Gene-Product Auto-Targeting to Tumor Vessels

项目摘要 对于复发或转移的肉瘤患者，治疗选择有限，预后很差。两者都很软 组织肉瘤和骨肉瘤最常转移到肺部，并经常对细胞毒产生耐药性 化疗。迫切需要新的治疗选择，如免疫疗法，以实现长期控制和 消除转移疾病。在这方面，T细胞(CAR-T和TIL)治疗和免疫检查点 封闭疗法已经在其他类型的肿瘤中得到了临床应用。事实上，野生型IL12武装T 在两种临床前肿瘤模型中，(CAR-或TIL)细胞在清除肿瘤方面都比单独的T细胞更强大 临床试验，因为IL12使T细胞极化为Th1表型，促进效应T细胞，下调 血管生成，重塑细胞外基质，改变免疫抑制细胞因子的水平。一张紧急票 无论是CAR-T还是野生型IL12武装T细胞疗法的挑战都是副作用。CAR-T细胞引起 严重细胞因子释放综合征(CRS)和野生型IL12会导致肝脏毒性。 要安全地使用IL12，关键是将IL12基因及其转录/翻译的基因产物靶向肿瘤。 为此，我们发明了一种新的肿瘤靶向IL12基因(ttIL12或chp-IL12)，它编码p35 P40-VNTANST融合亚基。这第一代ttIL12收到美国发布 专利(US9657077B2)。与野生型IL12不同，ttIL12疗法在减少髓系白血病方面也更有效。 衍生抑制细胞(MDSC)和FoxP3Tregs。MDSC和FoxP3的高水平表达是 与肉瘤患者的低存活率有关。 为了解决T细胞的不良反应，申请人发明了第二代ttIL12疗法-- 细胞膜锚定ttIL12(AttIL12)-T细胞疗法(PCT/US2017/055645；UTSC.P1424US.P1)。武装T 带有这种attIL12的细胞(CAR-T、自体T细胞或TIL)有可能降低CRS的风险，因为这 AtIL12-T细胞似乎不再诱导CRS细胞因子的表达，避免了T细胞在肺中的停滞，而是 积聚在肿瘤中。这种attIL-12臂T细胞疗法的安全性、有效性和免疫机制 将在此应用程序中进行研究。 这一应用是新颖和有效的，因为将研究一种新的、安全的T细胞疗法。

Project Summary Treatment options are limited and prognosis is poor for patients with recurrent or metastatic sarcoma. Both soft tissue sarcoma and osteosarcoma most frequently metastasize to the lungs and are often resistant to cytotoxic chemotherapy. Novel treatment options such as immune therapy are urgently needed for long-term control and elimination of metastatic disease. In that regard, both T cell (CAR-T and TILs) therapy and immune checkpoint blocking therapy have advanced to clinical applications in other types of tumors. In fact, wildtype IL12-armed T (CAR- or TIL) cells is more powerful in eliminating tumors than T cells alone in both preclinical tumor model or clinical trial because IL12 polarize T cells to the Th1 phenotype, boost effector T cells, downregulate angiogenesis, remodel the extracellular matrix, and alter levels of immune-suppressive cytokines. One urgent challenge for either CAR-T or wildtype IL12-armed T cell therapy is adverse effects. The CAR-T cells causes severe cytokine release syndrome (CRS) and wildtype IL12 causes liver toxicity. To safely use IL12, the key is to target the IL12 gene and its transcribed/translated gene product to the tumor. To that end, we have invented a novel tumor-targeted IL12 gene (ttIL12 or CHP-IL12) that encodes the p35 subunit and p40-VNTANST fusion subunit. This first generation of ttIL12 received US issued patent(US9657077B2). Different from wildtype IL12, ttIL12 therapy is also more effective in reducing myeloid- derived suppressor cells (MDSC) and FoxP3Tregs. High levels of MDSC and FoxP3 expression are associated with poor survival amongst sarcoma patients. To address the adverse effect of T cells, the applicant has invented the second generation of ttIL12 therapy— cell membrane anchored ttIL12 (attIL12)-T cell therapy (PCT/US2017/055645; UTSC.P1424US.P1). Arming T cells (CAR-T, autologous T, or TILs) with this attIL12 has potential to reduce the risk of CRS because this attIL12-T cells seems no longer induce CRS cytokine expression and avoids T cells stall in lungs but rather accumulates in tumors. The safety, efficacy, and the immune mechanism of this attIL12-armed T cell therapy will be investigated in this application. This application is novel and impactful because a novel and safe T cell therapy will be investigated.