Antibody association with HER-2/neu-targeted vaccine enhances CD8 T cell responses in mice through Fc-mediated activation of DCs.

The pathogenic nature of cancer is attributed, at least in part, to the ability of tumors cells to induce systemic and local mechanisms of immune tolerance. However, we previously reported that tumor-free survival in up to 100% of tolerized HER-2/neu transgenic mice can be achieved by administration of neu-specific mAb concurrently with a HER-2/neu-expressing, GM-CSF-secreting whole cell vaccine. In this report, we show that one mechanism of improved antitumor activity induced by the combination of these 2 neu-targeted interventions was enhanced Fc-mediated activation of APCs. Specifically, in vivo studies demonstrated localization of radiolabeled neu-specific mAb at the vaccine site. Subsequently, increased accumulation of neu-specific mAb at the vaccine-draining lymph node correlated with increased vaccine cell uptake by DCs in vivo. This led to enhancement of CD8(+) neu-specific T cell function in terms of proliferation, cytokine production, and central memory development. Thus, the administration of a neu-specific mAb with a neu-targeted GM-CSF-secreting tumor vaccine enhanced induction of neu-specific CD8(+) T cells through Fc-mediated activation of DCs. This multimodality attack on the same tumor antigen may have the potential to overcome tolerance to self antigens and weaken the immunosuppressive networks within the tumor microenvironment.

Squamous cell carcinoma of the sinonasal cavity arising as a second primary in individuals with head and neck cancer.

OBJECTIVES/HYPOTHESIS: Second primary tumors occur frequently in patients with head and neck carcinoma. This may be caused by generalized exposure to carcinogens resulting in "field cancerization" or to the individuals' generalized susceptibility to cancer. The paranasal sinuses are not commonly included in the sites considered at risk for this process. We therefore sought to assess the overall risk of contracting a primary cancer in this region after having a tumor elsewhere in the upper aerodigestive tract. STUDY DESIGN: Retrospective. METHODS: Two thousand four hundred seventy-five patients with squamous cell carcinoma of the upper aerodigestive tract were analyzed using a tumor registry at a tertiary care institution. RESULTS: Five (0.2%) patients were identified as having a second primary in the sinonasal tract. The average interval between the index and second primary tumors was 28.4 (range 8-60) months. All five patients presented with symptoms typical of sinus inflammatory disease and had advanced sinus lesions at the time of diagnosis. These findings are typical of those with sinonasal carcinoma in that they present with nonspecific signs and symptoms and were diagnosed with locally advanced disease despite being in a surveillance program for their index cancer. CONCLUSIONS: Although uncommon, the data reported here support inclusion of the sinonasal tract in these surveillance programs. This could result in earlier detection and greater opportunity for curative intervention.

OX40 costimulation synergizes with GM-CSF whole-cell vaccination to overcome established CD8+ T cell tolerance to an endogenous tumor antigen.

T cell costimulation via OX40 is known to increase CD4+ T cell expansion and effector function and enhances the development of T cell memory. OX40 costimulation can also prevent, and even reverse, CD4+ T cell anergy. However, the role of OX40 in CD8+ T cell function is less well defined, particularly in the setting of immune tolerance. To determine the effects of OX40 costimulation on the induction of the host CD8+ T cell repertoire to an endogenous tumor Ag, we examined the fate of CD8+ T cells specific for the immunodominant rat HER-2/neu epitope, RNEU420-429, in FVB MMTV-neu (neu-N) mice, which express rat HER-2/neu protein in a predominantly mammary-restricted fashion. We show that the RNEU420-429-specific T cell repertoire in neu-N mice expands transiently after vaccination with a neu-targeted GM-CSF-secreting whole-cell vaccine, but quickly declines to an undetectable level. However, OX40 costimulation, when combined with GM-CSF-secreting tumor-targeted vaccination, can break established CD8+ T cell tolerance in vivo by enhancing the expansion, and prolonging the survival and effector function of CD8+ T cells specific for RNEU420-429. Moreover, we demonstrate that OX40 expression is up-regulated on both CD4+ and CD8+ T cells shortly after administration of a GM-CSF expressing vaccine. These studies highlight the increased efficacy of OX40 costimulation when combined with a GM-CSF-secreting vaccine, and define a new role for OX40 costimulation of CD8+ T cells in overcoming tolerance and boosting antitumor immunity.

Severe tracheobronchial stenosis in the X-linked recessive form of chondrodysplasia punctata.

The X-linked recessive form of chondrodysplasia punctata, characterized by chondrodysplasia and punctate calcification of cartilage, is caused by a defect in the vitamin K-dependent enzyme arylsulfatase E. We herein describe a male infant with chondrodysplasia punctata and stenosis and calcification of the entire trachea and main bronchi. To our knowledge, this is the first case of chondrodysplasia punctata reported in the English literature with such extensive airway manifestations.

HER-2/neu-specific monoclonal antibodies collaborate with HER-2/neu-targeted granulocyte macrophage colony-stimulating factor secreting whole cell vaccination to augment CD8+ T cell effector function and tumor-free survival in Her-2/neu-transgenic mice.

HER-2/neu is overexpressed in several cancers including 30% of breast carcinomas, and correlates with a poor outcome. HER-2/neu-transgenic (neu-N) mice that overexpress the non-transforming rat neu develop spontaneous mammary carcinomas and demonstrate immunotolerance to the neu protein similar to that observed in patients with neu-expressing cancers. In neu-N mice, neu-targeted vaccination induces weak T cell and negligible Ab responses sufficient to delay but not eradicate transplanted neu-expressing tumor. Here we demonstrate that passive infusion of neu-specific mAbs in sequence with whole cell vaccination significantly improves tumor-free survival over either modality alone. Importantly, treatment of neu-N mice with vaccine in combination with two distinct neu-specific Abs is particularly efficacious, preventing tumor in 70% and eradicating established tumor in 30% of neu-N mice. In vivo lymphocyte subpopulation depletion experiments demonstrate that the efficacy of Ab, alone or combined with vaccine, is dependent on both CD4(+) and CD8(+) T cells. Furthermore, the in vivo antitumor effects of vaccine and Ab are associated with a significant increase in the number and function of neu-specific CD8(+) T cells. Collectively, these observations suggest that similarly increased efficacy could be obtained by combining neu-targeted vaccination and neu-specific Abs such as trastuzumab (Herceptin) in patients with neu-expressing cancers.