Phase 1/2 trial of PEP-CMV + nivolumab for newly diagnosed diffuse midline glioma/high-grade glioma and recurrent diffuse midline glioma/high-grade glioma, medulloblastoma, and ependymoma (PRiME II)

Washington University, Saint Louis MO

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Abstract

Abstract Brain tumors are the most common cause of cancer death in patients aged 0-19 and treatment advances are elusive. Pediatric high-grade glioma (HGG), diffuse midline glioma (DMG), recurrent medulloblastoma (MB), and recurrent ependymoma (EPN) are devastating diseases. The median overall survival (OS) of these diagnoses are less than 15 months. Current treatments for these malignant tumors typically entail surgical resection or biopsy, radiation, and sometimes chemotherapy. Pediatric HGG, DMG, MB and EPN express human cytomegalovirus (CMV) proteins that are not found in normal brain, thereby providing unique immunotherapeutic targets. Our group has developed a peptide vaccine (PEP-CMV) directed to the CMV antigen, pp65. Results from a recently completed Phase I clinical trial (PRiME, NCT03299309) of 42 patients age 3-35 with recurrent HGG/DMG and MB demonstrated significant antigen-specific T cell immune responses to pp65 and prolonged clinical/imaging responses in many patients. Importantly, PEP-CMV was well tolerated with only 3 Grade 3/4 adverse events. In PRiME, increased immune response to PEP-CMV and favorable baseline immune status (low percentage of immunosuppressive Tregs and high percentage of terminally differentiated cytotoxic T cells [TEMRAs]) were associated with better survival. The addition of checkpoint blockade such as anti-PD-1 therapies has not been explored in immunotherapies targeting CMV, however, it has enhanced the immunogenicity of cancer vaccines in preclinical brain tumor models and other non-brain solid tumors. Anti-PD-1 agents also decrease Tregs and increase TEMRA percentages. Given this, our hypotheses are that 1) the combination of PEP-CMV plus checkpoint blockade will be safe and feasible for the treatment of DMG, HGG, MB, and EPN, 2) the addition of checkpoint blockade will enhance the immunogenicity and effectiveness of PEP-CMV thereby improving survival (compared to PRiME), 3) patients with newly diagnosed DMG/HGG will have significantly more robust immune responses that patients with recurrent DMG/HGG, and 4) PEP-CMV plus checkpoint blockade will produce an antigen-specific response in patients with EPN. Our primary objective is to perform a multi-institutional Phase I/II trial to evaluate the safety, clinical efficacy, and immunogenicity of PEP-CMV plus checkpoint blockade in patients aged 3-35 with recurrent DMG, HGG, MB, or EPN or newly diagnosed DMG and HGG. To attain this objective, the following specific aims will be pursued: Aim 1: Establish the safety and feasibility of PEP-CMV in combination with checkpoint blockade for the treatment of patients with DMG, HGG, MB, or EPN. Aim 2: Determine the clinical outcomes of patients who receive PEP-CMV plus checkpoint blockade. Aim 3: Assess the immunogenicity of PEP-CMV plus checkpoint blockade in patients.