CONSTRUCTION AND TESTING OF A TRIVALENT VACCINE AGAINST NEUROBLASTOMA ADMINISTERE

描述（由申请人提供）：本1期SBIR申请旨在为一项针对神经母细胞瘤的抗体诱导三价疫苗的随机、安慰剂对照、双盲、多中心II期临床试验准备方案和疫苗。它的基础是3年的研究，在此期间1）确定了针对确定的癌细胞表面抗原的最佳抗体应答的疫苗设计，包括抗原与载体分子钥孔血蓝蛋白（KLH）的化学缀合和皂苷免疫佐剂QS-21的施用（我们的QS- 21被称为OPT-821），2）在循环肿瘤细胞，微转移和部分治疗的转移是主要的目标，在临床前研究中得到证实，这种好处被证明是放大的口服联合，施用β-葡聚糖，3）确定了常见癌症表达的抗原，并确定了与神经母细胞瘤疫苗最相关的3种抗原为GD 2、GD 3和聚唾液酸，4）证实了针对这三种抗原的单价和多价疫苗的安全性和免疫原性，并确定了在化疗后辅助环境中患者中每种缀合物和佐剂的最佳剂量，和5）证实了含有GD 2、GD 3和OPT-821的疫苗与β-葡聚糖联合给药在神经母细胞瘤患者中的安全性、免疫原性和最佳剂量。拟定随机II期试验的主要终点（将在随后的II期SBIR申请中解决）是与仅接种OPT-821的患者相比，接种全三价疫苗的第二或第三例完全缓解4期神经母细胞瘤患者的无病生存期和总生存期延长。在本1期申请中，方案将获得IRB批准，疫苗将制备，并获得该疫苗和安慰剂的IND。 公共卫生相关性： 由本文提出的针对神经母细胞瘤细胞表面抗原的三价疫苗（GD 2、GD 3和聚唾液酸）诱导的抗体非常适合于根除循环神经母细胞瘤细胞、微转移和部分治疗的转移。如果可以诱导足够滴度的抗体对抗这些抗原，以消除血液中的肿瘤细胞并根除早期转移，这将极大地改变我们治疗神经母细胞瘤患者的方法。建立新的转移将不再是可能的，所以化疗治疗可能导致长期控制甚至转移性神经母细胞瘤。

DESCRIPTION (provided by applicant): This Phase 1 SBIR application is for preparation of protocol and vaccine for a randomized, placebo-controlled, double-blind, multicenter Phase II clinical trial of an antibody-inducing trivalent vaccine against neuroblastoma. Its foundation is 3 years of studies during which time 1) vaccine design for optimal antibody responses against defined cancer cell surface antigens was determined to include chemical conjugation of antigen to carrier molecule keyhole limpet hemocyanin (KLH) and administration with the saponin immunological adjuvant QS-21 (our QS- 21 is termed OPT-821), 2) the benefit of immunization in the minimal disease setting where circulating tumor cells, micrometastases and partially treated metastases are the primary targets was demonstrated in preclinical studies and this benefit was shown to be magnified by oral co- administration of beta-glucan, 3) the antigens expressed by the common cancers were defined and 3 antigens most relevant for a neuroblastoma vaccine identified as GD2, GD3 and polysialic acid, 4) the safety and immunogenicity of monovalent and polyvalent vaccines against these three antigens was confirmed and the optimal dose of each conjugate and adjuvant in patients in the post-chemotherapy adjuvant setting determined, and 5) the safety, immunogenicity and optimal dose in neuroblastoma patients of a vaccine containing GD2, GD3 and OPT-821 co- administered with beta-glucan were demonstrated. The primary endpoints of the proposed randomized Phase II trial (that would be addressed in a subsequent Phase 2 SBIR application) are prolongation of disease-free and overall survival of second or third complete response stage 4 neuroblastoma patients vaccinated with the full trivalent vaccine compared to those vaccinated with OPT-821 alone. Under this Phase 1 application, the protocol will be IRB approved, the vaccines prepared and the IND for this vaccine and placebo obtained. PUBLIC HEALTH RELEVANCE: Project Narrative Antibodies induced by the trivalent vaccine (GD2, GD3 and polysialic acid) proposed here against neuroblastoma cell surface antigens are ideally suited for eradication of circulating neuroblastoma cells, micrometastasis and partially-treated metastases. If antibodies of sufficient titer can be induced against these antigens to eliminate tumor cells from the blood and to eradicate early metastasis, this would dramatically change our approach to treating the neuroblastoma patient. Establishment of new metastasis would no longer be possible so treatment with chemotherapy might result in long-term control of even metastatic neuroblastoma.