Erev E. Tubb

The efficacy of therapeutic vaccination for the treatment of cancer is limited by peripheral tolerance to tumor antigens. In vivo blockade of CTLA-4, a negative regulator of T cell function, can induce the regression of established tumors and can augment the tumor rejection achieved through therapeutic vaccination. These outcomes may reflect enhanced tumor-specific T cell priming and/or interference with the development of tolerance to tumor antigens. We examined the effect of CTLA-4 blockade on the fate and function of T cells specific for a model tumor antigen in the tumor-bearing host. We found that while CTLA-4 blockade enhanced the priming of responsive T cells, it did not prevent the induction of tolerance to tumor antigens. These results demonstrate that there is a critical window in which the combination of CTLA-4 blockade and vaccination achieves an optimal response, and they point to mechanisms other than CTLA-4 engagement in mediating peripheral T cell tolerance to tumor antigens.

OBJECTIVE: Growth factor overexpression has been shown to be an integral part of the growth promotion of a number of tumors, including breast carcinoma, colon carcinoma, and sarcomas. The role of peptide growth factors in the regulation of growth of head and neck cancers has not been extensively investigated, however. In this study, we present our preliminary results of the pattern of expression of four growth factors: insulin-like growth factor II, transforming growth factor-alpha, basic fibroblast growth factor, and platelet-derived growth factor A chain in human head and neck tumors. DESIGN: We examined eight benign and 27 malignant human head and neck surgical specimens for the expression of growth factor messenger RNAs using the polymerase chain reaction technique. RESULTS: Our preliminary data demonstrate that growth factor messenger RNA is expressed by most of our malignant head and neck cancer specimens and by all eight benign head and neck tissue specimens. However, we were not able to show any distinction in the pattern of growth factor RNA expression among the malignant head and neck surgical specimens for the four growth factors studied to date. CONCLUSIONS: These findings demonstrate that the expression of specific biologically active genes can be studied in routine surgical specimens using the polymerase chain reaction. The clinical prognostic significance of the overexpression of growth factors in head and neck malignancy as well as future therapeutic implications are discussed.

15065 Background: Pmab is a fully human mAb against EGFr approved by the US FDA for treating pts with mCRC who have disease progression on or following regimen based on fluoropyrimidine, oxaliplatin, and irinotecan. Due to the important role of the EGFr in skin growth, cutaneous reactions are common adverse events of Pmab, mainly an acneiform follicular eruption. Other skin toxicities of Pmab include hypertrichosis and trichomegaly. The mechanism behind the EGFr-induced hair growth is poorly understood. This study attempted to find patterns distinguishing the group of pts that developed hypertrichosis from the group of pts which did not. Methods: The dermatological manifestations of 24 pts on four clinical studies were noted. When comparing skin toxicities of the pts, the worst severity grade developed while on study was used. Hypertrichosis is defined as excessive hair growth growing in places that do not normally have hair and not induced by androgens. Trichomegaly is defined as excessive growth of the eyelashes. Pts were separated into a group that developed hypertrichosis and a group that did not, with further delineation according to gender, race and therapy (tx) regimen. Results: 41.6% of pts developed hypertrichosis or trichomegaly in a median 3.46 months after the first dose of Pmab. The majority of pts developed hair growth on the cheeks, upper lip, chin; two pts had periobital and three had chest hair growth. No statistically significant differences were noted in gender, race, or median age of pts with and without hypertrichosis. There is no correlation between hypertrichosis and severity of the other skin toxicities, monotx or combination tx, or presence of anti-tumor response. Patterns of hair growth and histologic features will be presented. Conclusions: Pmab may alter the growth cycle of the hair follicle in both men and women. The characteristic trichomegaly and hypertrichosis are related to duration of tx and show no relationship to the other skin toxicities. A higher response rate was observed in pts with hypertrichosis, but this is related to the duration of anti-tumor tx. Further studies are needed to characterize the etiology and mechanism of this cutaneous toxicity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Amgen, Genentech, Pfizer, sanofi-aventis