Combining Virotherapy and Immunotherapy for Cancer

结合病毒疗法和免疫疗法治疗癌症

• 批准号: 6846599
• 负责人: NORIYUKI KASAHARA
• 金额: $ 31.59万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-02 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6846599
• 关键词: Retroviridae; active immunization; aminohydrolases; antitumor antibody; astrocytoma; combination cancer therapy; cytotoxicity; disease /disorder model; flow cytometry; gene delivery system; gene therapy; glioma; laboratory rat; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; radiotracer; transfection /expression vector

DESCRIPTION (provided by applicant): The most prevalent problem in cancer therapy is the re-growth and metastasis of malignant cells after standard treatment with surgery, radiation, and chemotherapy. Gene therapy approaches have suffered from the inadequate transduction efficiencies of replication-defective vectors that have been used thus far. Replication-competent vectors represent an emerging technology that shows considerable promise as a novel treatment option, particularly for locally advanced or recurrent cancer. In contrast to conventional replication-defective retrovirus vectors, gene transfer using replication-competent murine leukemia virus (MLV)-based retrovirus vectors has proven to be highly efficient, resulting in >98% transduction throughout entire tumors over a period of several weeks in breast cancer, prostate cancer, and glioma models, even with an initial inoculum of vector supematant as low as 10e(4-5) total infectious units, corresponding to MOIs as low as 0.001. While various other replicating oncolytic viruses are now in development as cancer therapeutics, the use of replication-competent retrovirus (RCR) vectors has rarely been contemplated due to the potential risks that might be associated with uncontrolled spread of virus. In fact, MLV-based RCR vectors exhibit a significant degree of inherent tumor-selectivity, as extratumoral spread was undetectable by sensitive PCR assays in all normal tissues tested, presumably due to the intrinsic inability of MLV to infect quiescent cells, and MLV exhibits additional advantageous characteristics including a simple genome and well-characterized life cycle, fidelity of transcriptional regulation, and efficient non-lyric transmission of suicide genes which are stably expressed until maximal intratumoral vector spread and optimal timing for pro-drug administration is reached. Using RCR vectors expressing the suicide gene cytosine deaminase, we have now demonstrated highly efficient killing of cancer cells both in culture and in tumor models in vivo. Treatment of intracranial gliomas with RCR vector-mediated suicide gene therapy resulted in 100% survival for >120 days, compared to 0% survival of control groups in < 40 days, and viral persistence was observed in all metastatic ectopic foci. We now propose that the efficient and stable conferral of viral neo-antigens to the tumor cells present an opportunity to further improve the long-term efficacy of this therapy by combining multiple approaches, including (1) seroimmunotherapy by follow-up administration of radioisotope-conjugated antibodies directed against viral proteins, and (2) active immunotherapy by peripheral sensitization with tumor vaccines expressing viral antigens, combined with intratumoral gene transfer of immunostimulatory cytokines. In this application, we have combined the expertise of multiple collaborators to directly test these approaches in syngeneic intracranial glioma models in vivo.

描述（由申请人提供）：癌症治疗中最普遍的问题是通过手术，放射和化学疗法进行标准治疗后恶性细胞的重新增长和转移。迄今为止使用的复制缺陷向量的转导效率不足，基因治疗方法的转导效率不足。具有复制能力的载体代表了一种新兴技术，该技术表现出很大的希望作为一种新的治疗选择，尤其是对于本地晚期或经常性癌症。与常规复制反逆转录病毒载体相反，基因转移基因转移基于复制的鼠白血病病毒（MLV）的逆转录病毒载体已被证明非常有效，在整个肿瘤的整个肿瘤中，在整个肿瘤的整个肿瘤中，乳腺癌，前列腺癌，前列腺癌，以及在整个肿瘤中都具有> 98％的转导，以及在乳腺癌中，以及在前列腺癌中，以及在乳腺癌中，以及胶质瘤的最初效果，以及在乳腺癌中的初步效果。 10E（4-5）总传染单元，对应于MOI低至0.001。尽管目前作为癌症治疗剂现在正在开发其他各种复制的溶瘤病毒，但由于可能与可能与病毒的不受控制传播有关的潜在风险，因此很少考虑使用复制能力逆转录病毒（RCR）载体（RCR）载体。实际上，基于MLV的RCR载体表现出很大程度的固有肿瘤选择性，因为在所有经过测试的正常组织中，无法通过敏感的PCR测定无法检测到肿瘤的蔓延，这可能是由于MLV对MLV的内在能力而导致的，并且MLV表现出更简单的基因组和良好的生命效果，并表现出额外的优势特征，并具有良好的基因组和良好的生命周期（firditive confortials ford）。自杀基因的非乳酸传播稳定地表达，直到达到最大肿瘤内载体扩散和用于促毒物给药的最佳时机。使用表达自杀基因胞嘧啶脱氨酶的RCR载体，我们现在已经证明了体内培养物和肿瘤模型中癌细胞的高效杀死。用RCR介导的自杀基因治疗对颅内神经胶质瘤的治疗可导致100％的存活率> 120天，而对照组在<40天内的存活率为0％，并且在所有转移性分泌灶中均观察到病毒持久性。现在，我们提出，病毒新抗原对肿瘤细胞的有效且稳定的赋予了一个机会，通过结合多种方法，包括（1）通过对放射性偶发偶联性抗体的导致病毒蛋白和（2）促进性抗体（2）促进性抗体（2）抗体的抗体，以进一步提高该疗法的长期疗效，包括（1）血清免疫疗法（2），（1）通过（1）疗法进行（2）疗法。抗原，结合免疫刺激细胞因子的肿瘤内基因转移。在此应用程序中，我们将多个合作者的专业知识结合在一起，可以直接测试体内颅内胶质瘤模型中的这些方法。