Weiming Shi

Immunologic Escape After Prolonged Progression-Free Survival With Epidermal Growth Factor Receptor Variant III Peptide Vaccination in Patients With Newly Diagnosed Glioblastoma

PURPOSE Immunologic targeting of tumor-specific gene mutations may allow precise eradication of neoplastic cells without toxicity. Epidermal growth factor receptor variant III (EGFRvIII) is a constitutively activated and immunogenic mutation not expressed in normal tissues but widely expressed in glioblastoma multiforme (GBM) and other neoplasms. PATIENTS AND METHODS A phase II, multicenter trial was undertaken to assess the immunogenicity of an EGFRvIII-targeted peptide vaccine and to estimate the progression-free survival (PFS) and overall survival (OS) of vaccinated patients with newly diagnosed EGFRvIII-expressing GBM with minimal residual disease. Intradermal vaccinations were given until toxicity or tumor progression was observed. Sample size was calculated to differentiate between PFS rates of 20% and 40% 6 months after vaccination. RESULTS There were no symptomatic autoimmune reactions. The 6-month PFS rate after vaccination was 67% (95% CI, 40% to 83%) and after diagnosis was 94% (95% CI, 67% to 99%; n = 18). The median OS was 26.0 months (95% CI, 21.0 to 47.7 months). After adjustment for age and Karnofsky performance status, the OS of vaccinated patients was greater than that observed in a control group matched for eligibility criteria, prognostic factors, and temozolomide treatment (hazard ratio, 5.3; P = .0013; n = 17). The development of specific antibody (P = .025) or delayed-type hypersensitivity (P = .03) responses to EGFRvIII had a significant effect on OS. At recurrence, 82% (95% CI, 48% to 97%) of patients had lost EGFRvIII expression (P < .001). CONCLUSION EGFRvIII-targeted vaccination in patients with GBM warrants investigation in a phase III, randomized trial.

Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma

Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation widely expressed in glioblastoma multiforme (GBM) and other neoplasms, but absent from normal tissues. Immunotherapeutic targeting of EGFRvIII could eliminate neoplastic cells more precisely but may be inhibited by concurrent myelosuppressive chemotherapy like temozolomide (TMZ), which produces a survival benefit in GBM. A phase II, multicenter trial was undertaken to assess the immunogenicity of an experimental EGFRvIII-targeted peptide vaccine in patients with GBM undergoing treatment with serial cycles of standard-dose (STD) (200 mg/m(2) per 5 days) or dose-intensified (DI) TMZ (100 mg/m(2) per 21 days). All patients receiving STD TMZ exhibited at least a transient grade 2 lymphopenia, whereas those receiving DI TMZ exhibited a sustained grade 3 lymphopenia (<500 cells/μL). CD3(+) T-cell (P = .005) and B-cell (P = .004) counts were reduced significantly only in the DI cohort. Patients in the DI cohort had an increase in the proportion of immunosuppressive regulatory T cells (T(Reg); P = .008). EGFRvIII-specific immune responses developed in all patients treated with either regimen, but the DI TMZ regimen produced humoral (P = .037) and delayed-type hypersensitivity responses (P = .036) of greater magnitude. EGFRvIII-expressing tumor cells were also eradicated in nearly all patients (91.6%; CI(95): 64.0%-99.8%; P < .0001). The median progression-free survival (15.2 months; CI(95): 11.0-18.5 months; hazard ratio [HR] = 0.35; P = .024) and overall survival (23.6 months; CI(95): 18.5-33.1 months; HR = 0.23; P = .019) exceeded those of historical controls matched for entry criteria and adjusted for known prognostic factors. EGFRvIII-targeted vaccination induces patient immune responses despite therapeutic TMZ-induced lymphopenia and eliminates EGFRvIII-expressing tumor cells without autoimmunity.

Prognostic significance of preoperative MRI scans in glioblastoma multiforme

Tumor necrosis, enhancement, and associated edema in patients with glioblastoma multiforme (GBM) represent biological variables that can be quantitated on preoperative MRI scans. We reviewed 48 highly selected patients, all of whom had supratentorial lesions, had undergone gross total tumor resection, and had received adjuvant treatments (radio- and chemotherapies). None of these patients had had surgery for recurrent tumor resection and none had harbored multifocal tumors. The median age was 50 years. The median Karnofsky performance score was 80. Multivariate analysis using the Cox regression model revealed that the strongest prognostic variable was the amount of tumor necrosis on preoperative scan (P < 0.001), with median survivals of 42, 24, 15, and 12 months for tumor necrosis grades of 0 (7 ‘pts’), I (11 ‘pts’),11 (9 ‘pts’), and III (21 ‘pts’), respectively. The intensity of enhancement of the tumor nodule was another prognostic factor (P = 0.003), with median survivals of 35, 18, and 13.5 months for enhancement grades of 0 (2 ‘pts’), I (22 ‘pts’), and II (24 ‘pts’), respectively. The extent of peritumoral edema had a quadratic effect (P = 0.001), with grades I (19 ‘pts’), II (22 ‘pts’), and III (7 ‘pts’) surviving for 24,12, and 20 months respectively. Location and volume of tumors were not statistically significant predictors of survival (P < 0.05). In conclusion, in this highly selected group, GBM patients with little or no necrosis and with less tumor nodule enhancement on preoperative MRI survive longer than patients with greater amounts of necrosis and greater degrees of tumor enhancement. In addition, a moderate degree of peritumoral edema is associated with worse prognosis.

The natural history of EGFR and EGFRvIII in glioblastoma patients

BackgroundThe epidermal growth factor receptor (EGFR) is over expressed in approximately 50–60% of glioblastoma (GBM) tumors, and the most common EGFR mutant, EGFRvIII, is expressed in 24–67% of cases. This study was designed to address whether over expressed EGFR or EGFRvIII is an actual independent prognostic indicator of overall survival in a uniform body of patients in whom gross total surgical resection (GTR; ≥ 95% resection) was not attempted or achieved.MethodsBiopsed or partially/subtotally resected GBM patients (N = 54) underwent adjuvant conformal radiation and chemotherapy. Their EGFR and EGFRvIII status was determined by immunohistochemistry and Kaplan-Meier estimates of overall survival were obtained.ResultsIn our study of GBM patients with less than GTR, 42.6% (n = 23) failed to express EGFR, 25.9% (n = 14) had over expression of the wild-type EGFR only and 31.5 % (n = 17) expressed the EGFRvIII. Patients within groups expressing the EGFR, EGFRvIII, or lacking EGFR expression did not differ in age, Karnofsky Performance Scale (KPS) score, extent of tumor resection. They all had received postoperative radiation and chemotherapy. The median overall survival times for patients with tumors having no EGFR expression, over expressed EGFR only, or EGFRvIII were 12.3 (95% CI, 8.04–16.56), 11.03 (95% CI, 10.18–11.89) and 14.07 (95% CI, 7.39–20.74) months, respectively, log rank test p > 0.05). Patients with tumors that over expressed the EGFR and EGFRvIII were more likely to present with ependymal spread, 21.4% and 35.3% respectively, compared to those patients whose GBM failed to express either marker, 13.0%, although the difference was not statistically significant. There was no significant difference in multifocal disease or gliomatosis cerebri among EGFR expression groups.ConclusionThe over expressed wild-type EGFR and EGFRvIII are not independent predictors of median overall survival in the cohort of patients who did not undergo extensive tumor resection.

Factors influencing the risk of local recurrence after resection of a single brain metastasis

OBJECT Local recurrence (LR) of a resected brain metastasis occurs in up to 46% of patients. Postoperative whole-brain radiation therapy (WBRT) reduces that incidence. To isolate factors associated with the risk of LR after resection, the authors only studied patients who did not receive adjuvant radiotherapy. METHODS The authors reviewed data from 570 cases involving patients who had undergone resection of a previously untreated single brain metastasis at The University of Texas M. D. Anderson Cancer Center between 1993 and 2006 without receiving postoperative WBRT. All tumors were measured preoperatively on MR images. The resection method (en bloc resection [EBR] or piecemeal resection [PMR]) was noted at the time of surgery. Predictors of LR were assessed using the Cox proportional hazards model. RESULTS The median patient age was 58 years, 55% were male, and 88% had a Karnofsky Performance Scale Score > or = 80. The most common primary cancers were those of the lung (28%), skin (melanoma, 21%), kidney (19%), and breast (11%). Piecemeal resection was performed in 201 patients (35%) and EBR in 369 (65%). Local recurrence developed in 84 patients (15%). The histological type of the primary cancer did not significantly predict LR; however, 7 of 22 patients with sarcoma developed LR (p = 0.16). The authors identified 2 variables that increased the risk of LR. Undergoing PMR carried a significantly higher LR risk than EBR (crude hazard ratio [HR] 1.7, 95% CI 1.1-2.6, p = 0.03). Tumors exceeding the median volume (9.7 cm(3)) had a significantly higher LR risk than those that were < 9.7 cm(3) (crude HR 1.7; 95% CI 1.1-2.6; p = 0.02). In the multivariate analysis, small tumors removed by EBR had a significantly lower LR risk. CONCLUSIONS The LR risk of a single brain metastasis is influenced by biological factors (such as tumor volume) and treatments (such as the resection method). Early administration of postoperative WBRT may be particularly warranted when such negative tumor-related prognostic factors are noted or when treatment-related ones such as PMR are unavoidable.

Multiple brain metastases: a rare manifestation of adenoid cystic carcinoma of the parotid gland

A rare case of multiple hematogenous brain metastases from adenoid cystic carcinoma of the parotid gland is reported. The patient had a parotid tumor that was treated ten years prior to the appearance of the brain metastases. Magnetic resonance imaging (MRI) and histological findings, as well as the radiation therapy response, of this tumor are presented.