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bminev
Member since: Aug 31, 2008
From: California, United States
Status: Immunology Moderator
My points: 6    what's this
Name: [Privacy]
 


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My Disciplines: not given
Areas of Interest: not given

About My Research

Research Topics
Cancer, Cancer Vaccines, Glioma, Melanoma, Nanotechnology, Prostate Cancer

My research has been focused on the discovery of new target antigens for immunotherapy of cancer and the development of optimized cancer vaccines. Most recently, I worked on a new nanotechnology-based cancer vaccine delivery platform.

In order to effectively treat the very heterogenic metastatic tumors, it is critical to identify novel markers and therapeutic targets for tumor immunotherapy. My group utilizes a variety of predictive computer algorithms, binding assays and in vitro sensitization assays to identify new antigens and antigenic peptides suitable for specific immunotherapy of several tumor types. Recently identified target antigens and relevant antigenic peptides include STEAP (six-transmembrane epithelial antigen of the prostate), expressed in prostate cancer and many other cancer types; oncofetal antigen (OFA), expressed in breast cancer and most of the tumor types tested so far; PRAME – a member of the cancer/testis family of antigens, widely expressed in many different tumor types; the universal tumor antigen telomerase; the melanoma antigen MG50; and the universal tumor antigen survivin.

Significance: These antigens are up regulated in many tumor types of different histological origin. This renders the tumor cells susceptible to destruction by the cytotoxic T lymphocytes (CTL) and underscores the potential advantage antigen immunization may have in the control of primary tumors and metastases in a large variety of tumor types in humans.

Because most attempts to treat cancer patients with antigen-derived synthetic peptides have not been successful, further research aimed at enhancing the stability and immunogenicity of the peptides used for vaccination of patients with cancer is essential. In order to design synthetic vaccines for cancer, suitable for clinical application, my group utilizes several modern approaches for vaccine design, including terminal modifications to inhibit proteolytic degradation of the peptides, amino acid substitutions to enhance the MHC binding affinity and the T cell receptor binding affinity of these peptides, and endoplasmic reticulum insertion signal sequences to enhance their antigen presentation. My group then uses these vaccines to generate in vitro antigen-specific CTL lines and clones from healthy volunteers and from patients with cancer. They also test the ability of these antigen-specific CTL to recognize and kill cancer cells in a class I-restricted and antigen-dependent fashion. 

Significance: The design of optimized vaccines based on tumor associated antigen-derived peptides will undoubtedly contribute to the development of more efficient approaches for treatment of cancer. These vaccines might be used directly to immunize patients with cancer. Dendritic cells loaded with these vaccines can also be used to elicit powerful anti-tumor immune responses. In addition, antigen-specific CTL might be extremely useful for cellular immunotherapy of cancer. Therefore, the findings of these studies will be used in translational and clinical programs that will benefit many patients with cancer.

I also work on a new approach for the immunotherapy of cancer, which is based on the synergistic effect created by using hyperthermia and immunotherapy. This approach uses whole-body hyperthermia induced by dengue virus to selectively kill tumor cells due to their altered blood supply and lactic acid production rates. The levels of fever induced by dengue virus are capable of killing most of the tumor cells, allowing for a higher efficiency of killer cells created by a subsequent vaccination with peptide-pulsed dendritic cells. In addition, dengue infection induces large quantities of TH1 and inflammatory cytokines, which increase the vulnerability of the tumor cells by upregulating their MHC molecules, and by inducing massive proliferation of highly activated killer cells. Therefore, the use of whole body hyperthermia in combination with peptide-pulsed dendritic cells offers a promising new approach to immunotherapy of cancer.

Gliomas are among the most common tumors of the central nervous system and even with the best conventional treatments, the median survival time for patients with gliomas is only one year. Therefore, there is a critical need to discover new therapeutic strategies that specifically target gliomas. Recently, the apoptosis-inhibitor protein survivin has been recognized as a widely occurring tumor antigen. We suggested that survivin is an ideal target for the immunotherapy of the gliomas because of its strong expression in most gliomas, little or no expression in adult tissues, and its essential role for the survival of the tumor cells. He identified recently a variety of class I-restricted immunogenic survivin-derived peptides and designed new synthetic vaccines with enhanced stability and immunogenicity. Importantly, using these vaccines, he was able to generate survivin-specific CTL that effectively recognized and killed glioma cells, expressing survivin. These findings confirm that peptides derived from the sequence of survivin are naturally expressed on the surface of the glioma cells, serving as targets for the cytotoxic T lymphocytes. Because survivin is highly expressed in most gliomas, vaccine strategies aimed at this antigen may have important clinical applications.

Significant advances in biotechnology and biochemistry have led to the discovery of a large number of cancer vaccines based on peptides and proteins. However, the development of suitable and efficient carrier systems remains a major challenge since the vaccine bioavailability is limited by enzymatic degradation. We suggested that polymeric nanoparticles, defined as solid particles with a size in the range of 10-1000 nm, allow encapsulation of the vaccines inside a polymeric matrix, protecting them against enzymatic and hydrolytic degradation. In addition, the nanoparticle vaccine approach offers the possibility of providing tailor-made properties of the vaccine materials that may improve their function. We proposed a new strategy for the design and synthesis of polymeric nanoparticles that enhance the cytoplasmic delivery of the peptide vaccines into the antigen presenting cells by disrupting the endosomal membrane at the acidic pH of the endosome. These acid-sensitive nanoparticles, 200-500 nm in diameter, are designed to disrupt the endosomes and deliver protein antigens into the cytoplasm of the antigen-presenting cells for class I antigen presentation. They are chemically stable at pH 7.4 but degrade into linear polymer chains and small molecules under mildly acidic conditions. The molecular design of these nanoparticles should allow them to circulate in the blood, at pH 7.4, but then rapidly hydrolyze after endocytosis in the acidic environment of the endosomes. In this project we utilized several tumor antigen-derived peptides encapsulated in acid-sensitive nanoparticles to induce potent and specific CTL responses against the tumor antigens. We designed and prepared a variety of nanoparticles formulated with different tumor antigen-derived peptides, and is testing their ability to induce antigen-specific CTL in vitro and in vivo

Significance: The development of nanoparticle-based vaccines for cancer is innovative and holds great promise. Like the biological systems, these nanoparticles combine targeting elements that direct cellular uptake, together with the sensing of pH changes within the endosome to activate membrane destabilization and cytosolic delivery. Their intrinsic modular design makes it possible to tailor the targeting and membrane destabilizing activities for a wide range of biotherapeutics and vaccine applications. These vaccines might be used directly to immunize patients with cancer. In addition, they may be used in the future to generate and expand in vitro CTL for adoptive transfer therapies. Therefore, the findings of this study will potentially benefit many patients with cancer.

My Affiliations:

not given

My Publications:

No Publications found

Off the bench I enjoy:

not given