RESUMO
The 37-kDa immature laminin receptor protein (iLRP) is a speciesconserved, universal immunogenic protein that is expressed in all thus-far examined embryonic and early fetal cells of inbred and outbred rodents. It has also been identified in human concepti. It is altered through normal maturation processes to become a non-immunogenic 67-kDa dimeric mature laminin receptor protein (mLRP) in mid-to late gestation in the mammalian fetus. This antigen ceases to be expressed as an active autoimmunogen in the full-term fetus and in the normal differentiating tissues and organs of the neonate or adult organism, apparently due to dimerization, but it is re-expressed as an immunogenic monomer in tumor cells. In this review, we highlight the known mechanisms of immune responses with particular emphasis on the possible role of the 37-kDa oncofetal antigen/immature laminin receptor (OFA/iLRP) in both pregnancy and cancer.
Assuntos
Neoplasias/imunologia , Receptores de Laminina/imunologia , Proteínas Ribossômicas/imunologia , Adulto , Animais , Feminino , Humanos , Camundongos , Modelos Imunológicos , Neoplasias/metabolismo , Gravidez , Receptores de Laminina/metabolismo , Proteínas Ribossômicas/metabolismoRESUMO
Treatment of metastatic melanoma with chemotherapeutic regimens has led to disappointing response rates, duration of response and no appreciable impact on survival. Intralesional injection of a low dose of an HLA-B7/beta2 microglobulin plasmid formulated with cationic lipids (Allovectin-7 is a registered trademark of Vical, Incorporated, San Diego, California, USA) has been shown previously to be safe and well tolerated. A phase 2, open-label study was performed at 16 centers in the United States. Seventy-seven patients were treated with 10 mug intralesional Allovectin-7 weekly for 6 weeks and clinical response to treatment were evaluated by World Health Organization criteria. Minimal adverse events were associated with the Allovectin-7 injections. Seven patients (9.1%) had complete or partial response with 4.8 months median duration of response. Allovectin-7 was shown to be safe and exhibit biological activity at this dose. Its safety profile may enable Allovectin-7 to be used at higher doses, which may provide greater clinical activity.
Assuntos
DNA/uso terapêutico , Lipídeos/uso terapêutico , Melanoma/terapia , Neoplasias Cutâneas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , DNA Recombinante , Técnicas de Transferência de Genes , Terapia Genética , Humanos , Injeções Intralesionais , Lipossomos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Neoplasias Cutâneas/secundário , Taxa de Sobrevida , Resultado do Tratamento , Estados UnidosRESUMO
We describe here for the first time an efficient high yield production method for clinical grade recombinant human Oncofetal Antigen/immature laminin receptor protein (OFA/iLRP). We also demonstrate significant antitumor activity for this protein when administered in liposomal delivery form in a murine model of syngeneic fibrosarcoma. OFA/iLRP is a therapeutically very promising universal tumor antigen that is expressed in all mammalian solid tumors tested so far. We have cloned the human OFA/iLRP cDNA in a bacterial expression plasmid which incorporates a 6x HIS-tag. Large scale cultures of the plasmid transformed Escherichia coli were performed and the crude HIS-tagged OFA/iLRP was isolated as inclusion bodies and solubilized in guanidine chloride. The protein was then purified by successive passage through three column chromatography steps of immobilized metal affinity, anion exchange, and gel filtration. The resulting protein was 94% pure and practically devoid of endotoxin and host cell protein. The purified OFA/iLRP was tested in mice for safety and efficacy in tumor rejection with satisfactory results. This protein will be used for loading onto autologous dendritic cells in an FDA approved phase I/II human cancer vaccine trial in OFA/iLRP-positive breast cancer patients.
Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Fibrossarcoma/imunologia , Receptores de Laminina/imunologia , Proteínas Ribossômicas/imunologia , Sequência de Aminoácidos , Animais , Antígenos de Neoplasias/química , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/isolamento & purificação , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/metabolismo , Linhagem Celular Tumoral/imunologia , Ensaios Clínicos como Assunto , Clonagem Molecular , Modelos Animais de Doenças , Escherichia coli/genética , Feminino , Fibrossarcoma/metabolismo , Guanidina/farmacologia , Histidina/química , Humanos , Corpos de Inclusão/imunologia , Corpos de Inclusão/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Peso Molecular , Plasmídeos/genética , Controle de Qualidade , Receptores de Laminina/química , Receptores de Laminina/genética , Receptores de Laminina/isolamento & purificação , Proteínas Recombinantes/química , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/isolamento & purificação , Proteínas Ribossômicas/química , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/isolamento & purificação , Solubilidade , Transformação Bacteriana , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: Belagenpumatucel-L is a nonviral gene-based allogeneic tumor cell vaccine that demonstrates enhancement of tumor antigen recognition as a result of transforming growth factor beta-2 inhibition. PATIENTS AND METHODS: We performed a randomized, dose-variable, phase II trial involving stages II, IIIA, IIIB, and IV non-small-cell lung cancer patients. Each patient received one of three doses (1.25, 2.5, or 5.0 x 10(7) cells/injection) of belagenpumatucel-L on a monthly or every other month schedule to a maximum of 16 injections. Immune function, safety, and anticancer activity were monitored. RESULTS: Seventy-five patients (two stage II, 12 stage IIIA, 15 stage IIIB, and 46 stage IV patients) received a total of 550 vaccinations. No significant adverse events were observed. A dose-related survival difference was demonstrated in patients who received > or = 2.5 x 10(7) cells/injection (P = .0069). Focusing on the 61 late-stage (IIIB and IV) assessable patients, a 15% partial response rate was achieved. The estimated probabilities of surviving 1 and 2 years were 68% and 52%, respectively for the higher dose groups combined and 39% and 20%, respectively, for the low-dose group. Immune function was explored in the 61 advanced-stage (IIIB and IV) patients. Increased cytokine production (at week 12 compared with patients with progressive disease) was observed among clinical responders (interferon gamma, P = .006; interleukin [IL] -6, P = .004; IL-4, P = .007), who also displayed an elevated antibody-mediated response to vaccine HLAs (P = .014). Furthermore, positive enzyme-linked immunospot reactions to belagenpumatucel-L showed a correlation trend (P = .086) with clinical responsiveness in patients achieving stable disease or better. CONCLUSION: Belagenpumatucel-L is well tolerated, and the survival advantage justifies further phase III evaluation.