Reprogramming the Canine Glioma Microenvironment with Tumor Vaccination plus Oral Losartan and Propranolol Induces Objective Responses.
Reprogramming the Canine Glioma Microenvironment with Tumor Vaccination plus Oral Losartan and Propranolol Induces Objective Responses.
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DOI：
10.1158/2767-9764.crc-22-0388
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发表时间：
2022-12
期刊：
影响因子：
--
通讯作者：
Dow S
中科院分区：
文献类型：
--
作者：
Ammons DT;Guth A;Rozental AJ;Kurihara J;Marolf AJ;Chow L;Griffin JF 4th;Makii R;MacQuiddy B;Boss MK;Regan DP;Frank C;McGrath S;Packer RA;Dow S
恶性神经胶质瘤具有高度免疫抑制的肿瘤微环境（TME），这使得它们在很大程度上对常规治疗无反应。因此，目前的研究评估了一种治疗方案，旨在通过将骨髓细胞靶向免疫治疗与肿瘤疫苗接种相结合来克服免疫屏障。我们利用自发发生的犬胶质瘤模型来研究口服TME修饰免疫疗法与癌症干细胞（CSC）疫苗接种的结合。犬每天接受氯沙坦（单核细胞迁移抑制剂）和普萘洛尔（髓源性抑制细胞耗竭剂）联合抗CSC疫苗接种，每两周一次，然后每月一次。通过MRI监测肿瘤体积，并与患者的免疫反应相关。10只患有组织学证实的神经胶质瘤的狗被招募到一项前瞻性、开放标签的临床试验中，以评估免疫治疗方案。在2只狗中观察到部分肿瘤消退，而6只狗经历了稳定的疾病，总体临床获益率为80%。总生存时间（中位数= 351天）和无进展间期（中位数= 163天）与既往评估手术减瘤后免疫治疗的研究相当。与未产生抗体应答的犬相比，具有可检测到的抗CSC抗体应答的犬的总生存时间延长（疫苗应答者MST = 500天;疫苗无应答者MST = 218天; P = 0.02）。这些发现表明，将骨髓细胞靶向口服免疫治疗与肿瘤疫苗接种相结合，即使在没有常规治疗的情况下，也可以产生客观的肿瘤反应。总的来说，这种方法有希望作为一种易于实施的治疗策略用于脑癌患者。在一项对10只患有神经胶质瘤的狗进行的初步研究中，我们发现口服氯沙坦和普萘洛尔加疫苗接种在10只治疗狗中的8只中诱导了持久的肿瘤反应。免疫治疗方案耐受性良好，无全身或局部毒性。这些发现表明，持续口服免疫治疗加肿瘤疫苗接种是一种很有前途的神经胶质瘤管理新策略，可以很容易地应用于临床试验。
Malignant gliomas have a highly immune-suppressive tumor microenvironment (TME) which renders them largely unresponsive to conventional therapeutics. Therefore, the current study evaluated a therapeutic protocol designed to overcome the immune barrier by combining myeloid cell–targeted immunotherapy with tumor vaccination. We utilized a spontaneously occurring canine glioma model to investigate an oral TME modifying immunotherapy in conjunction with cancer stem cell (CSC) vaccination. Dogs were treated daily with losartan (monocyte migration inhibitor) and propranolol (myeloid-derived suppressor cell depleting agent) plus anti-CSC vaccination on a biweekly then monthly schedule. Tumor volume was monitored by MRI and correlated with patient immune responses. Ten dogs with histologically confirmed gliomas were enrolled into a prospective, open-label clinical trial to evaluate the immunotherapy protocol. Partial tumor regression was observed in 2 dogs, while 6 dogs experienced stable disease, for an overall clinical benefit rate of 80%. Overall survival times (median = 351 days) and progression-free intervals (median = 163 days) were comparable with prior studies evaluating surgical debulking followed by immunotherapy. Dogs with detectable anti-CSC antibody responses had an increased overall survival time relative to dogs that did not generate antibody responses (vaccine responder MST = 500 days; vaccine nonresponder MST = 218 days; P = 0.02). These findings suggest that combining myeloid cell–targeted oral immunotherapy with tumor vaccination can generate objective tumor responses, even in the absence of conventional therapy. Overall, this approach has promise as a readily implemented therapeutic strategy for use in patients with brain cancer. In a pilot study of 10 dogs with glioma, we found that orally administered losartan and propranolol plus vaccination induced durable tumor responses in 8 of 10 treated dogs. The immunotherapy protocol was well tolerated, without systemic or local toxicities. These findings indicate that continuous oral immunotherapy plus tumor vaccination is a promising new strategy for glioma management that can be readily applied in clinical trials.
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DOI：
10.1007/s00262-021-03033-z
发表时间：
2022-04
期刊：
Cancer immunology, immunotherapy : CII
影响因子：
--
作者：
Lenz JA;Assenmacher CA;Costa V;Louka K;Rau S;Keuler NS;Zhang PJ;Maki RG;Durham AC;Radaelli E;Atherton MJ
通讯作者：
Atherton MJ
影响因子：
3.8
作者：
LI, ZH;BAINS, JS;FERGUSON, AV
通讯作者：
FERGUSON, AV
影响因子：
3.2
作者：
Koehler, Jennifer W.;Miller, Andrew D.;LeBlanc, Amy K.
通讯作者：
LeBlanc, Amy K.
影响因子：
11.2
作者：
Andersen, Brian M.;Pluhar, G. Elizabeth;Ohlfest, John R.
通讯作者：
Ohlfest, John R.
影响因子：
2.4
作者：
Hidalgo Crespo E;Farré Mariné A;Pumarola I Battle M;Borrego Massó JF;Luján Feliu-Pascual A
通讯作者：
Luján Feliu-Pascual A