SBIR Phase I: Engineered B-cell Therapeutics for the Early Detection and Treatment of High-risk Breast Cancer

这一小型企业创新研究(SBIR)第一阶段项目的广泛影响/商业潜力包括创造一种新的基于免疫细胞的治疗方法，以满足局部晚期(III期)乳腺癌患者在标准护理手术和药物治疗后复发风险高的妇女未得到满足的身体和心理健康需求。这些被称为癌症哨兵的“活药物”是从患者血液中提取的B细胞制成的，这些细胞经过分离、化学激活和基因改造，在形成可检测到的肿瘤并扩散到重要器官之前，有选择地寻找和摧毁残留的乳腺癌细胞。治愈依赖于在远处扩散之前及早发现和消除癌细胞。这些工程疗法可能会以多种方式促进对乳腺癌细胞的破坏，包括激活免疫系统和分泌杀癌抗体。其他实体肿瘤癌症类型，如结直肠癌、肺癌和卵巢癌，也可能被未来的癌症哨兵产品解决。总体而言，每年有超过20万名美国癌症患者可能受益。这个小企业创新研究(SBIR)第一阶段项目解决了每年近50,000名美国女性的未得到满足的需求，这些女性因新诊断的当地晚期乳腺癌而遭受焦虑、恐惧和生活方式中断。从癌症诊断开始的情绪毒性，往往在标准的“观察和等待”癌症监测期间达到顶峰，以及在最初的手术切除和术后辅助治疗之后复发的不确定性。该项目将人类B细胞的天然和独特的抗原结合、淋巴结归巢、抗原呈递、蛋白质分泌、T细胞共刺激和免疫记忆能力与大容量、非病毒、CRISPR/Cas9和同源介导的基于末端连接的基因组编辑技术相结合，创造出癌症哨兵。癌症哨兵的目的是在微小残留癌症时和在远处转移之前，通过局部分泌基因工程的抗癌抗体和/或细胞因子来摧毁残留和复发的乳腺癌细胞。为了获得这种多功能的B细胞药物，将对自体血液来源的B细胞进行基因修饰，以表达与特定肿瘤相关抗原(TAA)具有亲和力的表面B细胞受体(BCR)。工程BCR与TAAs的结合可能会触发工程抗癌反应分子的局部分泌。血液中这些反应分子的检测也可以作为生物标记物，提醒医生癌症残留的存在。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase I project involves creation of a new, immune-cell-based treatment to address the unmet physical and psychological health needs of women with locally advanced (Stage III) breast cancer at high risk for relapse following standard-of-care surgery and drug therapy. Called cancer sentinels, these “living drugs” are made from patient blood-derived B-cells that have been isolated, chemically activated, and genetically modified to selectively seek and destroy residual breast cancer cells before they form detectable tumors and spread to vital organs. Cure is dependent on early detection and cancer cell elimination prior to distant spread. These engineered therapeutics may promote the destruction of breast cancer cells in multiple ways, including activation of immune system and the secretion of cancer-killing antibodies. Additional solid tumor cancer types, such as colorectal cancer, lung cancer, and ovarian cancer may also be addressable by future cancer sentinel products. In total, greater than 200,000 American cancer patients each year may benefit. This Small Business Innovation Research (SBIR) Phase I project addresses unmet needs of nearly 50,000 American women annually who are subjected to anxiety, fear, and lifestyle disruption because of newly diagnosed, locally advanced breast cancer. Emotional toxicity, beginning at cancer diagnosis, tends to peak during standard “watch and wait” cancer surveillance and the relapse uncertainty that follows initial surgical resection and post-surgery adjuvant therapy. This project combines the natural and unique antigen binding, lymph node-homing, antigen presentation, protein secretion, T-cell co-stimulation, and immune memory capabilities of human B-cells with large-cargo, non-viral, CRISPR/Cas9 and homology-mediated end joining-based genome editing techniques, to create cancer sentinels. Cancer sentinels are intended to destroy residual and relapsed breast cancer cells by locally secreting engineered anti-cancer antibodies and/or cytokines at the time of minimal residual cancer and prior to distant metastasis. To achieve such a multi-functional B-cell drug, autologous blood-derived B-cells will be genetically modified to express surface B-cell receptors (BCRs) with affinity for specific tumor-associated antigens (TAAs). Engineered BCR binding to TAAs may trigger local secretion of the engineered anti-cancer response molecules. Detection of these response molecules in the blood may also serve as a biomarker and alert physicians to the presence of residual cancer.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.