomized open-label, multicenter phase 2 HERIZON trial (NCT02795988), which compared HER-Vaxx plus chemotherapy to chemotherapy alone. The study aimed to evaluate clinical (primary endpoint) and antibody (secondary endpoint) responses in patients with HER2-overexpressing gastric/gastro-esophageal junction (GC) cancer naïve to anti HER2 therapy. Methods: Patients were randomized to chemotherapy alone (n=17) or HER-Vaxx (50µg, recommended phase 2 dose) plus chemotherapy (n=19). In the HER-Vaxx group, patients received the vaccine at days 0, 14, 35, and 77, then every 63 days until disease progression. Chemotherapy consisted of oxaliplatin plus capecitabine and was started at day 0, repeated every 21 days for a maximum of 6 cycles. The clinical responses were assessed by RECIST 1.1 criteria. FACS analysis of PBMCs for immunophenotyping was carried out, as well as in vitro phosphorylation inhibition assays of HER2 and the signaling pathway kinases Akt and MAPK, and mediation of ADCC to characterize the vaccine-induced IgG antibodies. Results: A 42% survival benefit for patients treated with HER-Vaxx plus chemotherapy [median overall survival: 13.9 months (7.5, 14.3)] compared to chemotherapy alone [mOS: 8.3 months (6.0, 9.6)] was shown, which translated into an OS HR of 0.580 (80% 2-sided CI: 0.362, 0.927). A highly significant HER2-specific IgG and IgG1 antibody response at all time points, particularly after 3 or more doses of HER-Vaxx were induced (P<0.001). The HER-Vaxx antibody response correlated well with mediating ADCC (IgG, P=0.003; IgG1, P=0.05) and the anti-tumor effect (IgG, P=0.001; IgG1, P=0.016). Moreover, the HER-Vaxx-induced IgG antibodies exhibited binding to the gastric cancer cell line N87, with capacity to inhibit HER2 signaling pathway kinases Akt and MAPK phosphorylation. It also demonstrated decreased levels of Foxp3+ Tregs (P=0.0013). Conclusions: The previously shown safety profile of HER-Vaxx, along with the improved clinical and antibody responses in HER2-overexpressing GC patients shown here, validate the proof of concept for a first-in-class B-cell immunotherapy based on HER2 B-cell peptides. Clinical trials evaluating further treatment with HER-Vaxx in HER2+ GC are ongoing. Citation Format: Joshua Tobias, Michael Kundi, Erika Garner-Spitzer, Christoph Zielinski, Marina Maglakelidze, Zoran Andric, Zoran Petrovic, Rajnish Nagarkar, Tanuj Chawla, Leslie Mi Ok Chong, Bonnie Nixon, Sharon Yavrom, Nicholas J. Ede, Ursula Wiedermann. Frontline vaccination with the B-cell peptide compound HER-Vaxx (IMU-131), combined with standard-of-care chemotherapy induces high levels of HER2-specific antibodies mediating ADCC and intracellular phosphorylation inhibition resulting in overall survival benefit in patients with HER2+ metastatic or advanced gastric/GEJ adenocarcinoma - Final results from Phase II/HERIZON study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT215.

P1.15-08 Phase 1: IMU-201 (PD1-Vaxx), a B-Cell Immunotherapy as Monotherapy or in Combination with Atezolizumab, in Adults with Non-Small Cell Lung Cancer

Therapies with monoclonal antibodies targeting PD-1 and its ligands are associated with remarkable outcomes and have revolutionized cancer treatment (Honey 2017). However, patients treated with PD-1/PD-L1 blockade may develop “a primary or secondary resistance” to therapy (Sharma, Hu-Lieskovan et al. 2017).Contrary to monoclonal antibodies, chimeric B-cell cancer vaccines have the advantage of producing polyclonal B-cell antibodies that can potentially induce memory B- and T-cell responses, while reducing immune evasion and suppression.

IMPRINTER: An open label, multicenter, dose escalation/expansion, phase 1 study of imu-201 (PD1-Vaxx), a B-cell immunotherapy as monotherapy or in combination with atezolizumab, in adults with non-small cell lung cancer (IMU.201.101).

e21134 Background: Therapies with monoclonal antibodies targeting PD-1 and its ligands are associated with remarkable outcomes and have revolutionized cancer treatment (Honey 2017). However, patients treated with PD-1/PD-L1 blockade may develop “a primary or secondary resistance” to therapy (Sharma, Hu-Lieskovan et al. 2017). Contrary to monoclonal antibodies, chimeric B-cell cancer vaccines have the advantage of producing polyclonal B-cell antibodies that can potentially induce memory B- and T-cell responses, while reducing immune evasion and suppression. The hypothesis is that a polyclonal induced B-cell antibody response will be more effective or as effective with improved safety over current monoclonal antibody therapy. IMU-201 (PD1-Vaxx) is being developed using an active immunization approach to treat cancers that overexpress PD-L1 by inducing the production of anti-PD-1 antibodies with a peptide epitope designed to stimulate polyclonal antibodies against PD-1 (Kaumaya et al. 2020). Methods: The IMPRINTER study is an ongoing open-label dose escalation study of IMU-201 as monotherapy (Phase 1) or in combination with atezolizumab (Phase 1b) for patients with PD-L1 expressing non-small cell lung cancer (NSCLC). All patients enrolled in Phase 1 of the study must have previously received an immune checkpoint inhibitor and experienced disease progression. The primary objective is to evaluate the safety and tolerability of IMU-201 and identify the optimal biological dose (OBD). The secondary objective is to evaluate the efficacy of IMU-201 as monotherapy and in combination with atezolizumab. Humoral and cellular immunogenicity data will be evaluated, including IMU-201 and PD-1 specific antibodies (IgG, IgM), vaccine-specific cytokine levels, and regulatory and effector T and B cells. IMU-201 is administered by intramuscular (IM) injection on Day 1, Day 15, and Day 29. Dose-limiting toxicity (DLT) assessment is completed after 29 days on treatment. Tumor progression is evaluated according to RECIST 1.1 at Day 43 then every 42 days until progression or withdrawal. Results: In Phase 1, four patients were enrolled into each of the three cohorts at 10 μg/dose, 50 μg/dose and 100 μg/dose IMU-201 with no DLTs observed. In the 10 μg/dose cohort, one patient achieved CR and one patient SD; in the 50 μg/dose cohort, four patients achieved SD; and in the 100 μg/dose cohort, one patient achieved PR and two patients achieved SD. Within the 100 μg/dose cohort, one patient experienced an immune related pneumonitis after two IMU-201 administrations and discontinued from study treatment. Conclusions: IMU-201 had no observed DLT and demonstrated preliminary signs of efficacy. The study will therefore move into Phase 1b with IMU-201 being assessed in combination with atezolizumab. Clinical trial information: NCT04432207.

1367TiP IMPRINTER: An open label, multi-center, dose escalation/expansion, phase I study of IMU-201 (PD1-Vaxx), a B-cell immunotherapy, in adults with non-small cell lung cancer

Therapies with monoclonal antibodies targeting PD-1 and its ligands are associated with remarkable outcomes in various cancers and, together with antibodies targeting CTLA-4, have revolutionized cancer treatment (Honey 2017). Some patients treated with PD-1/PD-L1 blockade may develop a primary or secondary resistance” to therapy (Sharma, Hu-Lieskovan et al. 2017). The hypothesis is that a polyclonal induced B-cell antibody response will be more effective or as effective with improved safety over current monoclonal antibody therapy.

Abstract CT128: IMU-201-101 - an open-label, multi-center, dose escalation/expansion, phase 1 study of IMU-201 (PD1-Vaxx), a B-cell immunotherapy, in adults with non-small cell lung cancer

Abstract Background: The inhibitory immune pathway, consisting of the receptor programmed cell death 1 (PD-1) and its ligands, PD-L1 and PD-L2, plays a vital role in the maintenance of peripheral tolerance. Therapies with monoclonal antibodies targeting PD-1 and its ligands are associated with remarkable response rates in various cancers. Imugene is proposing to develop an anti-PD-1 immunotherapy using a vaccine approach to treat patients with tumors that over-express PD-L1. The hypothesis is that a polyclonal-induced B-cell antibody response will be more effective or as effective with improved safety over current monoclonal antibody therapy. IMU-201, is a B-cell epitope (amino acids 92-110 from PD-1) linked to a promiscuous T cell epitope (amino acid residues 288-302 from measles virus fusion protein) via a 4-amino acid linker (G-P-S-L), combined in an aqueous phase vaccine to be emulsified in Montanide ISA 720 VG, to form the drug product. Study Design: IMU-201-101 is a 2-part open-label dose escalation/dose expansion study of IMU-201. Part 1 will dose escalate IMU-201 as monotherapy and in combination with Standard of Care (SOC) treatment to evaluate safety, tolerability and immunogenicity and assess the optimal biologic dose (OBD) of IMU-201. Part 2 will expand the number treated with IMU-201 at OBD in combination with SOC treatment. OBD is defined as the dose resulting in the best safety/tolerability and immunogenicity and will be determined after all dose cohorts have completed Day 29 of Part 1. A total of approximately 30 adult patients aged 18 years with NSCLC expressing PD-L1 will be enrolled in the study at sites in North America and Australia. In Part 1, three cohorts (25, 125 and 250 µg of IMU-201) of 3-6 participants per cohort are anticipated to establish the Optimum Biological Dose (OBD) of IMU-201 as monotherapy (mOBD). After establishing mOBD, combination dose escalation will combine IMU-201 with SOC treatment which may include ICI, chemotherapy or their combination, to establish combination OBD (cOBD). The starting dose for combination dose escalation will be one dose level below mOBD. The same dosing schedule of IMU-201, DLT criteria, and dose escalation rules will be used to establish mOBD and cOBD. In Part 2, the number of patients treated in combination with IMU-201 at cOBD will be expanded to 12 patients. Patients will receive IMU-201 at Baseline/Day 1, Day 15 and Day 29. Dosing with IMU-201 will continue at Day 64 (± 7 days) and every subsequent 63 days (± 7 days) until progressive disease or complete response. Therapy may continue beyond progression if the treating physician feels that the patient is deriving benefit. Primary Objectives: To evaluate the safety/tolerability and immunogenicity of IMU-201 as monotherapy and in combination with SOC treatment. To identify OBD of IMU-201 as monotherapy and in combination with SOC treatment. To evaluate changes in immunological, biochemical and additional radiological markers of tumor progression in patients treated with IMU-201 as monotherapy and in combination with SOC treatment. To evaluate changes in humoral and cellular immunogenicity data including PD-1 specific antibodies (IgG, IgM), vaccine-specific cytokine levels and regulatory and effector T and B cells. Citation Format: Pravin Kaumaya, Tanios Bekaii-Saab, Tri Phan, Mark T. Marino, Nick Ede, Anthony Good. IMU-201-101 - an open-label, multi-center, dose escalation/expansion, phase 1 study of IMU-201 (PD1-Vaxx), a B-cell immunotherapy, in adults with non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT128.

A new identified CD20-spliced protein as potential target for T cell-based immunotherapy in B-cell lymphoma/leukemia patients

A new identified CD20-spliced protein as potential target for T cell-based immunotherapy in B-cell lymphoma/leukemia patients

Updates on B-cell immunotherapies for systemic lupus erythematosus and Sjogren's syndrome

Last year was marked by important clinical and mechanistic studies that improved our understanding of B-cell immunotherapy for systemic lupus erythematosus (SLE) and Sjogren's syndrome. Here, we will highlight the most relevant studies published in the last 18 months. The highlight of the year was the approval of belimumab on the basis of two major trials. On the flip side, the disappointing results of rituximab in lupus nephritis provided a clinical and mechanistic counterpoint in SLE. Still, major limitations in the LUpus Nephritis Assessment with Rituximab (LUNAR) trial, positive subset analysis and new open studies and registries continue to provide hope for and major insights into the use of B-cell depletion. In Sjogren's syndrome, the role of B-cell depletion has been further investigated, both for glandular and extraglandular manifestations of the disease with mixed results in a disease in which outcomes are notoriously hard to measure. The approval of anti-B cell activating factor therapy and an increasing body of open studies with rituximab as well as subset studies and secondary analysis of the Efficacy and Safety of Rituximab in Moderately-to-Severely Active Systemic Lupus Erythematosus (EXPLORER) and LUNAR trials provide hope for B-cell immunotherapy and significant insight into its mechanisms of action and utilization in a selected subset of patients. Ongoing clinical trials of other B-cell targeting agents are eagerly anticipated.

Anti-BR3 antibodies: a new class of B-cell immunotherapy combining cellular depletion and survival blockade

AbstractRemoval of pathogenic B lymphocytes by depletion of monoclonal antibodies (mAbs) or deprivation of B-cell survival factors has demonstrated clinical benefit in both oncologic and immunologic diseases. Partial clinical responses and emerging data demonstrating incomplete B-cell depletion after immunotherapy fuels the need for improved therapeutic modalities. Lessons from the first generation of therapeutics directed against B-cell-specific antigens (CD20, CD22) are being applied to develop novel antibodies with additional functional attributes. We describe the generation of a novel class of B-cell-directed therapy (anti-BR3 mAbs) that combines the depleting capacity of a therapeutic mAb and blockade of B-cell-activating factor (BAFF)–BR3 B-cell survival. In mice, treatment with antagonistic anti-BR3 antibodies results in quantitatively greater reduction in some B-cell subsets and qualitatively different effects on bone marrow plasma cells compared with BR3-Fc BAFF blockade or with anti-CD20 treatment. Comparative analysis of BR3-Fc and anti-BR3 mAb reveals a lower B-cell dependence for BAFF-mediated survival in nonhuman primates than in mice. This novel class of B-cell-targeted therapies shows species characteristics in mice and primates that will guide translation to treatment of human disease.

Clinical virology in real time.

The ability to detect nucleic acids has had and still has a major impact on diagnostics in clinical virology. Both quantitative and qualitative techniques, whether signal or target amplification based systems, are currently used routinely in most if not all virology laboratories. Technological improvements, from automated sample isolation to real time amplification technology, have given the ability to develop and introduce systems for most viruses of clinical interest, and to obtain clinical relevant information needed for optimal antiviral treatment options. Both polymerase chain reaction (PCR) and nucleic acid sequence-based amplification (NASBA) can currently be used together with real time detection to generate results in a short turn-around time and to determine whether variants relevant for antiviral resistance are present. These new technologies enable the introduction of an individual patient disease management concept. Within our clinical setting, we have introduced this e.g. for quantitative detection of Epstein–Barr Virus (EBV) in T-dell depleted allogeneic stem cell transplant patients. This enabled us to develop models for pre-emptive anti B-cell immunotherapy for EBV reactivation, thereby effectively reducing not the incidence of EBV-lymphoproliferative disease but the virus related mortality. Furthermore, additional clinically relevant viruses can now easily be detected simultaneously. It also becomes more feasible to introduce molecular testing for those viruses that can easily be detected using classical virological methods, like culture techniques or antigen detection. Prospective studies are needed to evaluate the clinical importance of the additional positive samples detected. It should however be made clear that a complete exchange of technologies is unlikely to occur, and that some complementary technologies should stay operational enabling the discovery of new viruses. The implementation of these molecular diagnostic technologies furthermore warrants the use and introduction of standardized materials as well as participation in international quality control programs. Finally, the use of an internal control throughout the whole procedure not only ensures the accuracy of the results generated, but also is necessary to enable precise quantification of these results and to determine detection thresholds more accurately. Since so many targets do have clinical implications, laboratories might prefer to use universal internal controls before the in-house developed assays should be introduced in clinical virology.