The goal of therapeutic cancer vaccines is to "teach" the patient's own immune system to attack cancer cells while sparing other cells. This is done by repeatedly exposing the immune system to a substance (antigen) that is specific to cancer cells in a way that subsequently induces an immune response to any cells that express that antigen on their surface. We believe that the characteristics of telomerase make it an ideal antigen for cancer vaccines.
GRNVAC1 is an autologous product consisting of mature dendritic cells (the body's most powerful antigen-presenting cells) pulsed with RNA for the protein component of human telomerase (hTERT) and a portion of a lysosomal targeting signal (LAMP). GRNVAC1 is injected into the patient?s skin; from there the dendritic cells travel to the lymph nodes and instruct cytotoxic T-cells to kill tumor cells that express telomerase on their surface.
The first clinical study of GRNVAC1 was conducted at Duke University Medical Center. Data from this Phase I clinical trial in prostate cancer patients were published in the Journal of Immunology in March 2005. Several small additional Phase I/II trials, which concluded in 2006, in patients with prostate cancer, hematologic malignancies and renal cell carcinoma were performed at Duke in order to optimize the vaccination process. As a result of positive data from these studies, we brought the vaccine manufacturing process in-house for further optimization and transferred it to a contract manufacturer.
The Geron-sponsored clinical study of GRNVAC1 is being conducted at six U.S. medical centers. This Phase II clinical trial is using a prime-boost vaccination protocol in patients with acute myelogenous leukemia (AML) in complete clinical remission and examines the safety and feasibility of a prime-boost vaccination regimen to extend the duration of telomerase immunity. Also we are evaluating the immune response to GRNVAC1 and exploring the effects of vaccination on minimal residual disease and relapse rates. This trial completed patient enrollment in December 2009.
In the AML Phase II trial, patients enter the study in their first or second complete remission. Prior to or shortly after completing consolidation chemotherapy, patients undergo leukapheresis to harvest normal peripheral blood mononuclear cells for vaccine manufacture. Patient mononuclear cells are differentiated in culture to immature dendritic cells, which are transfected with messenger RNA encoding hTERT and LAMP. Transfected dendritic cells are matured, aliquoted and cryopreserved. GRNVAC1 is released for patient dosing contingent on several product specifications including, identity of mature dendritic cells, confirmation of positive transfection with hTERT, number of viable cells per dose after thawing and product sterility. Patients are vaccinated weekly for six weeks, followed by a rest period of four weeks, and subsequent boost injections every other week for 12 weeks. Monthly extended boost injections are then administered until the vaccine product supply is depleted or the disease relapses. Click here for clinical trial information.
Twenty patients in the study have received GRNVAC1 product. One patient relapsed prior to vaccination. GRNVAC1 was found to be safe and generally well tolerated over multiple vaccinations, including one patient who has received 28 serial vaccinations. Idiopathic thrombocytopenic purpura (grade 4) was reported in one patient. Other toxicities were mild to moderate, including rash or headache in 15-20% of patients.
At the December 2009 American Society of Hematology annual meeting we presented interim data from the Phase II study in patients with AML. At the time of the presentation, 14 out of 20 patients in the study remained in complete clinical remission (CR). Median duration of CR, including the patients who had relapsed, was 12 months. Six of the patients in CR were in the extended boost phase of vaccination and the duration of their remission since the start of vaccination ranged from four to 20 months. Four of these six patients are considered at a high risk of relapse as predicted by their cytogenetics or because they are in the second CR. Follow-up of the patients for an additional nine months is required in order to estimate the impact of vaccination on disease-free survival.
Expression of WT-1, as a marker of minimal residual disease, was sequentially analyzed by qPCR in 19 patients. The 14 patients who remain in CR were negative for WT-1, while four of five with clinical relapse were WT-1 positive. One patient was positive for WT-1 prior to vaccination with GRNVAC1 and became WT-1 negative during the course of vaccination.
Patient immune response to telomerase after vaccination with GRNVAC1 was evaluated using two methods: the delayed-type hypersensitivity (DTH) skin response and the ELISPOT assay to measure the presence of activated T-cells specific to hTERT. Positive overall immune responses were detected in 12 out of 20 patients. No correlation has yet emerged between positive immune response and patient remission status.
In 2004, we acquired rights from Argos Therapeutics, Inc. (formerly Merix) to commercialize the ex vivo dendritic cell processing technology used in the Duke clinical trials for telomerase and other defined tumor-specific antigens. We own the rights to the telomerase antigen and its use in therapeutic vaccines.
In 2006, we licensed rights from Immunomic Therapeutics, Inc. to the LAMP antigen targeting sequence for use in cancer vaccines. The LAMP sequence causes an antigen to which it is attached to be taken up by the lysosomal subcellular compartment of the cell. This has been shown to increase presentation on MHC class II molecules, which in turn, can produce greater CD4+ T-cell responses against the antigen and a more potent and longer lasting overall immune response.
In July 2005, we entered into a worldwide exclusive research, development and commercialization license agreement with Merck & Co., Inc. for cancer vaccines targeting telomerase by methods other than dendritic cell delivery. In December 2007, Merck filed an IND to initiate a clinical trial for their cancer vaccine candidate that targets telomerase. In 2008, Merck initiated a Phase I clinical trial of V934/V935, a non-dendritic cell-based cancer vaccine candidate targeting telomerase. The trial will assess the safety, tolerability and immunogenicity of the vaccine candidate in patients with solid tumors, including non-small cell lung cancer and prostate carcinoma. The trial has completed patient enrollment and boost vaccination and/or follow-up of patients is ongoing.
In 2006, we entered into a worldwide exclusive license and collaboration agreement with the University of Oxford to produce dendritic cells from hESCs. The scalable production of dendritic cells from hESCs could serve as an alternative to isolating dendritic cells from each patient, and possibly as a broadly useful vaccine delivery vehicle. In another form, dendritic cells may act to block an immune response against an antigen by teaching the immune system not to attack it - a process known as "tolerizing" the individual to that antigen. Since the same pluripotent hESC line could be used to generate both tolerizing dendritic cells and therapeutic cells, co-administration of these two cell populations could potentially circumvent immune rejection without the need for immunosuppressive drugs.
With our collaborators in Oxford, we have demonstrated that dendritic cells scalably manufactured from hESCs exhibit the normal functions of naturally occurring human dendritic cells found in the bloodstream. The data, published in Regenerative Medicine in July 2009, showed that immature hESC-derived dendritic cells are able to take up, process and present antigens, and then, following maturation in the manufacturing process, are able to migrate, produce pro-inflammatory cytokines and induce specific immune responses to both tumor and viral antigens in vitro.
The goal of therapeutic cancer vaccines is to "teach" the patient's own immune system to attack cancer cells while sparing other cells. This is done by repeatedly exposing the immune system to a substance (antigen) that is specific to cancer cells in a way that subsequently induces an immune response to any cells that express that antigen on their surface. We believe that the characteristics of telomerase make it an ideal antigen for cancer vaccines.
