Individual Patient-Specific Immunity against High-Grade Glioma after Vaccination with Autologous Tumor Derived Peptides Bound to the 96 KD Chaperone Protein

Abstract

Purpose: Cancer immunotherapy offers hope of a highly specific nontoxic adjuvant treatment. Heat shock protein peptide complexes (HSPPCs) found in cancer cells carry tumor-specific antigenic proteins and can facilitate adaptive and innate immune responses. Here we show that peptides bound to a 96 kD chaperone protein (HSP-96) from brain tissue containing glioblastoma multiforme (GBM) can be used to safely immunize patients with recurrent GBM.Experimental Design: Multimodality immunomonitoring was completed on 12 patients with recurrent GBM before and after immunization with an autologous HSPPC vaccine derived from surgically resected tumor. Clinical endpoints included safety assessments and overall survival.Results: No adverse events attributable to the vaccine were found. Testing of peripheral blood leukocytes before and after vaccination revealed a significant peripheral immune response specific for the peptides bound to HSP-96, in 11 of the 12 patients treated. Brain biopsies of immune responders after vaccination revealed focal CD4, CD8, and CD56 IFNg positive cell infiltrates, consistent with tumor site specific immune responses. Immune responders had a median survival of 47 weeks after surgery and vaccination, compared with 16 weeks for the single nonresponder.Conclusions: These data provide the first evidence in humans of individual patient-specific immune responses against autologous tumor derived peptides bound to HSP-96.

Isolation and Identification of Renal Cell Carcinoma-Derived Peptides Associated with GP96

“…However, these trials have shown a statistically significant benefit to the vaccination of patients with minimal or stable residual disease. In addition, a recent study has demonstrated a general mechanism to elicit individual patient-specific immune responses and appeared to correlate with the clinical outcome showing that immune responders have a median survival of 47 wk compared with 16 wk for the non-responder (28). The adjuvant treatment of RCC was approved by the Russian Ministry of Health (29).…”

Phase II trial of adjuvant immunotherapy with autologous tumor-derived Gp96 vaccination in patients with gastric cancer.

“…Heat shock protein peptide complex 96 can be easily purified from solid tumor and has been safely tested in patients with a variety of solid tumors [11][12][13][14]. In a Phase III trial, no treatment-related grade 3 or 4 adverse events were observed among patients treated with adjuvant HSP vaccine obtained after nephrectomy [3].…”

Immunotherapy for Glioblastoma

“…One HSP of interest, GP96, released following cell death, has been shown to interact with Toll-like receptor 2 (TLR-2) and receptor 4 (TLR-4) on dendritic cells and macrophages. Binding of GP96 to TLR-2 or TLR-4 upon these cells increases expression of co-stimulatory molecules CD80, CD86, and CD40 as well as MHC II, IL-12, and TNF-α expression [74][75][76].…”

“…Eleven patients demonstrated specific peripheral immune responses and seven demonstrated increased immune cell infiltrate in post-vaccine tumor resection samples as well [76]. Bloch et al conducted a phase II study evaluating tumor antigenic peptides in the context of HSP-96 for recurrent GBMs.…”