Targeting gp100 and TRP-2 with a DNA vaccine: incorporating T cell epitopes with a human IgG1 antibody induces potent T cell responses that are associated with favourable clinical outcome in a phase I/II trial

A DNA vaccine, SCIB1, incorporating two CD8 and two CD4 epitopes from TRP-2/gp100 was evaluated in patients with metastatic melanoma. Each patient received SCIB1 via intramuscular injection with electroporation. The trial was designed to find the safest dose of SCIB1 which induced immune/clinical responses in patients with or without tumour. Fifteen patients with tumor received SCIB1 doses of 0.4-8 mg whilst 20 fully-resected patients received 2-8 mg doses. Twelve patients elected to continue immunization every 3 months for up to 39 months. SCIB1 induced dose-dependent T cell responses in 88% of patients with no serious adverse effects or dose limiting toxicities. The intensity of the T cell responses was significantly higher in patients receiving 4 mg doses without tumor when compared to those with tumor (p< 0.01). In contrast, patients with tumor showed a significantly higher response to the 8 mg dose than the 4 mg dose (p< 0.03) but there was no significant difference in the patients without tumor. One of 15 patients with measurable disease showed an objective tumor response and 7/15 showed stable disease. 5/20 fully-resected patients have experienced disease recurrence but all remained alive at the cut-off date with a median observation time of 37 months. A positive clinical outcome was associated with MHC-I and MHC-II expression on tumors prior to therapy (p=0.027). We conclude that SCIB1 is well tolerated and stimulates potent T cell responses in melanoma patients. It deserves further evaluation as a single agent adjuvant therapy or in combination with checkpoint inhibitors in advanced disease

High grade encapsulated papillary carcinoma of the breast: An under recognised entity

Encapsulated papillary carcinoma (EPC) is a recognised special type of breast carcinoma. Despite compelling evidence indicating its invasive nature, although not of a conventional form, current consensus opinion is to manage EPC as an in situ disease based on its indolent clinical behaviour. Although most EPC are recognised to be low and intermediate grade, a distinct proportion of these tumours do show high cytonuclear grade features. The existence and behaviour of these rare high grade variants remains to be defined. In this study, we have identified 12 high grade EPC without associated conventional stromal invasion. To further characterise these high grade tumours, a series of invasive papillary carcinoma (n=30) was assessed for coexistence of EPC. Literature was also reviewed. RESULTS: Approximately 3% of pure EPC exhibit high grade features as defined by nuclear pleomorphism and increased mitotic activity. These tumours not only show histological features associated with aggressive behaviour but also are often hormone receptor negative, tend to be of larger size and more frequently associated with stromal invasion. Of the 10 patients with follow up data, one with pure high grade EPC developed recurrence and died of her disease. CONCLUSION: High grade EPC is rare and its histological features and more aggressive clinical behaviour suggest that consideration should be made to managing it in a similar fashion to conventional forms of invasive breast carcinoma based on established clinic-pathological parameters. This article is protected by copyright. All rights reserved

Breslow density is a novel prognostic feature that adds value to melanoma staging

Histomorphologic prognostic biomarkers that can be measured using only an hematoxylin and eosin stain are very attractive because they are simple and cheap. We conceived an entirely novel biomarker of this type, the Breslow density (BD), which measures invasive melanoma cell density at the site where Breslow thickness (BT) is measured. This study assessed BD’s prognostic value. In this study, BD was measured in 1329 melanoma patients. Measurement accuracy and precision was assessed using intraclass correlation coefficient (ICC). Survival was assessed with a primary end-point of melanoma-specific survival (MSS) and also overall survival and metastasis-free survival. We found that BD measurement was accurate compared with gold standard image analysis (ICC, 0.84). Precision was excellent for 3 observers with different experience (ICC, 0.93) and for an observer using only written instructions (ICC, 0.93). BD was a highly significant predictor in multivariable analysis for overall survival, MSS, and metastasis-free survival (each, P<0.001) and it explained MSS better than BT, but BT and BD together had best explanatory capability. A BD cut point of ≥65% was trained in 970 melanomas and validated in 359. This cut point showed promise as a novel way to upstage melanoma from T stage “a” to “b.” BD was combined with BT to create a targeted burden score. This was a validated as an adjunct to American Joint Committee on Cancer stage. In summary, BD can be measured accurately and precisely. It demonstrated independent prognostic value and explained MSS better than BT alone. Notably, we demonstrated ways that BD could be used with American Joint Committee on Cancer version 8 staging