Guy T. Clifton

Clinical trial results of the HER-2/neu (E75) vaccine to prevent breast cancer recurrence in high-risk patients: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02.

The authors conducted exploratory phase 1‐2 clinical trials vaccinating breast cancer patients with E75, a human leukocyte antigen (HLA) A2/A3–restricted HER‐2/neu (HER2) peptide, and granulocyte‐macrophage colony‐stimulating factor. The vaccine is given as adjuvant therapy to prevent disease recurrence. They previously reported that the vaccine is safe and effective in stimulating expansion of E75‐specific cytotoxic T cells. Here, they report 24‐month landmark analyses of disease‐free survival (DFS).

Incidence rates of exocrine and endocrine pancreatic cancers in the United States

Descriptive studies of pancreatic cancer incidence have been sparse particularly in terms of tumor histology and stage. The purpose of this study was to examine the incidence rate trends of exocrine and endocrine pancreatic cancers by demographic and tumor characteristics using data from the Surveillance, Epidemiology, and End Results (SEER) program from 1977 to 2005. During this period, the incidence of exocrine pancreatic cancer generally decreased whereas the incidence of endocrine pancreatic cancer increased. This difference in trends by histology was evident across age, gender, and racial groups. It was also evident among different racial/ethnic groups using data from 1992 to 2005. Variation in trends was observed by stage. The incidence of exocrine cancers declined for all stages except regional. Endocrine cancer incidence increased for all tumor stages, and the increase was most prominent for localized tumors. When exocrine tumors were stratified by tumor subsite, the incidence of cancers in the tail and body regions increased while the incidence in other regions decreased. While better detection and classification of tumors through improved diagnostic procedures may be related to these changing trends, etiologic factors warrant study.

Use of booster inoculations to sustain the clinical effect of an adjuvant breast cancer vaccine

The authors are conducting clinical trials of the HER‐2/neu E75‐peptide vaccine in clinically disease‐free breast cancer (BC) patients. Their phase 1‐2 trials revealed that the E75 + granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) vaccine is safe and effective in stimulating clonal expansion of E75‐specific CD8+ T cells. They assessed the need for and response to a booster after completion of primary vaccination series.

AE37: a novel T-cell-eliciting vaccine for breast cancer

Introduction: Immunotherapy, including vaccines targeting the human EGFR2 (HER-2/neu) protein, is an active area of investigation in combatting breast cancer. Several vaccines are currently undergoing clinical trials, most of which are CD8+ T-cell-eliciting vaccines. AE37 is a promising primarily CD4+ T-cell-eliciting HER-2/neu breast cancer vaccine currently in clinical trials. Areas covered: This article reviews preclinical investigations as well as findings from completed and ongoing Phase I and Phase II clinical trials of the AE37 vaccine. Expert opinion: Clinical trials have shown the AE37 vaccine to be safe and capable of generating peptide-specific, durable immune responses. This has been shown in patients with any level of HER-2/neu expression. Early clinical findings suggest there may be benefit to AE37 vaccination in preventing breast cancer recurrence.

Comparison of different HER2/neu vaccines in adjuvant breast cancer trials: implications for dosing of peptide vaccines

We have performed multiple adjuvant clinical trials using immunogenic peptides from the HER2/neu protein (AE37/E75/GP2) plus (GM-CSF) given intradermally to breast cancer patients. Four trials were performed with similar dose-escalation design with increasing doses of peptide (AE37/E75/GP2) and varying amounts of GM-CSF. Dose reductions (DRs) were made for significant local and/or systemic toxicity by decreasing GM-CSF for subsequent inoculations. Ex vivo and in vivo immunologic responses were used to compare groups. Of 132 patients, 39 required DR (30 for robust local reactions [DR-L]). DR patients, particularly DR-L, had greater immune responses both ex vivo and in vivo. Postvaccine delayed-type hypersensitivity in DR-L patients compared with all others was larger for E75 (p = 0.001), AE37 (p = 0.077) and GP2 (p = 0.076). All three peptide vaccines were safe and well-tolerated. These findings have led to a clinically relevant optimal vaccine dosing strategy, which may be applicable to other peptide-based cancer vaccines.

Circulating regulatory T cells (CD4+CD25+FOXP3+) decrease in breast cancer patients after vaccination with a modified MHC class II HER2/neu (AE37) peptide.

Regulatory T cells (T(Reg)), CD4(+)CD25(+)FOXP3(+), are implicated in suppressing tumor immune responses. We analyzed peripheral blood lymphocytes (PBL) from breast cancer patients receiving a modified HLA class II HER2/neu peptide (AE37) vaccine for T(Reg) cells and correlated their levels with vaccine-specific immune responses. The mean CD4(+)CD25(+)FOXP3(+) T(Reg) cells decreased in patients with vaccination with no significant difference in serum TGF-β levels. IFN-γ ELISPOT and DTH increased after vaccination with a good correlation between T(Reg) cell reduction and size of DTH to AE37. The T(Reg) cell reduction and associated immune response suggest that AE37 may be clinically useful.

Trends in Cancer Screening Among Hispanic and White Non-Hispanic Women, 2000–2005

BACKGROUND Hispanics are the largest and fastest growing ethnic group in the United States. Compared with white non-Hispanic women, however, Hispanic women have significantly lower cancer screening rates. Programs designed to increase cancer screening rates, including the national Screen for Life campaign, which specifically promoted colorectal cancer (CRC) screening, regional educational/research programs, and state cancer control programs, have been launched. Screen for Life and some of these other intervention programs have targeted Hispanic populations by providing educational materials in Spanish in addition to English. METHODS The objective of this study was to compare changes in colorectal, breast, and cervical cancer screening rates from 2000 to 2005 among Hispanic and white non-Hispanic women, using data from the National Health Interview Survey (NHIS). The age ranges of study subjects and the definitions of cancer screening were site specific and based on the American Cancer Society (ACS) screening recommendations. RESULTS Although overall screening rates were found to be lower among Hispanic women, CRC screening increased about 1.5-fold among both Hispanic and white non-Hispanic women, mainly driven by endoscopic screening, which increased 2.1-fold and 2.9-fold, respectively, from 2000 to 2005 (p < 0.01). Fecal occult blood testing (FOBT) for CRC declined among white non-Hispanic women and remained stable among Hispanic women during the same period. Mammogram and Pap smear screening tended to decline during the study period for both ethnic groups, especially white non-Hispanic women. CONCLUSION Although cancer screening rates may be affected by multiple factors, culturally sensitive and linguistically appropriate national educational programs may have contributed to the increase in endoscopic CRC screening compliance.

Folate receptor α: A storied past and promising future in immunotherapy

Folate receptor alpha (FR α) is a membrane-bound transport protein with several features which make it an attractive target for cancer immunotherapy. FR α is largely shielded from the immune system in normal tissue but exposed while expressed on a variety of malignancies; it is functionally active in cancer pathogenesis; and it is immunogenic. A variety of different immunotherapeutic methods targeting FR α are being explored to treat cancer. Passive immunotherapy includes monoclonal antibodies, antibodies modified to deliver treatments, and modified T cell therapy. Active immunotherapy has focused on using FR α to increase the immunogenicity of cancer or to generate active FR α-directed immunity through a range of vaccination techniques. We will review the rationale behind targeting immunotherapy to FR α and cover the various techniques designed to do this.

Overcoming Cancer Immune Tolerance and Escape

Although HER2/neu–targeted cancer vaccines have shown initial promise in the adjuvant setting, a therapeutic vaccine remains elusive due to the tumor escape mechanisms of established cancer. As described by Seavey et al. in this issue of CCR, a Listeria-delivered vaccine may help overcome immune tolerance, leading to an effective therapeutic vaccine.

Primary analysis of the prospective, randomized, phase II trial of GP2+GM-CSF vaccine versus GM-CSF alone administered in the adjuvant setting to high-risk breast cancer patients.

134 Background: GP2 is a HER2 derived, HLA-A2+-restricted immunogenic peptide designed to stimulate CD8+T cells to recognize tumor cells with any level of HER2 expression (IHC 1-3+). Accrual to a prospective, randomized, multi-center, phase II trial of the GP2 vaccine for prevention of breast cancer recurrence has completed. Here, the planned primary analysis of disease-free survival (DFS) is presented. METHODS HLA-A2+ node positive or high-risk node negative breast cancer patients (pts) with any level of HER2 expression rendered disease-free by standard of care therapy (to include trastuzumab where appropriate) were randomized to receive GP2+GM-CSF (VG) or GM-CSF (CG) alone. Pts received 6 monthly inoculations (primary vaccine series = PVS) followed by 4 boosters administered every 6 months. The Kaplan Meier method was used for statistical analysis. The intention-to-treat (ITT) population is defined as the entire randomly assigned population. The per-treatment (PT) group excluded pts who recurred during the PVS or developed a second malignancy. A pre-specified subgroup analysis was performed based on HER2 expression level. HER2 overexpression (OE) is defined as IHC 3+or FISH >2.2. RESULTS With 89 VG and 91 CG pts enrolled and vaccinated, there are no differences between groups with respect to age, node positivity, tumor size, grade, ER/PR status, and HER2 expression (p>0.05). The vaccine has been well tolerated with toxicities comparable between the VG and CG. Only one grade 3 local and systemic toxicity reaction has been reported in the VG. At 34 (1-60) month median follow-up, DFS was compared in the ITT (85% VG v 81% CG, p = 0.57) and PT (94% VG v 85% CG, p = 0.17) populations. In OE patients (51 VG and 50 CG) DFS was 94% VG v 89% CG, p = 0.86 (ITT) and 100% VG v 89% CG, p = 0.08 (PT). CONCLUSIONS GP2+GM-CSF is a novel vaccine that is safe and well tolerated. This phase II trial demonstrates potentially greater benefit in pts with HER2 OE tumors, in whom there have been no recurrences in the PT group. This may be due to synergism with trastuzumab therapy, thus justifying a phase III trial evaluating GP2 administered in the adjuvant setting to a HER2 OE population. CLINICAL TRIAL INFORMATION NCT00524277.