Alzeeb George, Tortorelli Corinne, Taleb Jaqueline, De Luca Fanny, Berge Benoit, Bardet Chloé, Limagne Emeric, Brun Marion, Chalus Lionel, Pinteur Benoit, Bravetti Paul, Gongora Céline, Apetoh Lionel, Ghiringhelli Francois
Brenus-Pharma, Lyon, France.
Imthernat, Université Claude Bernard Lyon 1, Therapies and Immune REsponse in Cancers (TIRECs), Lyon, France.
Front Oncol. 2024 Jul 24;14:1427428. doi: 10.3389/fonc.2024.1427428. eCollection 2024.
Colorectal cancer (CRC) remains a significant global health burden, emphasizing the need for innovative treatment strategies. 95% of the CRC population are microsatellite stable (MSS), insensitive to classical immunotherapies such as anti-PD-1; on the other hand, responders can become resistant and relapse. Recently, the use of cancer vaccines enhanced the immune response against tumor cells. In this context, we developed a therapeutic vaccine based on Stimulated Tumor Cells (STC) platform technology. This vaccine is composed of selected tumor cell lines stressed and haptenated to generate a factory of immunogenic cancer-related antigens validated by a proteomic cross analysis with patient's biopsies. This technology allows a multi-specific education of the immune system to target tumor cells harboring resistant clones. Here, we report safety and antitumor efficacy of the murine version of the STC vaccine on CT26 BALB/c CRC syngeneic murine models. We showed that one cell line (1CL)-based STC vaccine suppressed tumor growth and extended survival. In addition, three cell lines (3CL)-based STC vaccine significantly improves these parameters by presenting additional tumor-related antigens inducing a multi-specific anti-tumor immune response. Furthermore, proteomic analyses validated that the 3CL-based STC vaccine represents a wider quality range of tumor-related proteins than the 1CL-based STC vaccine covering key categories of tumor antigens related to tumor plasticity and treatment resistance. We also evaluated the efficacy of STC vaccine in an MC38 anti-PD-1 resistant syngeneic murine model. Vaccination with the 3CL-based STC vaccine significantly improved survival and showed a confirmed complete response with an antitumor activity carried by the increase of CD8+ lymphocyte T cells and M1 macrophage infiltration. These results demonstrate the potential of this technology to produce human vaccines for the treatment of patients with CRC.
结直肠癌（CRC）仍然是一个重大的全球健康负担，这凸显了创新治疗策略的必要性。95%的CRC患者是微卫星稳定（MSS）的，对诸如抗PD-1等经典免疫疗法不敏感；另一方面，有反应者可能会产生耐药性并复发。最近，癌症疫苗的使用增强了针对肿瘤细胞的免疫反应。在此背景下，我们基于刺激肿瘤细胞（STC）平台技术开发了一种治疗性疫苗。这种疫苗由经过应激和半抗原化处理的选定肿瘤细胞系组成，通过与患者活检样本进行蛋白质组交叉分析来验证，可产生免疫原性癌症相关抗原工厂。这项技术能够对免疫系统进行多特异性训练，以靶向带有耐药克隆的肿瘤细胞。在此，我们报告了STC疫苗小鼠版本在CT26 BALB/c CRC同基因小鼠模型上的安全性和抗肿瘤疗效。我们发现基于一种细胞系（1CL）的STC疫苗可抑制肿瘤生长并延长生存期。此外，基于三种细胞系（3CL）的STC疫苗通过呈现额外的肿瘤相关抗原诱导多特异性抗肿瘤免疫反应，显著改善了这些参数。此外，蛋白质组分析证实，与基于1CL的STC疫苗相比，基于3CL的STC疫苗代表了更广泛的与肿瘤相关蛋白质质量范围，涵盖了与肿瘤可塑性和治疗耐药性相关的关键肿瘤抗原类别。我们还在MC38抗PD-1耐药同基因小鼠模型中评估了STC疫苗的疗效。用基于3CL的STC疫苗进行接种显著提高了生存率，并显示出确诊的完全缓解，其抗肿瘤活性由CD8 + 淋巴细胞T细胞增加和M1巨噬细胞浸润介导。这些结果证明了该技术生产用于治疗CRC患者的人类疫苗的潜力。
