Jeannine Villella

Vaccination with an NY-ESO-1 peptide of HLA class I/II specificities induces integrated humoral and T cell responses in ovarian cancer.

NY-ESO-1 is a “cancer-testis” antigen expressed in epithelial ovarian cancer (EOC) and is among the most immunogenic tumor antigens defined to date. The NY-ESO-1 peptide epitope, ESO157–170, is recognized by HLA-DP4-restricted CD4+ T cells and HLA-A2- and A24-restricted CD8+ T cells. To test whether providing cognate helper CD4+ T cells would enhance the antitumor immune response, we conducted a phase I clinical trial of immunization with ESO157–170 mixed with incomplete Freunds adjuvant (Montanide ISA51) in 18 HLA-DP4+ EOC patients with minimal disease burden. NY-ESO-1-specific Ab responses and/or specific HLA-A2-restricted CD8+ and HLA-DP4-restricted CD4+ T cell responses were induced by a course of at least five vaccinations at three weekly intervals in a high proportion of patients. There were no serious vaccine-related adverse events. Vaccine-induced CD8+ and CD4+ T cell clones were shown to recognize NY-ESO-1-expressing tumor targets. T cell receptor analysis indicated that tumor-recognizing CD4+ T cell clones were structurally distinct from non-tumor-recognizing clones. Long-lived and functional vaccine-elicited CD8+ and CD4+ T cells were detectable in some patients up to 12 months after immunization. These results confirm the paradigm that the provision of cognate CD4+ T cell help is important for cancer vaccine design and provides the rationale for a phase II study design using ESO157–170 epitope or the full-length NY-ESO-1 protein for immunotherapy in patients with EOC.

Efficacy of Levo-1-Methyl Tryptophan and Dextro-1-Methyl Tryptophan in Reversing Indoleamine-2,3-Dioxygenase-Mediated Arrest of T-Cell Proliferation in Human Epithelial Ovarian Cancer

It has been reported that levo-1-methyl tryptophan (L-1MT) can block indoleamine-2,3-dioxygenase (IDO) expressed by human dendritic cells (DC), whereas dextro-1-methyl tryptophan (D-1MT) is inefficient. However, whether L-1MT or D-1MT can efficiently reverse IDO-induced arrest of human T-cell proliferation has not been clarified. Here, we show a marked immunosuppressive effect of IDO derived from INDO-transfected 293 cell, IDO+ ovarian cancer cells, and monocyte-derived DCs on CD4+ Th1 cells, CD8+ T cells, and natural killer cells derived from peripheral blood, ascites, and tumors of ovarian cancer patients. We found that, whereas L-1MT and D/L-1MT can restore proliferation of tumor-derived and peripheral blood T-cell subsets, D-1MT does not effectively restore IDO-induced arrest of T-cell proliferation. Although D-1MT inhibited kynurenine production at high concentrations, L-1MT was more effective in abrogating kynurenine generation and tryptophan depletion, whereas tryptophan was completely depleted by IDO even in the presence of high amounts of D-1MT. Together, the results indicate that, whereas the generation of tryptophan metabolites (kynurenines) by IDO is important in mediating suppression of T-cell proliferation, the degree to which tryptophan depletion is restored by 1MT is also critical in overcoming IDO-induced arrest of T-cell proliferation.

Consumption of black tea or coffee and risk of ovarian cancer.

The goal of this study was to investigate the associations between ovarian cancer risk and usual consumption of black tea, regular coffee, or decaffeinated coffee. Using a hospital-based case–control design, participants included 414 women with primary epithelial ovarian, fallopian, or peritoneal cancer and 868 age- and region-matched women with nonneoplastic conditions. All participants completed a comprehensive epidemiologic questionnaire. Black tea consumption was associated with a linear decline in ovarian cancer risk (P for trend 0.03), with individuals consuming two or more cups daily experiencing a 30% decline in risk (adjusted OR 0.70, 95% CI 0.51–0.97). Similar declines were noted among individuals consuming two or more cups of decaffeinated coffee daily (adjusted OR 0.71, 95% CI 0.51–0.99; P for trend 0.002). However, no association was noted between any level of regular coffee consumption and risk of ovarian cancer. The chemoprotective effects of phytochemicals in black tea and decaffeinated coffee may be important, although the effects of phytochemicals in regular coffee may be counteracted by the elevated risk associated with its higher caffeine content.

Regular Analgesic Use and Risk of Endometrial Cancer

Background: Analgesic use has been implicated in the chemoprevention of a number of solid tumors, but thus far, no previous research has focused on the role of aspirin in endometrial cancer etiology. Methods: We conducted a hospital-based case-control study of 427 women with primary, incident endometrial cancer, and 427 age- and residence-matched controls without benign or malignant neoplasms. All participants received medical services at Roswell Park Cancer Institute in Buffalo, NY, and completed a comprehensive epidemiologic questionnaire. Women who reported analgesic use at least once a week for at least 6 months were classified as regular users and served as the reference group throughout the analyses. We used unconditional logistic regression analyses to compute crude and adjusted odds ratios (OR) with corresponding 95% confidence intervals (CI). Results: Compared with nonusers, regular aspirin users were not at reduced risk of endometrial cancer (adjusted OR, 0.91; 95% CI, 0.66-1.26), nor were women with the highest frequency, duration, or cumulative lifetime aspirin use. When the sample was divided by body mass index status, regular aspirin use was not associated with risk among women classified as normal weight or overweight, but a significant risk reduction was seen for obese women (adjusted OR, 0.50; 95% CI, 0.27-0.92). Significant decreases in risk were also observed for obese women with the greatest frequency, duration, and cumulative aspirin use. No significant associations in the overall sample or among obese women were noted for acetaminophen use. Conclusion: We observed no evidence of an overall chemoprotective effect of aspirin on endometrial cancer risk, but the significant risk reductions among obese women warrant further investigation. (Cancer Epidemiol Biomarkers Prev 2005;14(12):2923–8)

Optimising Treatment of Elderly Patients with Ovarian Cancer

The aging population is the fastest growing segment of our population. Over the last century, the average life expectancy has increased by 25 years. The incidence of ovarian carcinoma, seen primarily in postmenopausal women, is, therefore, expected to increase. The current standard treatment of ovarian cancer has been determined on the basis of prospective, randomised clinical trials carried out by cooperative groups. Sixty-one percent of new cancer cases occur in women >65 years of age. Despite this fact, enrolment in clinical trials has been exceedingly low. In turn, this causes suboptimal treatment for a very fatal disease. The aetiology of this is multifactorial, and strategies for improvement are lacking. Elderly patients may be barred from participation based on physician biases alone. Elderly patients may have limited access to academic centres where clinical trials are conducted or be excluded on the basis of unrealistic inclusion criteria. As physicians, it is our duty to understand the elderly patient and the comorbidities in this age group that may influence the tolerability and toxicity of conventional therapies. Therefore, it is imperative that we make a conscious effort to examine ways in which we may improve enrolment of elderly women with ovarian cancer in clinical trials.

BORIS, a novel cancer-testis antigen, is a potential target for immunotherapy in epithelial ovarian cancer

9673 Background: Cancer-testis antigens (CTA), are selectively expressed in various types of human neoplasms but not in normal tissues other than testis. This characteristic feature of CTA makes th...