Abstract

Background

BO-112 is a dsRNA (poly I:C) formulated with polyethylenimine, that upon Intratumoral (IT) injection acts by activating TLR3, RIG-1 and MDA-5. This induces immunogenic cell death and potentiate systemic therapy with checkpoint inhibitors in animal models. In patients (pts), single-agent BO-112 IT increases necrosis, apoptosis and expression of pro-immune genes in solid cancers, with a manageable safety. 1 mg was the dose combined with anti-PD-1 in the current clinical trial (NCT02828098).

Methods

BO-112 was combined with anti PD-1 in 28 pts with solid tumors primarily resistant to anti PD-1 (nivolumab or pembrolizumab). A lesion >1 cm amenable to IT injection was required. 28 pts were treated with 1 mg IT BO-112 qw x 2 or 3 doses before continuing the previous anti PD-1 combined with BO-112, until progression, limiting toxicity or up to 1y. Pre & post BO-112 biopsies from injected lesion were analysed. Response was first assessed by RECIST 1.1 at week 8-12.

Results

BO-112 related AEs and biological effects at interim analysis are summarized in the table. The combination was well tolerated. No deaths were associated with BO-112. Of 18 evaluable pts for response, at first assessment: 2 have achieved an objective partial response (PR) (1 melanoma and 1 renal carcinoma), with 1 of them continuing treatment; 11 patients had stable disease (SD); 5 patients progressed (PD). Additionally 6 patients progressed prior to the first evaluation, 3 died before efficacy assessments and 1 received palliative radiotherapy and was considered not evaluable. Table: 100PAll G3-5 TEAEs (%)G3-4 BO-112 related TEAEs (%)Necrosis (D > 5%) (%)*CD8+ T cell infiltrate (D > 5%) (%)* *evaluableAll N = 2818 (64)1 (4)10 (50)7 (35)Melanoma N = 107 (70)05 (56)4 (44)Non-Small lung cancer N = 138 (62)1 (8)3 (38)1 (13)Other N = 53 (60)02 (67)2 (67)

Conclusion

BO-112 combined with anti PD-1 shows a manageable safety profile, direct antitumor effects and innate and adaptive immune system activation. Efficacy analyses suggest potential to reverse primary resistance to anti-PD1 treatment. Studies in other indications, including combination with radiotherapy, are planned.

Clinical trial identification

NCT02828098.

Legal entity responsible for the study

Bioncotech Therapeutics.

Funding

Bioncotech Therapeutics.

Disclosure

I. Marquez-Rodas: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pierre Fabre; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bioncotech; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Regeneron; Advisory / Consultancy, Research grant / Funding (institution): Incyte; Non-remunerated activity/ies: Biosequence; Research grant / Funding (institution): Idera. P. Lopez-Casas: Full / Part-time employment: Bioncotech. M. Martin: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Puma; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy: Tahio; Advisory / Consultancy: Pharmamar; Advisory / Consultancy: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Daiichi. D. Tersago: Full / Part-time employment: Bioncotech. M. Quintero: Full / Part-time employment, Officer / Board of Directors: Bioncotech. I. Melero: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Alligator; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Genentech; Advisory / Consultancy: Genmab; Advisory / Consultancy: Incyte; Advisory / Consultancy: Tusk; Advisory / Consultancy: Numab; Advisory / Consultancy: Molecular Partners; Advisory / Consultancy: F Star; Advisory / Consultancy: Bayer; Advisory / Consultancy: AstraZeneca. All other authors have declared no conflicts of interest.

中文翻译：

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抗PD-1难治性癌症患者肿瘤内双链RNA（dsRNA）BO-112与全身性抗PD-1的100P组合

抽象的

背景

BO-112是用聚乙烯亚胺配制的dsRNA（poly I：C），在肿瘤内注射（IT）时会激活TLR3，RIG-1和MDA-5。这会诱导免疫原性细胞死亡，并在动物模型中使用检查点抑制剂加强全身治疗。在患者中（pts），单药BO-112 IT可增加实体癌中的坏死，凋亡和免疫原基因的表达，并具有可控的安全性。在当前的临床试验（NCT02828098）中，与抗PD-1组合的剂量为1 mg。

方法

BO-112与抗PD-1合并治疗28例，其实体瘤主要对抗PD-1（尼古拉单抗或派姆单抗）耐药。需要> 1 cm的病变以适合IT注射。在继续使用先前的抗PD-1与BO-112组合之前，以1 mg IT BO-112 qw x 2或3剂量治疗28例患者，直到进展，限制毒性或长达1年。分析了注射病灶的BO-112活检前后。RECIST 1.1在第8-12周首先评估了反应。

结果

表中总结了BO-112相关的不良事件和中期分析的生物学效应。该组合耐受性良好。没有死亡与BO-112有关。在18例可评估的反应点中，初次评估时：2例达到了客观部分反应（PR）（1例黑素瘤和1例肾癌），其中1例继续治疗。11例病情稳定（SD）；5例进展（PD）。另外，有6例患者在首次评估前就已进展，3例在疗效评估前死亡，1例接受了姑息放疗，被认为无法评估。表：100P全部G3-5 TEAE（％）G3-4 BO-112相关TEAE（％）坏死（D> 5％）（％）* CD8 + T细胞浸润（D>

结论

BO-112与抗PD-1组合显示出可控的安全性，直接的抗肿瘤作用以及先天性和适应性免疫系统激活。功效分析表明有可能逆转抗PD1治疗的主要耐药性。计划进行其他适应症的研究，包括与放射疗法的结合。

临床试验鉴定

NCT02828098。

负责研究的法人实体

Bioncotech Therapeutics。

资金

Bioncotech Therapeutics。

揭露

I. Marquez-Rodas：咨询/顾问，研究补助金/资金（机构），差旅/住宿/费用：Bristol-Myers Squibb；咨询/顾问，研究补助金/资金（机构），差旅/住宿/费用：MSD；咨询/顾问，研究补助金/资金（机构），差旅/住宿/费用：诺华；咨询/顾问，研究补助金/资金（机构），差旅/住宿/费用：罗氏；咨询/顾问，研究补助金/资金（机构），差旅/住宿/费用：皮埃尔·法布尔（Pierre Fabre）；咨询/顾问，研究资助/资助（机构）：Amgen；咨询/顾问，研究补助金/资金（机构），差旅/住宿/费用：Bioncotech；咨询/顾问：赛诺菲；咨询/顾问：Regeneron；咨询/顾问，研究资助/资助（机构）：Incyte；无偿活动：生物序列；研究补助金/经费（机构）：Idera。P. Lopez-Casas：全职/兼职：Bioncotech。M. Martin：咨询/顾问，发言人局/专家证词，研究资助/资助（机构）：Roche；咨询/顾问，研究资助/资助（机构）：Puma；咨询/顾问，发言人局/专家证词，研究资助/资助（机构）：诺华；咨询/顾问，发言人局/专家证词：阿斯利康；咨询/顾问，发言人局/专家证词：Amgen；咨询/顾问：Tahio；咨询/顾问：Pharmamar；咨询/顾问：礼来公司；咨询/顾问，发言人局/专家证词：辉瑞；发言人办公室/专家证词：第一。D. Tersago：全职/兼职：Bioncotech。M. Quintero：全职/兼职，官员/董事会：Bioncotech。I. Melero：咨询/顾问，研究资助/资助（机构）：Bristol-Myers Squibb；咨询/顾问，研究资助/资助（机构）：鳄鱼；咨询/顾问，研究资助/资助（机构）：罗氏；咨询/顾问：默克-塞罗诺；咨询/顾问：Genentech；咨询/顾问：Genmab；咨询/顾问：Incyte；咨询/顾问：Tusk；咨询/顾问：Numab；咨询/顾问：分子合作伙伴；咨询/顾问：F星；咨询/顾问：拜耳；咨询/顾问：阿斯利康。所有其他作者都声明没有利益冲突。官员/董事会：Bioncotech。I. Melero：咨询/顾问，研究资助/资助（机构）：Bristol-Myers Squibb；咨询/顾问，研究资助/资助（机构）：鳄鱼；咨询/顾问，研究资助/资助（机构）：罗氏；咨询/顾问：默克-塞罗诺；咨询/顾问：Genentech；咨询/顾问：Genmab；咨询/顾问：Incyte；咨询/顾问：Tusk；咨询/顾问：Numab；咨询/顾问：分子合作伙伴；咨询/顾问：F星；咨询/顾问：拜耳；咨询/顾问：阿斯利康。所有其他作者都声明没有利益冲突。官员/董事会：Bioncotech。I. Melero：咨询/顾问，研究资助/资助（机构）：Bristol-Myers Squibb；咨询/顾问，研究资助/资助（机构）：鳄鱼；咨询/顾问，研究资助/资助（机构）：罗氏；咨询/顾问：默克-塞罗诺；咨询/顾问：Genentech；咨询/顾问：Genmab；咨询/顾问：Incyte；咨询/顾问：Tusk；咨询/顾问：Numab；咨询/顾问：分子合作伙伴；咨询/顾问：F星；咨询/顾问：拜耳；咨询/顾问：阿斯利康。所有其他作者都声明没有利益冲突。研究资助/资助（机构）：鳄鱼；咨询/顾问，研究资助/资助（机构）：罗氏；咨询/顾问：默克-塞罗诺；咨询/顾问：Genentech；咨询/顾问：Genmab；咨询/顾问：Incyte；咨询/顾问：Tusk；咨询/顾问：Numab；咨询/顾问：分子合作伙伴；咨询/顾问：F星；咨询/顾问：拜耳；咨询/顾问：阿斯利康。所有其他作者都声明没有利益冲突。研究资助/资助（机构）：鳄鱼；咨询/顾问，研究资助/资助（机构）：罗氏；咨询/顾问：默克-塞罗诺；咨询/顾问：Genentech；咨询/顾问：Genmab；咨询/顾问：Incyte；咨询/顾问：Tusk；咨询/顾问：Numab；咨询/顾问：分子合作伙伴；咨询/顾问：F星；咨询/顾问：拜耳；咨询/顾问：阿斯利康。所有其他作者都声明没有利益冲突。咨询/顾问：F星；咨询/顾问：拜耳；咨询/顾问：阿斯利康。所有其他作者都声明没有利益冲突。咨询/顾问：F星；咨询/顾问：拜耳；咨询/顾问：阿斯利康。所有其他作者都声明没有利益冲突。