Abstract P100: Use of a novel checkpoint inhibitor peptide ligand in a first-in-human phase 1 trial for adults with recurrent glioblastoma

Abstract

Abstract Cancer immunotherapy has revolutionized clinical management for many systemic malignancies by generating durable control and rendering a significant improvement on an otherwise dismal prognosis. Unfortunately, these therapies often elicit adverse events including autoimmunity and death. In addition, these therapies are not successful in all solid tumors and show no effect on cancers of the central nervous system. Our research is on the CD200 checkpoint that modulates the immune system through the inhibitory receptor (CD200R1) and activation receptors (CD200ARs). We demonstrated that targeting CD200ARs with our checkpoint inhibitor peptide ligand (CD200AR-L) activates the immune system and renders it impervious to the inhibitory effects of the tumor-associated protein, CD200. In a preclinical trial in pet dogs with spontaneous high-grade glioma (n=31), CD200AR-L added to tumor lysate vaccines increased the median OS and PFS compared to TL alone. We suggest these results were due to the ability of CD200AR-L to modulate multiple immune checkpoints. During the characterization of CD200AR-L, we discovered signaling molecules shared by the CD200 and PD-1/PD-L1 pathways, suggesting that these immune checkpoints are interconnected. We initiated a first-in-human, single-center dose-escalation phase 1 clinical trial (NCT04642937) utilizing a 3+3 design. Induction therapy consisted of injection of CD200AR-L (3.75 ug/kg BW) with an allogeneic-brain allogeneic brain tumor vaccine (GBM6-AD) weekly for 4 weeks while monitoring for dose-limiting toxicities. Six patients enrolled in this first cohort; 5 patients were at first recurrence and 1 at second, 5 had MGMT-promoter unmethylated cancers. Although all patients completed induction, one experienced a dose-limiting toxicity of grade III encephalopathy. Non-dose limiting toxicities included lymphopenia (n=1) and immunotherapy-related cerebral edema (n=2) that was mitigated with a bevacizumab rescue protocol. There were no local injection site reactions or other grade I-II toxicities. Three patients were taken off study for radiographic disease progression that was confirmed by histopathology (n=1) or by progressive neurological decline (n=2). The patient with 2 prior recurrences remains stable with no progression on protocol-directed maintenance therapy. . Immune stimulation, completed in 3 of 6 patients, correlated with increases in CD4/CD8 T cells, NK and NKT cells between weeks 2 and 4 post vaccination. A reduction in immunosuppression was documented by decreases in the expression of CD200R1, PD-1, PD-L1 and CTLA4 on CD4/8 T-cells, CD14, CD11c and MDSC populations compared to basline (n=5). The ability of PBMCs to overcome immunosuppression was shown by increases in IL-2, IL-6 and TNF alpha between weeks 2 and 4 after restimulation with PHA. Immune memory was suggested in 2 patients by increases in IFNg and TNFa. CONCLUSION: Therapy with CD200AR-L in combination with GBM6-AD was well -tolerated with early evidence of an immunological response. Dose escalation enrollment in the Phase 1 Trial continues. Citation Format: Michael R. Olin, G. Elisabeth Pluhar, Ingunn Stromnes, Anne Eaton, Shannon Lynn, Emily Greengard, Christopher L. Moertel. Use of a novel checkpoint inhibitor peptide ligand in a first-in-human phase 1 trial for adults with recurrent glioblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P100.