Abstract

Background

TG01/GM-CSF is an injectable antigen-specific cancer immunotherapy targeted to treat patients (pts) with KRAS mutations, found in > 90% of pancreatic adenocarcinomas (PAC). TG01 consists of a mixture of 7 synthetic peptides representing 7 of the most common codon 12 and 13 mutations associated with PAC. Pancreatic cancer is a heterogeneous and genetically unstable disease, meaning that more than one KRAS mutation may be present in a single tumor. We investigated if cancer-related DNA from pts with resected PAC had more than one KRAS mutation and if the mutation status changed during treatment with TG01/GM-CSF.

Methods

Pts were eligible after an R0 or R1 PAC resection. TG01 (0.7 mg intradermal injection id) together with GM-CSF (0.03 mg id) was given on day 1, 3, 5, 8, 15, 22 and 2-weekly until end of chemotherapy, 4-weekly up to 1 year and 12-weekly up to 2 yrs. Within 12 weeks after resection, pts were expected to receive gemcitabine for 6 cycles. Plasma samples (up to 9) from 21 pts were collected and cancer related KRAS DNA were analyzed using ARMS (real time qPCR) for the 6 most common mutations: 12D, 12V, 12A, 12R, 12S and 12C.

Results

21 pts from UK, median age 65 (46-77) enrolled between Jan-2014 and Apr-2016. Previous results from tumor specimen showed that 16 out of 21 pts had a KRAS mutation (single mutation). However, when analyzing mutations using ARMS 20 out of 21 pts had ≥1 KRAS mutations; 19 out of 21 pts (90%) had between 1-6 mutations throughout the study. 12D and 12V mutations co-occurred in 17 out of 21 (81%) of the pts. In one pt all 6 assessed KRAS mutations were detected throughout the study. In 5 pts mutations disappeared during the treatment while in 10 pts the mutations changed either revealing new mutations or shift of mutations over time, possibly indicating selection pressure.

Conclusion

The great majority of patients with PAC have multiple KRAS mutations; in addition, mutations changed during the course of the study. Single mutation vaccines and small molecules targeting single mutations are therefore unlikely to be effective while therapies targeting a mix of KRAS mutations (TG01) may be more beneficial.

Clinical trial identification

CT TG01-01; EudraCT: 2012-002400-40.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

中文翻译：

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TG01 / GM-CSF和吉西他滨治疗期间，切除的胰腺腺癌患者中由癌症相关DNA检测到的24P多个KRAS突变（CT TG01-01）

抽象的

背景

TG01 / GM-CSF是一种可注射的抗原特异性癌症免疫疗法，旨在治疗患有KRAS突变的患者（pts），该患者在90％以上的胰腺腺癌（PAC）中发现。TG01由7种合成肽的混合物组成，这些肽代表7个最常见的密码子12和13个与PAC相关的突变。胰腺癌是一种异质性和遗传上不稳定的疾病，这意味着单个肿瘤中可能存在多个KRAS突变。我们调查了患有PAC切除的患者的癌症相关DNA是否具有一个以上的KRAS突变，以及在用TG01 / GM-CSF治疗期间突变状态是否发生了改变。

方法

R0或R1 PAC切除后的患者符合条件。TG01（0.7 mg皮内注射内径）与GM-CSF（0.03 mg内径）在第1、3、5、8、15、22和2周的第2天给药，直到化疗结束为止，每4周给药一次（最长1年），每周12周，最多2年。切除后12周内，预计患者接受吉西他滨治疗6个周期。收集了21个患者的血浆样本（最多9个），并使用ARMS（实时定量PCR）分析了与癌症相关的KRAS DNA的6种最常见突变：12D，12V，12A，12R，12S和12C。

结果

2014年1月至2016年4月期间，来自英国的21分，年龄中位数为65岁（46-77岁）。肿瘤标本的先前结果显示，21例患者中有16例具有KRAS突变（单一突变）。但是，当使用ARMS分析突变时，有21分中有20分具有≥1KRAS突变。在整个研究过程中，有21分中的19分（占90％）具有1-6个突变。在21位患者中，有17位（81％）同时发生12D和12V突变。在一项研究中，检测到全部6个评估的KRAS突变。在治疗过程中，有5分的突变消失，而有10分的突变改变了，揭示了新的突变或随着时间的推移突变的发生，这可能表明选择压力。

结论

绝大多数PAC患者具有多个KRAS突变；此外，在研究过程中，突变发生了变化。因此，针对单突变的单突变疫苗和小分子不太可​​能有效，而针对KRAS突变（TG01）混合的疗法可能更有益。

临床试验鉴定

CT TG01-01; EudraCT：2012-002400-40。

负责研究的法人实体

作者。

资金

尚未收到任何资金。

揭露

所有作者均声明没有利益冲突。