Cell-based vaccines for renal cell carcinoma: genetically-engineered tumor cells and monocyte-derived dendritic cells (original) (raw)
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Translational Mini-Review Series on Vaccines: Dendritic cell-based vaccines in renal cancer
Clinical & Experimental Immunology, 2007
Renal cancer is a relatively uncommon solid tumor, accounting for about 3% of all adult malignancies, however this rate incidence is rising. The most common histological renal cell carcinoma (RCC) subtype is clear cell carcinoma that makes up approximately 70-80% of all renal neoplasms and appears to be the only histological subtype that is responsive to immunotherapeutic approaches with any consistency. Therefore, it has been hypothesized that immune-
A generic RNA-pulsed dendritic cell vaccine strategy for renal cell carcinoma
Journal of Translational Medicine, 2005
We present a generic dendritic cell (DC) vaccine strategy for patients with renal cell carcinoma (RCC) based on the use of RNA as a source of multiplex tumor-associated antigens (TAAs). Instead of preparing RNA from tumor tissue of each individual RCC patient, we propose to substitute RNA prepared from a well characterized highly immunogenic RCC cell line (RCC-26 tumor cells) as a generic source of TAAs for loading of DCs. We demonstrate here that efficient RNA transfer can be achieved using lipofection of immature DCs, which are subsequently matured with a cytokine cocktail to express high levels of MHC and costimulatory molecules as well as the chemokine receptor CCR7. Neither RNA itself nor the lipid component impacted on the phenotype or the cytokine secretion of mature DCs.
Dendritic Cell–Based Immunotherapy in Prevention and Treatment of Renal Cell Carcinoma
Journal of Immunotherapy, 2013
The dendritic cell vaccine DC-Ad-GMÁCAIX is an active, specific immunotherapy with the potential of providing a safe and effective therapy against renal cell carcinoma (RCC). Using immunocompetent Balb/c mouse models we tested the efficacy and mechanism of the vaccine to prevent and treat the growth of a syngeneic RCC (RENCA) engineered to overexpress the human TAA carbonic anhydrase IX (NPR-IX). In a prevention model, NPR-IX tumor development was specifically and significantly delayed by 13 days in DC-Ad-GMÁCAIX-treated mice (P < 0.001), tumor volumes were 79% smaller (day 24, P < 0.007), and body weight was maintained at study termination compared with the controls. Six of these mice remained tumor-free for >1 year. In a treatment model, NPR-IX tumors remained smaller in DC-Ad-GMÁCAIX-treated mice for 8 days (P < 0.002), achieving a 60% growth inhibition at termination. No vaccine-related organ toxicity was observed in either model. The critical mechanistic parameter separating responsive from nonresponsive tumors was hCAIX protein expression, demonstrated by aggressive growth of tumors that did not express hCAIX protein and in sham-treated mice (DC-Ad-Null). No murine serum anti-hCAIX antibodies were detected. Moreover, altered mechanisms of immunoediting as a means for immune evasion were suggested by differential gene expression (Ccl1, Hmgb1, Fgl2, Cd209a, and Klra2) and therapy evasion miRNAs (miR-1186, miR-98, miR-5097, miR-1942, and miR-708) in tumors that evaded DC-Ad-GMÁCAIX immunotherapy. This is the first study in immunocompetent mice that provides a proof of concept for the specificity, efficacy, safety, and activity of the DC-Ad-GMÁCAIX immunotherapy, forming the basis for a first-in-human phase I trial in RCC patients.
Update on vaccine development for renal cell cancer
Open Access Journal of …, 2010
Renal cell carcinoma (RCC) remains a significant health concern that frequently presents as metastatic disease at the time of initial diagnosis. Current first-line therapeutics for the advanced-stage RCC include antiangiogenic drugs that have yielded high rates of objective clinical response; however, these tend to be transient in nature, with many patients becoming refractory to chronic treatment with these agents. Adjuvant immunotherapies remain viable candidates to sustain disease-free and overall patient survival. In particular, vaccines designed to optimize the activation, maintenance, and recruitment of specific immunity within or into the tumor site continue to evolve. Based on the integration of increasingly refined immunomonitoring systems in both translational models and clinical trials, allowing for the improved understanding of treatment mechanism(s) of action, further refined (combinational) vaccine protocols are currently being developed and evaluated. This review provides a brief history of RCC vaccine development, discusses the successes and limitations in such approaches, and provides a rationale for developing combinational vaccine approaches that may provide improved clinical benefits to patients with RCC.
Cancer Immunology, Immunotherapy, 2002
In this study we have presented in vitro data and results of a preliminary clinical trial using dendritic cells (DC) in patients with progressive metastatic renal cell carcinoma. DC precursor cells were obtained from peripheral blood mononuclear cells (PBMC). DC were pulsed with autologous tumor cell lysate if available. In total, 15 patients were treated with a median of 3.95•10 6 DC administered and ultrasound-guided into a lymph node or into adjacent tissue. Seven patients remained with progressive disease (PD), 7 patients showed stable disease (SD), and one patient displayed a partial response (PR). Most interestingly, the patient who was treated with the highest number of DC (14.4•10 6 DC/ vaccine) displayed a PR. Delayed-type hypersensitivity (DTH) reaction using autologous tumor lysate was positive in 3 out of 13 patients, including the patient with PR. Two out of 3 patients receiving additional treatment with keyhole limpet hemocyanin (KLH) showed reactivity to KLH after vaccination. CD3 + CD4 + and CD3 + CD28 + cells as well as the proliferation rate of peripheral blood lymphocytes (PBL) increased significantly in the blood of patients during therapy. In conclusion, our observations confirm the capability of tumor-lysate pulsed autologous DC vaccines to stimulate an immune response in patients with metastatic renal cell carcinoma even in the presence of a large tumor burden. The lack of adverse effects together with immunologic effects support further investigation of this novel therapeutic approach. Further studies are necessary to demonstrate clinical effectiveness in cancer patients, in particular in patients with less advanced disease.
Cancer Biotherapy and Radiopharmaceuticals, 2000
Objective: We have tried to establish short-term cultures ofautologous tumors from patients with renal cell carcinoma that could be used as active specific immunotherapy (i.e., autologous vaccine) in such patients after resection ofprimary kidney cancer, and/or for the treatment of metastatic cancer. Methods: Between 10/90 and 9/99 the cell biology laboratory of the Hoag Cancer Center received 69 kidney tumor samples that had been surgically excised, including 43 primary tumors and 26 metastatic lesions. Efforts were made to establish short-term tumor cell cultures, as defined by the growth of IO8 cells; malignant nature and renal cell origin were confirmed by morphology and antigenic phenotyping. Variables associated with successful growth of short-term cell lines were examined. Results: Short-term cell lines were successfully established from 55/69 samples [80%] including 36/43 (84%) from primary tumors and 19/26 (73%) from metastatic lesions. The success rate for tumors harvested at Hoag Hospital was 40/50 (80%); the success rate for tumors obtained from other geographic areas was 15/19 (79%). Tumor cell lines were successfidly established from metastatic lesions ranging in size from a 0.5 g vertebral lesion toa 22 g rib/lung chest wall metastasis, and from primary renal cell lesions ranging in size from 1.5 g to 39. 7g. Conclusions: Short-term cell lines can be established for most patients with primary or metastatic renal cell carcinoma making a pure autologous tumor-cell vaccine approachfeasible. Vaccines have been preparedfor 41 patients and a vaccine therapy trial is in progress.
Vaccines in Renal Cell Carcinoma
Seminars in Oncology, 2006
Considerable progress in our understanding of the molecular and cellular events that promote growth and progression of renal cell carcinoma (RCC) has dramatically improved the prospects of significantly altering the progression and metastatic potential of renal neoplasms. Cancer vaccination, one form of active specific immunotherapy, represents a promising approach which aims to expand the number of T cells capable of reducing/ eradicating the tumor mass, and to induce tumor-specific memory T cells that control tumor recurrence. Over the past decade, a number of vaccine strategies have moved from the bench to the bedside and have now become subject to rigorous clinical investigation. This review will examine the current status of vaccine-based therapy for advanced RCC, discuss their mechanisms of action, and provide information on relevant clinical trials. Also discussed are future applications that seek to enhance the vaccine-mediated T-cell response or to make vaccines applicable to broader patient cohorts.
Developing a Rational Tumor Vaccine Therapy for Renal Cell Carcinoma: Immune Yin and Yang
Clinical Cancer Research, 2007
In patients with progressive malignancy, the natural balance between proinflammatory (Yang) and inhibitory (regulatory or Yin) immune pathways is disrupted and favors cancer-specific immune suppression. Therapy with interleukin 2 (IL-2) can mobilize immune effector cells that recognize and destroy cancer. High-dose IL-2 is the only therapy that has consistently induced complete durable remissions in patients with metastatic renal cell carcinoma (RCC) but only in a few of them. The lack of benefit in most metastatic RCC patients is likely due to the ineffective manipulation of other immune circuits critical in regulating tumor cytotoxic pathways. The limited clinical activity of IL-2, RCC vaccines, and other immune therapies to date leads us to postulate that effective clinical treatment strategies will need to simultaneously enhance proinflammatory pathways and disrupt regulatory pathways. We present preliminary studies in RCC patients to highlight the complexity of the regulatory pathways and our approach to shifting the balance of proinflammatory and regulatory immune pathways using dendritic cell^tumor lysate vaccine followed by cytokine therapy.