Selective Inhibition of T Cell Tolerance as a Means of Enhancing Tumor Vaccines in a Mouse Model of Breast Cancer PDF Download
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Languages : en
Pages : 8
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To determine if the addition of Go6976 to vaccine protocols will inhibit neu specific tolerance and enhance immunotherapy for breast cancer. Scope: In the Her-2/neu model of spontaneous breast cancer the immune system of these transgenic mice are tolerant to the neu protein. While immunity to neu can be demonstrated in the neu-transgenic mice (partial breaking of tolerance), this immunity is inadequate to prevent the spontaneous development of tumors and to prevent death from tumor challenge. Findings: By combining our regimen with a dose of cytoxan we can promote survival of tumor bearing mice when compared with no treatment, vaccine alone or vaccine + cytoxan. In particular, this combination is very effective in inhibiting tumor growth in the early period post-tumor challenge. Unfortunately, during the last year efforts to improve long term survival have not been successful. Significance: These data support the notion that the novel combination of PKC inhibitor + vaccine can enhance the efficacy of tumor vaccines. More work needs to be done to optimized the dosing schedule of this approach.
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Languages : en
Pages : 8
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To determine if the addition of Go6976 to vaccine protocols will inhibit neu specific tolerance and enhance immunotherapy for breast cancer. Scope: In the Her-2/neu model of spontaneous breast cancer the immune system of these transgenic mice are tolerant to the neu protein. While immunity to neu can be demonstrated in the neu-transgenic mice (partial breaking of tolerance), this immunity is inadequate to prevent the spontaneous development of tumors and to prevent death from tumor challenge. Findings: By combining our regimen with a dose of cytoxan we can promote survival of tumor bearing mice when compared with no treatment, vaccine alone or vaccine + cytoxan. In particular, this combination is very effective in inhibiting tumor growth in the early period post-tumor challenge. Unfortunately, during the last year efforts to improve long term survival have not been successful. Significance: These data support the notion that the novel combination of PKC inhibitor + vaccine can enhance the efficacy of tumor vaccines. More work needs to be done to optimized the dosing schedule of this approach.
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Languages : en
Pages : 25
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T cell tolerance to tumor-associated antigens is a significant barrier to immune based treatments of human cancers. One such tumor-associated antigen is the protooncogene HER-2/neu (neu) which is overexpressed in 35-40% of all human breast cancers. Although patients with neu expressing tumors develop antibody and T cell responses to this antigen, these responses are weak and unable to hinder tumor growth. Our work has focused on understanding these mechanisms of T cell tolerance using the neu-N transgenic mice that express the wild type rat neu cDNA under control of the MMTV promoter. Since neu is an endogenously expressed antigen, profound neu-specific immune tolerance exists in the neu-N mice. We have characterized the immunodominant T cell epitope of neu recognized by parental FVB/N mice, RNEU420-429. Studying T cell responses to this epitope has yielded important insights into the mechanisms of tolerance in the neu-N mice. Following a neu-targeted vaccine, 100% of FVE/N mice will activate T cells specific to RNEU420-429, whereas RNEU420-429-specific T cells are not activated in the neu-N mice. However, if vaccine is combined with immunomodulatory doses of chemotherapy in neu-N mice, RNEU420-420-specific are now activated in a subset of transgenic mice. Employing MHC tetramer technology, adoptive transfer of RNEU420.429-specific T cells, and T cell activation assays, we have begun to understand the mechanisms of tolerance that prevent the induction of protective immunity against tumors in the neu-N mice and ways to circumvent them. These findings are the basis for a Phase I Clinical Trial now underway at our institution.
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Languages : en
Pages : 0
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T cell tolerance to tumor-associated antigens is a significant barrier to immune based treatments of human cancers. One such tumor-associated antigen is the proto-oncogene HER-2/neu (neu) which is overexpressed in 35-40% of all human breast cancers. Although patients with neu expressing tumors develop antibody and T cell responses to this antigen, these responses are weak and unable to hinder tumor growth. Our work has focused on understanding these mechanisms of T cell tolerance using the neu-N transgenic mice that express the wild type rat neu cDNA under control of the MMTV promoter. Since neu is an endogenously expressed antigen, profound neu-specific immune tolerance exists in the neu-N mice. We previously reported the immunodominant T cell epitope of neu recognized by parental FVB/N mice, RNEU420-429. We have investigated whether altering RNEU420-429 can generate a more immunogenic peptide that will result in better protection from a HER-2/neu expressing tumor in the neu-N mice. Also, using GFP-expressing RNEU420-429-specific T cells, we demonstrate that high avidity CTL cannot persist in the periphery of neu-N mice but do persist in the periphery of parental mice. Further studies are underway to understand the role other immune cells (such as CD4(+)CD25(+) regulatory T cells) play in CD8(+) T cell tolerance. This work to further understand the mechanisms of T cell tolerance in this cancer model should lead to even further improvements in vaccination strategy for cancer immunotherapies.
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Languages : en
Pages : 0
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A limitation of specific adoptive immunotherapy this therapy is the poor survival and tumor localization of activated T cells after infusion into a host. A contributor to these problems is the appendage-bearing, adhesive form of activated T cells, which renders them poorly suited to circulate, and likely to embolize in microvasculature. We hypothesized that transient inhibition of T cell appendage formation and adhesiveness, induced just before infusion, will improve the survival and circulation of adoptively transfered T cells. We found previously that pretreatment of activated T cells with the myosin light-chain kinase inhibitor ML-7 renders the cells temporarily smooth and nonadhesive. In this project we developed an ML-7 pretreatment protocol which allowed activated T cells to recover normal adhesion, motility, cytotoxicity, and proliferation within 24 hr. We then found that this protocol decreased by eightfold the percentage of infused cells trapped in the lung and increased fourfold the homing of ErbB2-specific T cells to the ErbB2+ murine mammary tumor D2F2/E2. Homing of infused T cells to peripheral lymph nodes was also increased by a factor of 1.5. When tested in. a D2F2/E2 immunotherapy model, the ML-7 pretreatment of T cells was found neither to enhance nor reduce the tumor-delaying effects of T cell infusion in D2F2/E2-bearing mice. The results constitute the first proof that cytoskeletal alteration of T cells can improve their trafficking behavior after adoptive transfer. On the basis of our initial test, though it appears that this strategy alone is enough to enhance adoptive immunotherapy. The ML-7 depolarization strategy is easily combined with other new methods of improved- immunotherapy, such as transduction of T cells with cytokines and survival genes, and such combinations should be tested in the future.
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Languages : en
Pages : 7
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As described in the 2008 progress report, the revised hypothesis is that agonist DR5 Ab induced by DNA vaccination will trigger tumor cell apoptosis without compromising T cell activity. The specific aims are to (1)Construct and test DR5 vaccines to induce anti-DR5 Ab, (2) Test the agonist activity of vaccine-induced anti-DR5 Ab, and (3) Amplify anti-tumor activity of DR5 vaccination with novel chemotherapeutics. During the funding period, we established that immune sera to human DR5 exhibit agonist activity to induce apoptosis in triple negative breast cancer cells and to inhibit tumor growth in vivo. To enable the testing of human DR5 vaccine in tolerant hosts, hDR5 transgenic mice have been generated and they are being back-crossed into BALB/c background. These mice will continue to be useful for studies targeting hDR5. To test the principle of inducing greater immunity with heterologous DR5 DNA vaccine, we have cloned DR5 cDNA from rat and two species of wild mice. These new reagents can be tested in future studies. To complement DR5 vaccination with additional therapies, we showed Sp-1 mediated TRAIL induction by HDAC inhibitor and that Akt survival pathway contributes to TRAIL resistance. These findings provide strong basis for combining DR5 vaccination with targeted therapy.
Author: Bharat B. Aggarwal
Publisher: Springer
ISBN: 3034808372
Category : Medical
Languages : en
Pages : 489
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This volume examines in detail the role of chronic inflammatory processes in the development of several types of cancer. Leading experts describe the latest results of molecular and cellular research on infection, cancer-related inflammation and tumorigenesis. Further, the clinical significance of these findings in preventing cancer progression and approaches to treating the diseases are discussed. Individual chapters cover cancer of the lung, colon, breast, brain, head and neck, pancreas, prostate, bladder, kidney, liver, cervix and skin as well as gastric cancer, sarcoma, lymphoma, leukemia and multiple myeloma.
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Languages : en
Pages : 45
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Advanced breast cancer is managed with hormonal agents or conventional cytotoxic drugs, but intrinsic drug resistance ultimately causes treatment failure. We have applied the use of tumor cells genetically modified to secrete GM-CSF to the preclinical neu transgenic mouse model, characterized by spontaneous tumor development and pre-existing immune tolerance to HER-2/neu. Low doses of Cyclophosphamide and Doxorubicin in a specifically timed sequence with vaccine can augment the HER-2/neu-specific, vaccine-activated immune response in these mice, resulting in delayed tumor outgrowth compared to chemotherapy or vaccine alone. I have developed a GM-CSF-secreting breast cancer vaccine for human use, and designed a clinical trial to test it in patients with metastatic breast cancer. I have also designed a companion clinical study to govern the long-term follow-up of study participants. A number of regulatory approvals are in place including the FDA IND the RAC, and the JHM-IRB-4. The immune monitoring assays are under development.
Author: Suzanne L. Walker
Publisher:
ISBN: 9781635930184
Category :
Languages : en
Pages :
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Author: Xiaozhou Fan
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Category :
Languages : en
Pages : 212
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Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) is a crucial inhibitory molecule to restrain T cell functions. CTLA-4 blockade with a monoclonal antibody (anti-CTLA-4) induces anti-tumor responses in a subset of patients and has been approved by the FDA as standard therapy for melanoma. We recently identified inducible costimulator (ICOS) as a crucial player in the antitumor effects of CTLA-4 blockade. We now show that concomitant CTLA-4 blockade plus ICOS engagement by tumor cell vaccines engineered to express ICOS-ligand enhanced anti-tumor immune responses in both quantity and quality and significantly improved rejection of established melanoma and prostate cancer in mice. This study provides strong evidence to support future combinatorial approaches incorporating anti-CTLA-4 plus ICOS engagement in the clinic. We explored another strategy to enhance anti-tumor response by targeting the migration of regulatory T cells into the tumor. We proposed certain chemokines and their cognate receptors play key roles in this process. Chemokine receptors CCR4 and CCR8 are preferentially expressed by regulatory T cells in the tumor where their ligands CCL1 and CCL17 are upregulated. CCL17 was able to induce specific migration of regulatory T cells from tumor-bearing mice, and we identified a CD11b + F4/80 + Gr-1 - population in the tumor as the major source of CCL17. With an in vivo migration assay and a bone marrow chimera model, we demonstrated that CCR4 is required for the migration of regulatory T cells to the vaccine site. Lastly, we found that transfer of small numbers of naive tumor-reactive CD4 T cells into lymphopenic recipients induces substantial T cell expansion, differentiation, and regression of large established tumors without the need for in vitro manipulation. Surprisingly, CD4 T cells developed cytotoxic activity, and tumor rejection was dependent on class II-restricted recognition of tumors by tumor-reactive CD4 T cells. Furthermore, blockade of the CTLA-4 on transferred CD4 T cells resulted in greater expansion of effector T cells, diminished accumulation of regulatory T cells, and superior antitumor activity. These findings suggest a novel potential therapeutic role for cytotoxic CD4 T cells and CTLA-4 blockade in cancer immunotherapy, and the potential advantages of differentiating tumor-reactive CD4 cells in vivo.
Author: Shuren Zhang
Publisher: Springer
ISBN: 9401775559
Category : Medical
Languages : en
Pages : 293
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This book provides readers an extensive overview of recent progress in basic and clinical research on cancer immunotherapy. Thanks to rapid advances in molecular biology and immunology, it has become increasingly evident that cancer growth is influenced by host immune responses. With the success of a number of clinical trials, immunotherapy has become a promising treatment modality of cancer. This book covers five major topics, including monoclonal antibodies, biological response modifiers, cancer vaccines, adoptive cellular therapy and oncolytic viruses. It also examines the combination of different immune strategies as well as the combination of immunotherapy with other treatments to increase anti-tumor effects. Through the comprehensive discussion of the topic, the book sheds valuable new light on the treatment of tumors.
