Induction of CD8⁺T-Cell Responses Against Novel Glioma–Associated Antigen Peptides and Clinical Activity by Vaccinations With α-Type 1 Polarized Dendritic Cells and Polyinosinic-Polycytidylic Acid Stabilized by Lysine and Carboxymethylcellulose in Patients With Recurrent Malignant Glioma

Abstract

Purpose A phase I/II trial was performed to evaluate the safety and immunogenicity of a novel vaccination with α-type 1 polarized dendritic cells (αDC1) loaded with synthetic peptides for glioma-associated antigen (GAA) epitopes and administration of polyinosinic-polycytidylic acid [poly(I:C)] stabilized by lysine and carboxymethylcellulose (poly-ICLC) in HLA-A2+ patients with recurrent malignant gliomas. GAAs for these peptides are EphA2, interleukin (IL)-13 receptor-α2, YKL-40, and gp100. Patients and Methods Twenty-two patients (13 with glioblastoma multiforme [GBM], five with anaplastic astrocytoma [AA], three with anaplastic oligodendroglioma [AO], and one with anaplastic oligoastrocytoma [AOA]) received at least one vaccination, and 19 patients received at least four vaccinations at two αDC1 dose levels (1 × or 3 × 107/dose) at 2-week intervals intranodally. Patients also received twice weekly intramuscular injections of 20 μg/kg poly-ICLC. Patients who demonstrated positive radiologic response or stable disease without major adverse events were allowed to receive booster vaccines. T-lymphocyte responses against GAA epitopes were assessed by enzyme-linked immunosorbent spot and HLA-tetramer assays. Results The regimen was well-tolerated. The first four vaccines induced positive immune responses against at least one of the vaccination-targeted GAAs in peripheral blood mononuclear cells in 58% of patients. Peripheral blood samples demonstrated significant upregulation of type 1 cytokines and chemokines, including interferon-α and CXCL10. Nine (four GBM, two AA, two AO, and one AOA) achieved progression-free status lasting at least 12 months. One patient with recurrent GBM demonstrated sustained complete response. IL-12 production levels by αDC1 positively correlated with time to progression. Conclusion These data support safety, immunogenicity, and preliminary clinical activity of poly-ICLC-boosted αDC1-based vaccines.

Pseudoprogression, radionecrosis, inflammation or true tumor progression? challenges associated with glioblastoma response assessment in an evolving therapeutic landscape

“…The main difference from RANO is that iRANO advocates for additional confirmation scans if patients demonstrate PD within the first 6 months of initiating therapy and are neurologically stable. This window of observation was based on clinical data suggesting most immune-related changes appear to occur within the first 6 months of starting immunotherapy [58,59]; however, more investigations are necessary to truly understand the incidence of pseudoprogression in immunotherapies and the dependence of specific immune mechanisms on radiographic changes (e.g. active versus passive immunotherapies; checkpoint inhibitors versus vaccines; etc.).…”

Exosomes isolated from plasma of glioma patients enrolled in a vaccination trial reflect antitumor immune activity and might predict survival

“…14 Here, we have applied this method to isolate and analyze exosomes from plasma of patients with recurrent malignant glioma who were enrolled in a phase I/II clinical trial. The trial was performed at the University of Pittsburgh Cancer Institute 15 testing safety and efficacy of a novel vaccine which contained a-type1 polarized dendritic cells (aDC1) loaded with synthetic peptides specific for glioma-associated antigen (GAA) epitopes in combination with poly(I:C) and poly(ICLC). 15 The trial has demonstrated immunogenicity and clinical activity of this DC-based vaccine.…”

Re-defining response and treatment effects for neuro-oncology immunotherapy clinical trials

“…Extensive necrosis along with a small rim of viable tumor was noted at subsequent autopsy at many of the metastatic sites including the brain lesion [40]. Along the same lines, anecdotal reports highlight the occurrence of pseudoprogression among brain tumor patients treated with a variety of vaccine regimens [38,[41][42][43].…”

“…A growing number of clinical trials evaluating a wide array of immunotherapeutics across a spectrum of cancer indications demonstrate that a subset of patients treated with immunocytokines, cancer vaccines, T cell therapies and immune checkpoint inhibitors will achieve a radiographic response, durable stable disease or enhanced survival despite worsening of early imaging findings [21][22][23][30][31][32][33][34][35][36][37][38]. The most extensive experience derives from recent clinical trials investigating CTLA-4 and PD-1/PD-L1 immune checkpoint inhibitors which are currently being widely evaluated for multiple cancer indications.…”

“…macrophages and CD8? T cells [38] include either significant enlargement of existing lesions or the development of new lesions. In either case, irRC recommend that in medically stable patients, progression only be defined once follow-up imaging confirms radiographic findings that meet criteria for tumor progression.…”