Harnessing Naturally Occurring Tumor Immunity: A Clinical Vaccine Trial in Prostate Cancer

Abstract

BackgroundStudies of patients with paraneoplastic neurologic disorders (PND) have revealed that apoptotic tumor serves as a potential potent trigger for the initiation of naturally occurring tumor immunity. The purpose of this study was to assess the feasibility, safety, and immunogenicity of an apoptotic tumor-autologous dendritic cell (DC) vaccine.Methods and FindingsWe have modeled PND tumor immunity in a clinical trial in which apoptotic allogeneic prostate tumor cells were used to generate an apoptotic tumor-autologous dendritic cell vaccine. Twenty-four prostate cancer patients were immunized in a Phase I, randomized, single-blind, placebo-controlled study to assess the safety and immunogenicity of this vaccine. Vaccinations were safe and well tolerated. Importantly, we also found that the vaccine was immunogenic, inducing delayed type hypersensitivity (DTH) responses and CD4+ and CD8+ T cell proliferation, with no effect on FoxP3+ regulatory T cells. A statistically significant increase in T cell proliferation responses to prostate tumor cells in vitro (p = 0.002), decrease in prostate specific antigen (PSA) slope (p = 0.016), and a two-fold increase in PSA doubling time (p = 0.003) were identified when we compared data before and after vaccination.ConclusionsAn apoptotic cancer cell vaccine modeled on naturally occurring tumor immune responses in PND patients provides a safe and immunogenic tumor vaccine. (ClinicalTrials.gov number NCT00289341).Trial RegistrationClinicalTrials.gov NCT00289341

Combining T-cell immunotherapy and anti-androgen therapy for prostate cancer

“…25,33–37 However, the clinical responses to some of these vaccines in patients with metastatic disease have not always been successful, 38 likely reflecting the fact that vaccines are often administered to patients with bulky or metastatic disease whose immune systems are frequently compromised because of disease burden and prior therapy and whose tumors express or overexpress ‘self antigens’ that are poorly immunogenic and against which circulating T cells are often anergized or tolerized. 39 …”

Concise Review: Mechanisms Behind Apoptotic Cell-Based Therapies Against Transplant Rejection and Graft versus Host Disease

“…Interaction with apoptotic cells not always suppresses immunity. Phagocytosis of stressed, activated, tumor, or infected cells undergoing apoptosis promotes DC maturation and immunity, and proinflammatory apoptotic cells have been tested to boost immunity for vaccination against cancer and pathogens . Besides the intrinsic properties of the apoptotic cells, the rate of apoptotic cell clearance, the microenvironment where it occurs, and the opsonins deposited on the apoptotic cells are factors that influence the impact of apoptotic cells on the target APCs and therefore, the consequent ability of the APCs to stimulate or suppress immunity .…”

RNA Regulation in Neurologic Disease and Cancer

“…Cloning of the cerebellar antigen (cdr2) associated more commonly with gynecologic cancer revealed the presence of antigen-specific T cells in these patients, establishing a cellmediated component to the disorders, as well as a means by which tumor antigen is likely cross-presented from apoptotic cells to dendritic cells to initiate the anti-tumor immune response (12,13). These studies have led to clinical cancer vaccine trials in prostate cancer patients that have shown some evidence of efficacy in Phase I safety studies (14). Moreover, cloning of the genes encoding T cell receptors from these patients offers a possible new therapeutic strategy, by passive transfer of these genes into T cells to induce tumor-cell targeting (15).…”