Potentiating Antitumor Efficacy Through Radiation and Sustained Intratumoral Delivery of Anti-CD40 and Anti-PDL1.
Potentiating Antitumor Efficacy Through Radiation and Sustained Intratumoral Delivery of Anti-CD40 and Anti-PDL1.
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通过放射和持续肿瘤内递送抗cd40和抗pdl1增强抗肿瘤疗效。
DOI：
10.1016/j.ijrobp.2020.07.2326
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发表时间：
2021-06-01
期刊：
影响因子：
--
通讯作者：
Grattoni A
中科院分区：
文献类型：
--
作者：
Liu HC;Viswanath DI;Pesaresi F;Xu Y;Zhang L;Di Trani N;Paez-Mayorga J;Hernandez N;Wang Y;Erm DR;Ho J;Susnjar A;Liu X;Demaria S;Chen SH;Teh BS;Butler EB;Xuan Chua CY;Grattoni A
越来越多的证据表明，放射治疗（RT）与免疫治疗相结合可以减少一部分患者的肿瘤负担。然而，常规的全身免疫治疗往往伴随着显著的不良反应，迫使治疗停止。本研究的目的是探讨一种微创治疗方法，以改善临床反应，同时降低毒性。我们使用纳米流体药物洗脱种子（NDES）在肿瘤内持续递送组合抗体CD40和PDL1。为了增强免疫和肿瘤应答，我们将NDES肿瘤内平台与RT联合治疗晚期三阴性乳腺癌4T1小鼠模型。我们比较了NDES与腹腔内给药的疗效，腹腔内给药与常规全身治疗相似。记录肿瘤生长情况，并通过成像细胞术和流式细胞术评估局部和全身免疫反应。对肝脏和肺部分别进行组织学分析以评估毒性和转移。通过NDES （NDES CD40/PDL1）联合RT和持续的肿瘤内免疫治疗递送CD40和PDL1显示出局部和全身免疫应答的增加。与全身治疗相比，NDES CD40/PDL1联合RT治疗显著减轻了肿瘤负担，减轻了肝脏炎症。重要的是，我们的治疗策略增强了减轻肺转移负担的体外效果。总的来说，我们的研究表明，联合RT和通过NDES持续肿瘤内免疫治疗的疗效优越，有望提高治疗指标和临床反应。
Mounting evidence demonstrates that combining radiation therapy (RT) with immunotherapy can reduce tumor burden in a subset of patients. However, conventional systemic delivery of immunotherapeutics is often associated with significant adverse effects, which force treatment cessation. The aim of this study was to investigate a minimally invasive therapeutics delivery approach to improve clinical response while attenuating toxicity. We used a nanofluidic drug-eluting seed (NDES) for sustained intratumoral delivery of combinational antibodies CD40 and PDL1. To enhance immune and tumor response, we combined the NDES intratumoral platform with RT to treat the 4T1 murine model of advanced triple negative breast cancer. We compared the efficacy of NDES against intraperitoneal administration, which mimics conventional systemic treatment. Tumor growth was recorded, and local and systemic immune responses were assessed via imaging mass cytometry and flow cytometry. Livers and lungs were histologically analyzed for evaluation of toxicity and metastasis, respectively. The combination of RT and sustained intratumoral immunotherapy delivery of CD40 and PDL1 via NDES (NDES CD40/PDL1) showed an increase in both local and systemic immune response. In combination with RT, NDES CD40/PDL1 achieved significant tumor burden reduction and liver inflammation mitigation compared with systemic treatment. Importantly, our treatment strategy boosted the abscopal effect toward attenuating lung metastatic burden. Overall, our study demonstrated superior efficacy of combination treatment with RT and sustained intratumoral immunotherapy via NDES, offering promise for improving therapeutic index and clinical response.
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影响因子：
82.9
作者：
Gao, Hui;Korn, Joshua M.;Sellers, William R.
通讯作者：
Sellers, William R.
PD-1和PD-L1检查点信号传导抑制癌症免疫疗法：机制，组合和临床结果。
影响因子：
5.6
作者：
Alsaab HO;Sau S;Alzhrani R;Tatiparti K;Bhise K;Kashaw SK;Iyer AK
通讯作者：
Iyer AK
影响因子：
3.7
作者：
Keung EZ;Ukponmwan EU;Cogdill AP;Wargo JA
通讯作者：
Wargo JA
DOI：
10.1158/1078-0432.ccr-09-0265
发表时间：
2009-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Dewan MZ;Galloway AE;Kawashima N;Dewyngaert JK;Babb JS;Formenti SC;Demaria S
通讯作者：
Demaria S
影响因子：
6.4
作者：
Irenaeus, Sandra M. M.;Nielsen, Dorte;Ullenhag, Gustav J.
通讯作者：
Ullenhag, Gustav J.