Département d'Innovation Thérapeutique et d'Essais Précoces, Gustave Roussy, Université Paris-Saclay, Villejuif.
INSERM U1015, Gustave Roussy, Villejuif.
Ann Oncol. 2017 Dec 1;28(suppl_12):xii33-xii43. doi: 10.1093/annonc/mdx683.
Immune checkpoint-targeted monoclonal antibodies directed at Programmed Death Receptor 1 (PD-1), Programmed Death Ligand 1 (PD-L1) and Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4) are currently revolutionizing the prognosis of many cancers. By blocking co-inhibitory receptors expressed by antitumor T cells, these antibodies can break the immune tolerance against tumor cells and allow the generation of durable cancer immunity. Benefits in overall survival over conventional therapies have been demonstrated for patients treated with these immunotherapies, leading to multiple approvals of such therapies by regulatory authorities. However, only a minority of patients develop an objective tumor response with long-term survival benefits. Moreover, the systemic delivery of immunotherapies can be responsible for severe auto-immune toxicities. This risk increases dramatically with anti-PD(L)1 and anti-CTLA-4 combinations and currently hampers the development of triple combination immunotherapies. In addition, the price of these novel treatments is probably too high to be reimbursed by health insurances for all the potential indications where immunotherapy has shown activity (i.e. in more than 30 different cancer types). Intratumoral immunotherapy is a therapeutic strategy which aims to use the tumor as its own vaccine. Upon direct injections into the tumor, a high concentration of immunostimulatory products can be achieved in situ, while using small amounts of drugs. Local delivery of immunotherapies allows multiple combination therapies, while preventing significant systemic exposure and off-target toxicities. Despite being uncertain of the dominant epitopes of a given cancer, one can therefore trigger an immune response against the relevant neo-antigens or tumor-associated antigens without the need for their characterization. Such immune stimulation can induce a strong priming of the cancer immunity locally while generating systemic (abscopal) tumor responses, thanks to the circulation of properly activated antitumor immune cells. While addressing many of the current limitations of cancer immunotherapy development, intratumoral immunotherapy also offers a unique opportunity to better understand the dynamics of cancer immunity by allowing sequential and multifocal biopsies at every tumor injection.
免疫检查点靶向单克隆抗体针对程序性死亡受体 1（PD-1）、程序性死亡配体 1（PD-L1）和细胞毒性 T 淋巴细胞相关蛋白 4（CTLA-4），正在彻底改变许多癌症的预后。通过阻断抗肿瘤 T 细胞表达的共抑制受体，这些抗体可以打破对肿瘤细胞的免疫耐受，从而产生持久的癌症免疫。这些免疫疗法治疗的患者在总生存方面的获益已得到证实，这导致监管机构多次批准此类疗法。然而，只有少数患者出现客观肿瘤反应并获得长期生存获益。此外，免疫疗法的全身给药可能导致严重的自身免疫毒性。这种风险随着抗 PD(L)1 和抗 CTLA-4 联合用药而急剧增加，目前阻碍了三重联合免疫疗法的发展。此外，这些新型治疗药物的价格可能过高，无法为所有显示出免疫疗法活性的潜在适应症（即 30 多种不同类型的癌症）的医疗保险报销。肿瘤内免疫疗法是一种治疗策略，旨在利用肿瘤作为自身疫苗。通过直接注射到肿瘤中，可以在原位实现高浓度的免疫刺激产品，同时使用少量药物。局部递送免疫疗法允许多种联合治疗，同时防止严重的全身暴露和脱靶毒性。尽管对于给定癌症的优势表位不确定，但可以在无需对其进行特征分析的情况下，触发针对相关新抗原或肿瘤相关抗原的免疫反应。这种免疫刺激可以在局部强烈激发癌症免疫，同时由于适当激活的抗肿瘤免疫细胞的循环，产生全身（远隔）肿瘤反应。虽然解决了癌症免疫疗法发展的许多当前限制，但肿瘤内免疫疗法也为更好地了解癌症免疫动力学提供了独特的机会，因为它允许在每次肿瘤注射时进行顺序和多焦点活检。
