This clinical translational proposal aimed to assess the therapeutic potential of genetically targeted T cells in the treatment of leukemia and lymphoma. The introduction of genes that code for tumor-specific receptors into T lymphocytes, which are cells of the immune system that mediate tumor elimination, was a novel approach to cancer therapy.
Dr. Sadelain demonstrated that human peripheral blood T cells could be effectively redirected to recognize the CO19 antigen and eradicate established, systemic human B cell tumors borne by immunodeficient mice, This was the first publication showing that genetically modified human T cells can induce durable remissions in an in vivo setting.
Importantly, he found that T cell stimulation with the cytokine lnterleukln-15, but not the widely used lnterteukin-2, is critical for sustaining the therapeutic activity of infused CO19-spedflc T cells. Having examined the nature of the signals required by the T cells for their own survival and sustained functionality, Dr. Sadelain designed improved antigen receptors that provide both activating and co-stimulatory signals to the tumor-targeted T cell.
The specific alms of the 2004 application included:
- Demonstrating the therapeutic efficacy of leukemia and lymphoma patients’ cos+ T lymphocytes transduced with the 19/28z receptor In tumor-bearing mice
- Establishing clinical conditions for patient T cell purification, transduction and expansion, for review by the FDA
- Investigating, in a phase I clinical trial In patients with relapsed B cell leukemias, the safety, persistence and therapeutic efficacy of autologous IL15-actlvated CDS+ T cells that express 19/2Sz
Dr. Pun’s award is in honor of Patricia Zoch Tate who succumbed to pancreatic cancer in 2005. The study will research treatment of tumors using a targeted non-viral mode of delivery. Tumors exist as dense masses in the body. The physical structure of these solid tumors presents a formidable challenge to drug delivery vehicles that need to penetrate and reach all cancer cells in order to be optimally effective.
The goal of this research is to develop synthetic nanoparticles that efficiently penetrate solid tumors. I am convinced that the efficacy of gene therapy can be substantially improved by designing delivery systems that overcome physical barriers.
Ovarian cancer is the leading cause of gynecologic cancer death, and though most patients respond to initial chemotherapy, the majority will eventually relapse and die of chemotherapy resistant disease. Despite the advent of newer chemotherapies, the five-year survival for patients with advanced disease remains only 25 percent, and few patients are cured.
In preliminary studies, we have developed genetically engineered T cells as a complementary immunotherapy to augment traditional treatment strategies. The engineered T cells eradicate large tumors in pre-clinical experiments.
In this project, we will conduct FDA-mandated pre-clinical experiments, manufacture clinical grade vector, obtain local IRB approval and FDA and NIH/OBA RAC federal approval for the protocol, and then conduct the clinical protocol.
The protocol will test whether the T cells that are designed to withstand the toxic effects of the tumor are able to mediate tumor regression in patients with advanced ovarian cancer that has failed to regress after chemotherapy.
Anti-angiogenesis is a way of strangulating the blood supply of a tumor, since without new blood, the tumor cannot survive. Dr. Jain’s study will test an alternative treatment using a special polymer compound to deliver genes to the tumor site. Angiogenesis, the growth of new blood vessels, is critical for the development and progression of cancerous tumors. The identification of mechanisms to retard new blood vessel formation is likely to provide a novel approach to treat cancer.
Immunotherapy using gene-transduced tumor cells has emerged as a potentially plausible approach for the control of advanced stage ovarian cancer. We have recently demonstrated that vaccination with irradiated murine allogeneic ovarian cancer cells secreting heat shock protein 70 (Hsp70) were capable of generating potent tumor antigen-specific immune responses and strong anti-tumor effects against ovarian cancers (Chang et al. Cancer Research 2007; 67, 10047-10057).
Hsp70 has been shown to bind antigenic peptides from tumors. The secretion of Hsp70 from the ovarian cancer cells will allow the Hsp70-associated antigenic peptide to be concentrated and targeted to dendritic cells (DCs) with subsequent DC activation. Based on the encouraging preclinical data, we propose to generate a clinical grade tumor cell-based vaccine engineered to secrete high levels of Hsp70. We have access to several high grade serous carcinoma cell lines, that express several known tumor antigens, such as CA-125 and mesothelin.
The generation of the cGMP clinical lots of a tumor cell-based vaccine using high grade serous carcinoma cell lines that secrete high levels of Hsp70 represents an innovative approach that may create an opportunity for the therapy of these devastating ovarian cancers. This product will form the basis for the development of a pipeline of immunotherapeutic approaches at Johns Hopkins University. Thus, in the current proposal, we propose the following.
- Specific Aim 1: To generate and characterize a high grade serous carcinoma cell line that stably secretes high levels of Hsp70.
- Specific Aim 2: To cGMP manufacture and release Master Cell Banks and a clinical lot, per FDA CBER guidelines, of the Hsp70-secreting ovarian cancer cell-based vaccines.
- Specific Aim 3: To perform phase I clinical studies using clinical grade Hsp70-secreting ovarian cancer cell-based vaccines in patients with high grade serous carcinoma.
- Specific Aim 4: To characterize tumor antigen-specific CD8+ T cell immune responses in vaccinated individuals.
Successful implementation of the current proposal may lead to the development of an innovative therapeutic vaccine against high grade ovarian serous carcinoma. We are currently testing two distinct types of cancer vaccines developed at Johns Hopkins, including a mesothelin-expressing Listeria-based vaccine, which is being developed by Anza Therapeutics and the GM-CSF secreting K562 cell line, which is being developed by Cell Genesys.
The mesothelin-expressing Listeria-based vaccine is currently being tested in patients with pancreatic cancer and mesothelioma, while the GM-CSF secreting K562 cell line is being tested in chronic myeloid leukemia patients. Given the suitable safety of the proposed Hsp70-secreting ovarian cancer cell-based vaccine, we will also examine its application in combination with mesothelin- expressing Listeria and/or GM-CSF secreting K562 cell lines to further enhance the tumor specific immune responses.
Lung cancer remains one of the greatest public health threats, despite advancement in the understanding of molecular genetics. We have been accumulating preliminary data and developing reagents for this project for the past two years, and we are encouraged by the early results of using PUMA, a protein, as a novel target to selectively encourage apoptosis, cell death, in lung cancer cells. With this funding, we will be able to expand the research into animal model trials, and it is our hope that these efforts will allow us to examine the feasibility of moving PUMA gene therapy towards clinical trials.
