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Elizabeth M Jaffee

Publications and source records attributed to Elizabeth M Jaffee.

31 records · Page 2Linked to original sources
PubMed2004

Augmenting the potency of breast cancer vaccines: combined modality immunotherapy.

Rapid progress in defining the molecular underpinnings of the antitumor immune response has laid the foundation for tumor immunotherapy, leading to multiple early clinical studies testing vaccines for the treatment of breast cancer. Together, these small trials have provided early evidence for the induction of clinically relevant vaccine-induced tumor-specific immunity in some patients. However, they have not convincingly demonstrated a significant impact on disease progression or overall survival in women with advanced breast cancer. These disappointing results are likely due to the negative impact of standard cancer treatments on vaccine-activated antitumor immunity, the limited potency of current tumor vaccine formulations against large burdens of established tumor, and the presence of pre-existing tumor-specific immune tolerance. It is increasingly clear that standard and novel breast cancer treatments can influence the antitumor immune response. Also, signaling pathways that regulate immune responses have emerged as novel targets for immune modulation. The use of preclinical models to elucidate the pharmacodynamic interactions of standard breast cancer treatment modalities and novel, targeted immunotherapeutics with breast cancer vaccines will facilitate the development of combinatorial immunotherapeutic strategies. Combined modality immunotherapies should maximize the potency of the antitumor immune response, thereby improving the outcome of breast cancer therapy.

Breast Neoplasms↗
PubMed2003

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.

3T3 Cells↗
PubMed2003

Lentivirus-mediated gene transfer and expression in established human tumor antigen-specific cytotoxic T cells and primary unstimulated T cells.

In this report, we evaluated the efficiency of stable gene transfer into established CD8(+) human tumor antigen-specific cytotoxic T cell (CTL) lines and peripheral blood lymphocytes (PBL) by oncoretroviral and lentiviral vectors. In the oncoretroviral vector, the green fluorescent protein (GFP) reporter gene was regulated by the murine stem cell virus (MSCV) promoter. In three human immunodeficiency virus type 1 (HIV-1)-based lentiviral vectors, the GFP transgene was regulated by either a chimeric MSCV/HIV-1 promoter, or cellular promoters from human housekeeping genes PGK and EF1 alpha. We found that several lines of proliferating tumor-specific CTL were poorly (=2%) transduced by the oncoretroviral vector that transduced Jurkat T cell line efficiently (=80%). In contrast, three lentiviral vectors transduced 38-63% of these proliferating CTL. More interestingly, all lentiviral vectors packaged without the HIV-1 accessory proteins transduced human bulk PBL and purified CD4(+) and CD8(+) lymphocyte subsets without prior stimulation. Detailed analysis indicated that the lentiviral vectors containing the EF1 alpha or PGK ubiquitous promoter can transduce unstimulated PBL and achieve low-level transgene expression in the absence of any T-cell activation. However, T-cell activation subsequent to the transduction of unstimulated PBL is required for high-level transgene expression. Transduced PBL expressing transgene delivered by the lentiviral vectors still preserved resting and naïve cell phenotypes. Taken together, prior T cell stimulation and HIV-1 accessory proteins are dispensable for lentivirus-mediated gene transfer into resting naïve and memory T lymphocytes. These results will have significant implications for the study of T-cell biology and for the improvement of clinical gene therapies of acquired immune deficiency syndrome (AIDS) and cancer.

Animals↗
PubMed2003

Identification and characterization of the immunodominant rat HER-2/neu MHC class I epitope presented by spontaneous mammary tumors from HER-2/neu-transgenic mice.

The HER-2/neu (neu-N)-transgenic mice are a clinically relevant model of breast cancer. They are derived from the parental FVB/N mouse strain and are transgenic for the rat form of the proto-oncogene HER-2/neu (neu). In this study, we report the identification of a MHC class I peptide in the neu protein that is recognized by CD8(+) T cells derived from vaccinated FVB/N mice. This 10-mer was recognized by all tumor-specific FVB/N T cells generated regardless of the TCR Vbeta region expressed by the T cell or the method of vaccination used, establishing it as the immunodominant MHC class I epitope in neu. T cells specific for this epitope were able to cure FVB/N mice of transplanted neu-expressing tumor cells, demonstrating that this is a naturally processed peptide. Altered peptide analogs of the epitope were analyzed for immunogenicity. Vaccination with dendritic cells pulsed with a heteroclitic peptide provided FVB/N and neu-N mice with increased protection against tumor challenge as compared with mice immunized with dendritic cells loaded with either wild-type or irrelevant peptide. Discovery of this epitope allows for better characterization of the CD8(+) T cell responses in the neu-N mouse model in which neu-specific tolerance must be overcome to produce effective antitumor immunity.

3T3 Cells↗
PubMed2003

Apoptotic, but not necrotic, tumor cell vaccines induce a potent immune response in vivo.

Prophylactic tumor vaccination against subsequent tumor challenge depends on effective cross-priming in vivo. Professional APCs process tumor antigens from whole tumor cells and present them to CD4(+) and CD8(+) T cells. Data suggest that dendritic cells process antigens more efficiently from necrotic cells than from apoptotic cells in vitro. We compared the effect of apoptosis vs. necrosis in vivo using different tumor models (CT26, RENCA, B16 and CT26-HA). Apoptosis was induced by gamma-irradiation prior to injection and verified in vivo. Apoptotic CT26-HA, CT26-wt or RENCA prevented tumor outgrowth in 100%, 75% and 100%, respectively, of mice for more than 30 days after challenge. In contrast, injection of necrotic tumor cells led to protection of no more than 0-30%. Prolonged tumor-free survival was also observed in mice after vaccination with irradiated B16 cells. In vivo protection experiments correlated very well with in vitro cytotoxicity assays. Immunohistochemical analysis of the vaccine site showed a strong CD4(+) and CD8(+) T-cell response after injection of apoptotic cells, which was accompanied by the presence of dendritic cells. In contrast, necrotic cell vaccines attracted a strong local macrophage response. Our data clearly demonstrate that only apoptotic tumor cell vaccines induce a potent antitumor immune response.

Animals↗
PubMed2003

Major histocompatibility complex class II-restricted presentation of a cytosolic antigen by autophagy.

Biochemical and functional studies have demonstrated major histocompatibility complex (MHC) class II-restricted presentation of peptides derived from cytosolic proteins, but the underlying processing and presentation pathways have remained elusive. Here we show that endogenous presentation of an epitope derived from the cytosolic protein neomycin phosphotransferase II (NeoR) on MHC class II is mediated by autophagy. This presentation pathway involves the sequestration of NeoR into autophagosomes, and subsequent delivery into the lytic compartment. These results identify endosomes/lysosomes as the processing compartment for cytosolic antigens and furthermore link endogenous antigen presentation on MHC class II with the process of cellular protein turnover by autophagy.

Antigen Presentation↗
PubMed2003

Toward a breast cancer vaccine: work in progress.

Advances in biotechnology and basic immunology have converged to create an unprecedented opportunity to use vaccines to harness the power of the immune system in the fight against breast cancer. Cancer vaccines have several therapeutic advantages over more traditional breast cancer treatment modalities. First, targeting the antitumor immune response to critical tumor-specific antigens defines a therapy with exquisite specificity and minimal toxicity. Second, immune-mediated tumor destruction occurs by mechanisms distinct from those underlying the efficacy of chemotherapy and hormone therapy. Thus, immunotherapy offers an approach to circumventing the intrinsic drug resistance that currently underlies therapeutic failure. Third, the phenomenon of immunologic memory endows immunotherapy with the potential for creating a durable therapeutic effect that is reactivated at the onset of disease relapse. Moreover, immunologic memory also underlies the potential future use of vaccines for the prevention of breast cancer. Early clinical trials have highlighted the promise of breast cancer vaccines, and have further defined the challenges facing translational scientists and clinical investigators. The judicious application of laboratory advances to clinical trial design should facilitate the development of immunotherapy as an additional major therapeutic modality for breast cancer, with the potential for breast cancer prevention as well as treatment.

Antibodies, Anti-Idiotypic↗
PubMed2002

Cytokine modified tumor vaccines.

The immune system can recognize tumors, but may be actively tolerized to tumors during the tumorigenesis process. The identity of most tumor antigens remains unknown, but the number is growing due to new techniques. Most clinical trials using genetically modified tumor vaccines have shown immunological responses (DTH), but few clinical responses. Certain chemotherapeutic agents may enhance the immune effects of genetically modified tumor vaccines.

Antigens, Neoplasm↗
PubMedDate not supplied

Pancreatic cancer.

Explore the source record for details and available documents.

Adenocarcinoma↗
PubMedDate not supplied

Cancer vaccines: an old idea comes of age.

Cancer vaccines are at the forefront of novel, targeted approaches to cancer treatment. Low toxicity, the potential for circumventing drug cross-resistance, and the potential for persistence of the antitumor effect due to immunologic memory represent a mandate for accelerated clinical development. Advances in molecular immunology have suggested approaches for overcoming the formidable mechanisms of immune tolerance that are pre-established in cancer patients, and many have already been tested in preclinical models. Also, early studies revealed that not all tumor antigens are created equal, and identifying those capable of eliciting immune-mediated tumor rejection is essential to the development of effective recombinant cancer vaccines. While early trials have generally resulted in disappointing clinical outcomes, they have yielded insight into the critical parameters for the design of cancer vaccine trials and provided powerful reagents for tumor antigen identification. By utilizing the lessons learned from the research laboratory and these early clinical trials, informative second generation vaccine trials should have a high likelihood of success. Clinical protocols that consider how best to incorporate therapeutic cancer vaccines into the current standard of care should allow cancer vaccines to take their place alongside traditional cancer treatment modalities in oncology practice.

Animals↗