Vaccination with Irradiated Autologous Tumor Cells Mixed with Irradiated GM-K562 Cells Stimulates Antitumor Immunity and T Lymphocyte Activation in Patients with Recurrent Malignant Glioma

Abstract

Purpose: Recurrent malignant glioma carries a dismal prognosis, and novel therapies are needed. We examined the feasibility and safety of vaccination with irradiated autologous glioma cells mixed with irradiated GM-K562 cells in patients undergoing craniotomy for recurrent malignant glioma. Experimental Design: We initiated a phase I study examining the safety of 2 doses of GM-K562 cells mixed with autologous cells. Primary endpoints were feasibility and safety. Feasibility was defined as the ability for 60% of enrolled subjects to initiate vaccination. Dose-limiting toxicity was assessed via a 3+3 dose-escalation format, examining irradiated tumor cells mixed with 5 × 106 GM-K562 cells or 1 × 107 GM-K562 cells. Eligibility required a priori indication for resection of a recurrent high-grade glioma. We measured biological activity by measuring delayed type hypersensitivity (DTH) responses, humoral immunity against tumor-associated antigens, and T-lymphocyte activation. Results: Eleven patients were enrolled. Sufficient numbers of autologous tumor cells were harvested in 10 patients, all of whom went on to receive vaccine. There were no dose-limiting toxicities. Vaccination strengthened DTH responses to irradiated autologous tumor cells in most patients, and vigorous humoral responses to tumor-associated angiogenic cytokines were seen as well. T-lymphocyte activation was seen with significantly increased expression of CTLA-4, PD-1, 4-1BB, and OX40 by CD4+ cells and PD-1 and 4-1BB by CD8+ cells. Activation was coupled with vaccine-associated increase in the frequency of regulatory CD4+ T lymphocytes. Conclusions: Vaccination with irradiated autologous tumor cells mixed with GM-K562 cells is feasible, well tolerated, and active in patients with recurrent malignant glioma. Clin Cancer Res; 22(12); 2885–96. ©2016 AACR.

Triple combination immunotherapy with GVAX, anti-PD-1 monoclonal antibody, and agonist anti-OX40 monoclonal antibody is highly effective against murine intracranial glioma

“…15 We have shown that vaccination of patients with recurrent malignant glioma with irradiated autologous tumor cell mixed with irradiated GM-K562 cells (analogous to GVAX) leads to lymphocyte activation, specifically marked by significant upregulation of OX40 on CD4+ lymphocytes. 16 We, therefore, hypothesized that antigen-specific stimulation by whole tumor vaccination might synergize with OX40 ligation, which we confirmed in recently published preclinical work. 12 In the current study, we examine triple combination immunotherapy in the GL261 model, simultaneously treating with vaccination, anti-PD-1 antibody, and agonist anti-OX40 antibody.…”

Development of Tumor Cell-Based Vaccine with IL-12 Gene Electrotransfer as Adjuvant

“…In H&E stained histological sections of vaccination sites, no viable cells were observed, and immune cell infiltration coincided with the vaccine mixture injection site in both tumor models. The successful induction of an immune response was also indicated by a delayed type hypersensitivity-like reaction at the vaccination sites, which is generally considered a positive treatment response predictor [39].…”

A systems-based map of human brain cell-type enriched genes and malignancy-associated endothelial changes

“…In a mouse sarcoma model, TNFRSF4 was also expressed on EC which, following TNFRSF4-agonist treatment, responded with (T-cell independent) VCAM-1 expression (Pardee et al, 2010). Thus, one could speculate that TNFRSF4 expression on GBM EC could indicate a role for a direct EC-interaction in the antitumor effect of TNFRSF4-targeted immunotherapy (Curry et al, 2016). TBXA2R and PTGIR encode for prostaglandin receptors, which bind thromboxane A2 and prostacyclin, respectively, products of the short lived intermediate molecule prostaglandin H 2 , generated from arachidonic acid, via cyclooxygenase (COX)-1 or −2.…”