BACKGROUND Poor efficacy and adverse events limit the use of immunotherapy in the treatment of glioblastoma. CD200AR-L, a novel immunotherapy targeting multiple checkpoints with a single peptide inhibitory ligand, activates the immune system by downregulating CD200-inhibitory receptor, PD-1/PD-L1, and CTLA-4. METHODS Single-center, first-in-human, dose-escalation phase 1 clinical trial (NCT04642937) utilizing a 3 + 3 design initiated accrual in 12/2020 at dose level-1; CD200AR-L 3.75micrograms/kg/dose administered on days 1 and 2 by intradermal injection after topical imiquimod. On day 2, a fixed dose of an allogeneic vaccine is also injected intradermally. Induction Phase consists of this injection series weekly for 4 weeks with monitoring for dose-limiting toxicity through day 28. RESULTS Between 12/2020 to 3/2021, 6 patients were enrolled on dose level-1; aged 37-65 years, 4 men, all with KPS >/= 80, and 3 patients on daily dexamethasone (4mg (n=2), 2mg (n=1)). Five were at first recurrence, 1 at second and 5 had cancers MGMT-promoter unmethylated. All completed the 4 weeks of induction. One dose-limiting toxicity of a grade-III encephalopathy was observed. Non-dose-limiting grade-III toxicities included, lymphopenia (n=1) and immunotherapy-related intracranial edema (IrICE) (n=2). IrICE symptoms were temporarily mitigated with ‘bevacizumab rescue protocol.’ No patients had local injection site reactions. Three patients are off study for radiographic disease progression confirmed on pathology (n=1) and radiographic disease progression with progressive neurological decline (n=2). Completed investigational hematologic immune monitoring for 4/6 patients revealed, that between weeks 2 and 4 post-vaccination, evidence of immune stimulation with an increase in CD4/8 T-cells, natural killer, and natural killer T-cells. There was also a reduction in immunosuppressants noted by a decrease in PD-1/PD-L1 and CTLA-4 expression on CD4/8 T-cells, CD14, CD11c, and myeloid-derived suppressor cells. CONCLUSION Initial dosing of CD200AR-L was well tolerated with early positive signal of immunological effect. Enrollment continues, now at dose level-2; CD200AR-L at 5micrograms/kg/dose.
Background: Immunotherapy has revolutionized clinical management of malignancies rendering cancers that previously had a dismal prognosis more manageable. Unfortunately, these therapies can cause serious immune-related adverse events, including death. In CNS cancers, currently available immunotherapies have limited to no efficacy. Our work in glioblastoma (GBM), which is considered one of the most aggressive cancers as well as being universally fatal, is focused on the CD200 immune checkpoint that modulates the immune system through the inhibitory receptor (CD200R1) and activation receptor (CD200AR). The peptide checkpoint ligand (CD200AR-L) was developed to target the CD200AR that downregulates the inhibitory PD-1/PD-L1, CTLA4 and CD200R immune checkpoints, permitting immune system activation that is less hampered by the inhibitory effects of GBM. Following a positive clinical trial in dogs that spontaneously developed high-grade gliomas, we initiated a first-in-human Phase 1 Study of the CD200 Activation Receptor Ligand (CD200AR-L) and Allogeneic Tumor Lysate Vaccine (GBM6-AD) immunotherapy for Recurrent Glioblastoma (NCT04642937). Methods: This is a single-center, first-in-human, dose-escalation Phase 1 clinical trial utilizing a 3+3 design at three dose levels; 3.75micrograms/kg, 5micrograms/kg, and 7.25micrograms/kg. Adults 18 years and old with recurrent GBM and no pre-exiting immune-related condition plus adequate performance score were eligible. Accrual started in December 2020 at dose level 1 with a second cohort having received treatment on dose level 2. CD200AR-L is administered on days 1 and 2 by suprascapular intradermal injection following the application of topical imiquimod. On day 2, a fixed dose of the allogeneic vaccine is injected intradermally at the same site. The “Induction Phase” consists of this injection series weekly for 4 weeks with monitoring for dose-limiting toxicity through Day28. The “Maintenance Phase” doses the vaccine series monthly for 2 months, then the “Booster Phase” doses every eight weeks for 24 months or until end of treatment. Patients are monitored for adverse events, including immune-mediated intracranial edema and other immune-related complications, and their neurological function is scored per NANO criteria. Correlative studies include immune monitoring (including expression of CD200R1, PD1/PD-L1, and CTLA-4) and MRI imaging assessment per iRANO criteria. Citation Format: Michael R. Olin, Elizabeth C. Neil, Anne Eaton, Shannon Lunn, Christopher L. Moertel. First in human CD200 activation receptor ligand and tumor lysate vaccine immunotherapy for recurrent glioblastoma in adults [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT245.
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