Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade.
Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade.
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DOI：
10.1126/scitranslmed.abb3631
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发表时间：
2021-07-14
影响因子：
17.1
通讯作者：
Morris ZS
中科院分区：
文献类型：
--
作者：
Patel RB;Hernandez R;Carlson P;Grudzinski J;Bates AM;Jagodinsky JC;Erbe A;Marsh IR;Arthur I;Aluicio-Sarduy E;Sriramaneni RN;Jin WJ;Massey C;Rakhmilevich AL;Vail D;Engle JW;Le T;Kim K;Bednarz B;Sondel PM;Weichert J;Morris ZS
为了利用放射在癌症治疗中的免疫原性效应，我们假设将放射递送到所有肿瘤部位可能是有利的。使用靶向放射性核素疗法（TRT）将放射半选择性地递送到肿瘤，我们测试了通过TRT增强对免疫检查点抑制剂（ICI）的反应的方法。NM 600是一种治疗诊断的烷基磷酸胆碱类似物，优先在几乎所有肿瘤类型中积累。NM 600螯合放射性同位素并将其半选择性地递送到肿瘤微环境（TME）用于治疗或诊断应用。使用系列86 Y-NM 600 PET/CT成像，我们估计了90 Y-NM 600在免疫学“冷”同系小鼠模型中的剂量测定，所述小鼠模型不对单独的ICI作出响应。我们观察到了强的治疗效果，并报告了90 Y-NM 600与ICI组合的最佳剂量（2.5 - 5戈伊）和测序。在联合治疗后，45-66%的小鼠表现出完全反应和肿瘤特异性T细胞记忆，而单独使用90 Y-NM 600或ICI的小鼠为0%。这需要STING在肿瘤细胞中的表达。联合TRT和ICI激活TME中促炎细胞因子的产生，促进效应CD 8 + T细胞的肿瘤浸润和克隆扩增，并减少自发转移。在携带多个肿瘤的小鼠中，与ICI与单独TRT或EBRT的组合相比，TRT与靶向单个肿瘤的中等剂量（12戈伊）外束放疗（EBRT）的组合进一步增强了对ICI的反应。在犬研究中证实了TRT的安全性。低剂量TRT能够提供一种安全且快速可转化的方法，以促进对任何部位任何类型肿瘤的ICI反应。低剂量靶向放射性核素治疗和免疫检查点抑制的组合提高了临床前肿瘤模型的完全缓解率。
To capitalize on the immunogenic effects of radiation in cancer treatment, we hypothesized it may be advantageous to deliver radiation to all tumor sites. Using targeted radionuclide therapy (TRT) to deliver radiation semi-selectively to tumors, we tested an approach to enhance response to immune checkpoint inhibitors (ICIs) by TRT. NM600 is a theranostic alkylphosphocholine analog that preferentially accumulates in nearly all tumor types. NM600 chelates a radioisotope and semi-selectively delivers this to tumor microenvironments (TME) for therapeutic or diagnostic applications. Using serial 86Y-NM600 PET/CT imaging, we estimate the dosimetry of 90Y-NM600 in immunologically “cold” syngeneic murine models that do not respond to ICIs alone. We observed strong therapeutic efficacy and report optimal dose (2.5 – 5 Gy) and sequencing for 90Y-NM600 in combination with ICIs. Following combined treatment, 45–66% of mice exhibited complete response and tumor-specific T cell memory, compared to 0% with 90Y-NM600 or ICIs alone. This required expression of STING in tumor cells. Combined TRT and ICI activated production of pro-inflammatory cytokines in the TME, promoted tumor infiltration by and clonal expansion of effector CD8+ T cells, and reduced spontaneous metastases. In mice bearing multiple tumors, combining TRT with moderate-dose (12 Gy) external beam radiotherapy (EBRT) targeting a single tumor further augmented response to ICIs compared to combination of ICIs with either TRT or EBRT alone. Safety of TRT was confirmed in a canine study. Low-dose TRT enables a safe and rapidly translatable approach to promoting response to ICIs for potentially any tumor type in any location. Combination low dose targeted radionuclide therapy and immune checkpoint inhibition enhances complete response rates in preclinical tumors models.
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影响因子：
4.6
作者：
Crittenden MR;Zebertavage L;Kramer G;Bambina S;Friedman D;Troesch V;Blair T;Baird JR;Alice A;Gough MJ
通讯作者：
Gough MJ
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：
9.3
作者：
Baiu, Dana C.;Marsh, Ian R.;Otto, Mario
通讯作者：
Otto, Mario
影响因子：
6.7
作者：
Balogh, Andrea;Persa, Eszter;Lumniczky, Katalin
通讯作者：
Lumniczky, Katalin
影响因子：
82.9
作者：
Formenti SC;Rudqvist NP;Golden E;Cooper B;Wennerberg E;Lhuillier C;Vanpouille-Box C;Friedman K;Ferrari de Andrade L;Wucherpfennig KW;Heguy A;Imai N;Gnjatic S;Emerson RO;Zhou XK;Zhang T;Chachoua A;Demaria S
通讯作者：
Demaria S