Pilot trial with a tetravalent conjugate vaccine against small cell lung cancer

描述(由申请人提供)：这一阶段的STTR申请是针对小细胞肺癌的抗体诱导四价疫苗的试点临床试验。它的基础是30年的研究，在此期间，1)确定了针对癌细胞表面抗原的最佳抗体反应的疫苗设计，2)在临床前研究中证明了在循环肿瘤细胞和微转移为主要目标的最小疾病环境中免疫的好处，3)定义了常见癌症表达的抗原并确定了与SCLC疫苗相关的4种抗原，4)在随机第二阶段试验中选择了最有希望进行测试的SCLC四价疫苗，5)针对这4种抗原的单价疫苗的安全性和免疫原性被确认，并确定了在化疗后辅助环境中患者中每种疫苗的最佳剂量，6)疫苗生产技术被成功转移到GMP合同设施(Althea Technologies，Inc.)这样就可以为多中心的2期临床试验准备结合物。拟议的试点试验的主要终点是安全性和免疫原性。由于这种四价疫苗中的个别结合物是由GMP机构根据合同制备的，而不是像过去那样在MSKCC制备，而且将一起接种和给药，而不是单独给患者，所以安全性和免疫原性问题不是微不足道的。如果这种GMP级四价疫苗在第一阶段申请支持的试点试验中被证明是安全的和免疫原性的，将提交第二阶段STTR申请，以支持随机、安慰剂对照的第二阶段试验。本文提出的抗小细胞肺癌(SCLC)细胞表面抗原的四价疫苗产生的抗体和抗体非常适合于清除游离的SCLC细胞和微转移。如果能针对这些抗原诱导出效价足够高的抗体，以消除血液中的肿瘤细胞和微转移，这将极大地改变我们治疗小细胞肺癌患者的方法。新转移的建立将不再可能，所以更积极的局部治疗，包括手术或已知最小残留转移的放射治疗，可能导致即使是转移的小细胞肺癌的长期控制。

DESCRIPTION (provided by applicant): This Phase 1 STTR application is for a pilot clinical trial of an antibody inducing tetravalent vaccine against SCLC. Its foundation is 30 years of studies during which time 1) vaccine design for optimal antibody responses against cancer cell surface antigens was determined, 2) the benefit of immunization in the minimal disease setting where circulating tumor cells and micrometastases are the primary targets was demonstrated in preclinical studies, 3) the antigens expressed by the common cancers were defined and the 4 antigens relevant for a SCLC vaccine identified, 4) the SCLC tetravalent vaccine was selected as the most promising for testing in a randomized Phase 2 trial, 5) the safety and immunogenicity of monovalent vaccines against these four antigens was confirmed and, the optimal dose of each vaccine in patients in the post chemotherapy adjuvant setting was determined, and 6) technology for vaccine production was successfully transferred to a contract GMP facility (Althea Technologies, Inc.) so that conjugates could be prepared for a multicenter Phase 2 clinical trial. The primary endpoints of the proposed pilot trial are safety and immunogenicity. Since the individual conjugates in this tetravalent vaccine were prepared under contract by GMP facilities instead of at MSKCC as in the past, and will be vialed and administered together rather than individually to separate patients, the issues of safety and immunogenicity are not trivial. If this GMP grade tetravalent vaccine proves safe and immunogenic in the pilot trial to be supported by this Phase 1 application, a Phase 2 STTR application to support the randomized, placebo-controlled Phase 2 trial will be submitted. Administered antibodies and antibodies induced by the tetravalent vaccine proposed here against small cell lung cancer (SCLC) cell surface antigens are ideally suited for eradication of free SCLC cells and micrometastasis. If antibodies of sufficient titer can be induced against these antigens to eliminate tumor cells from the blood and to eradicate micrometastasis, this would dramatically change our approach to treating the SCLC patient. Establishment of new metastasis would no longer be possible so more aggressive local therapies including surgery or radiation therapy of minimal known residual metastasis might result in long term control of even metastatic SCLC.