1970-01-01
2018 AACR年会:免疫疗法新组合,解决检查点抑制抵抗
免疫疗法现已被越来越多地应用于不同癌症患者上。其原理是通过不同的机制来激活病人体内自身的免疫系统,从而有效靶向并摧毁癌症细胞。
免疫检查点抑制剂是目前广泛应用的疗法之一,其靶向了可抑制免疫响应的蛋白质,有效移除T细胞“制动器”,所以可使其对癌细胞攻击力量更大。但尽管科学家在这一领域已有诸多可喜的研究成果,仍有许多病人对检查点抑制不产生响应或产生抵抗,上一期博客中发出的帖子就专门提到了这个问题。
为了提高功效、解决检查点抑制剂抵抗问题,科学家们进行了大量的临床试验,试图通过结合免疫抑制剂和第二种药物来找到答案。事实上,2018 AACR年会上的多个环节,科学家们就已经重点讨论过一期临床试验,这些试验旨在探索怎样多种方式来结合PD-1/PD-L1抑制与可增大或调节免疫响应的药剂,形成更有效的疗法。
说明:靶向PD-1或PD-L1的药物可破坏免疫系统内的“断路开关”,从而有更多的T细胞参与进来杀死肿瘤细胞。
结合PD-1抑制和TLR9激活
2014年,FDA批准了几种用于治疗常见癌症:晚期黑色素瘤的检查点抑制剂,其中就有派姆单抗(靶向PD-1的单克隆抗体)。然而,根据爱荷华大学临床医学学士Mohammed Milhem的一份新闻稿研究报告,预计有50%的晚期黑色素瘤病人在用这一药物治疗时产生抵抗。不仅如此,更有一部分病人对这一疗法毫无响应。
为了解决这一问题,Milhem和同事们正进行一项临床试验,评估派姆单抗结合CMP-001药剂(可激活Toll样受体)的疗效。研究发现,当肿瘤免疫原性提高时,检查点抑制的效果更好,而已知的肿瘤免疫原性介体是干扰素。Milhem告诉我们:“IFN产生出的已知的最强的诱导物是TLR9路径,所以我们想着把TLR9激活剂与anti-PD-1疗法结合,也许可以在那些对PD-1抑制响应很差的病人体内激发响应。”
Milhem和同事试图通过直接注射带有CMP-001的肿瘤,来强制激发免疫响应。研究者们假设,一旦肿瘤微环境的免疫原性更高,PD-1的抑制就能促使更多T细胞更有效地杀死癌细胞。
这一试验对PD-1抑制抵抗的转移性黑色素瘤病人结合使用了不同剂量的CMP-001和派姆单抗。研究者在可评价的患者群中测得的客观缓解率为22%。
Mohammed Milhem,MBBS
Milhem表示:“我们需要在这一患者群体中进行更多更广的研究,来进一步评估临床受益情况。但如果现有的结果被进一步确定了,我们可以认为这一结合疗法可以成为对派姆单抗不响应的晚期黑色素瘤病人的又一治疗方案。”
结合PD-1与HDAC抑制
肿瘤通常有异常表观基因组---对DNA包装的不规则修饰会影响基因表达---这就导致肿瘤抑制因子和致癌基因的转录改变,从而助长了癌细胞的存活。正因此,十多年来,表观遗传机制一直都被视为治疗靶点,以此确定更多癌症治疗的答案。
组蛋白脱乙酰酶(HDACs)是表观遗传调节剂的一种。通过将组蛋白和其他基质中的乙酰基去除,HDACs便能调节靶向基因的表达。
研究发现,HDAC抑制剂能降低粒细胞髓源性抑制细胞(MDSCs)的活性,而MDSCs具有免疫抑制特性,是从荷瘤小鼠中分离出来的。研究人员还发现,结合HDAC抑制剂和检查点抑制,可消除小鼠体内的原发肿瘤和转移肿瘤。
Anthony Tolcher,医学博士,加拿大皇家内科医师学会会员(FRCP(C)),南德克萨斯州加速研究疗法(START)临床研究主任,呈现了一期试验的数据,该一期试验旨在研究HDAC抑制剂:恩替诺特,结合派姆单抗对晚期实体瘤病人的治疗效果。Tolcher和同事们在所有治疗组中都发现了单核细胞MDSCs的减少。实验对象,共26名病人,三名有部分响应,两名病情稳定;四名病人接受治疗超过40周。
PD-1抑制结合个体化新抗原疫苗
个体化癌症疫苗是药物发现领域中令人心潮澎湃的分支,尽管它仍旧处于发展的极早期。通过排序病人的肿瘤,科学家正试图确定新抗原,开发个体化疫苗来刺激肿瘤特异性T细胞。
此前,在晚期黑色素瘤病人体内,科学家们已对此法进行了研究,这些病人接种了个体化新抗原疫苗,以及在术后给药免疫增强剂Poly-ICLC。Anti-PD-1疗法在所有复发病人群体中都获得了完全响应。不仅如此,研究者们发现病人接受检查点抑制治疗后,T细胞对新颖靶向产生响应。研究人员已开始了另一临床试验,研究检查点抑制纳武单抗和个体化新抗原NEO-PV-01结合,对各种癌症病人有什么样的疗效。
在此一期试验中,病人每两周服用一次纳武单抗,单药给药。12周后,病人接受NEO-PV-01和Poly-ICLC的结合治疗。Patrick Ott,医学博士,来自丹娜法伯癌症研究院,他提出的这一研究表明,14名全程接受了疫苗接种的病人中,5名有部分响应,5名病情稳定,4名病情恶化。
研究人员还在一半的试验病人体内发现T细胞对肿瘤内的新抗原产生相应,但非疫苗内的新抗原(表位扩展)。
在未来,还有哪些结合方式?
2018 AACR年会上,专家们讨论了诸多的免疫疗法的结合,这篇博文只是带着大家浅尝辄止。但文章详细介绍了许多其他话题,包括全体大会上研究的肺癌的免疫疗法结合,都让人们对现有的免疫检查点抑制的发展成果为之振奋。确实,会议上,Keynote-189三期临床试验(评估派姆单抗和化疗的结合)也已登上了纽约时报。
AACR Annual Meeting 2018: Novel immunotherapy combinations to combat resistance to checkpoint inhibition
Immunotherapy is being increasingly utilized in patients with different cancer types. It works by stimulating the patient’s immune system to effectively target and destroy cancer cells through different mechanisms.
A widely used class of immunotherapeutics are immune checkpoint inhibitors, which target proteins that downregulate the immune response, effectively removing the “brake” on T cells so they can better attack the cancer cells. Despite the advances made in this area, many patients either do not respond to checkpoint inhibition, or they develop resistance to their treatments, an issue that was highlighted in a previous post on this blog.
To increase efficacy and combat resistance to checkpoint inhibitors, many clinical trials are centered on combining an immune checkpoint inhibitor with a second drug. In fact, several sessions at the AACR Annual Meeting 2018 focused on phase I clinical trials that investigated different combinations of PD-1/PD-L1 inhibition in conjunction with agents that augment or regulate immune responses.
Caption: Drugs that target PD-1 or PD-L1 disrupt an “off switch” in the immune system, allowing T cells to engage and kill tumor cells.
Initially approved by the FDA in 2014 as a treatment for advanced melanoma, pembrolizumab (Keytruda; a monoclonal antibody that targets PD-1) is one of several checkpoint inhibitors approved for treating this common cancer. However, it is estimated that over 50 percent of patients with advanced melanoma treated with pembrolizumab develop resistance, explained Mohammed Milhem, MBBS, from the University of Iowa in a press release discussing his research. Additionally, some patients never respond to this therapy.
To combat this, Milhem and colleagues are evaluating the combination of pembrolizumab with CMP-001, an agent that activates Toll-like receptor 9 (TLR9), in an ongoing clinical trial. Studies have shown that checkpoint inhibition tends to work better when tumor immunogenicity is increased, and known mediators of immunogenicity are interferons (IFNs). “The strongest known inducer of IFN production is the TLR9 pathway, so we thought that adding a TLR9 activator to anti-PD-1 therapy would elicit a response in patients who stopped or never responded to PD-1 inhibition,” Milhem noted.
Milhem and colleagues are attempting to kick-start the immune response by directly injecting tumors with CMP-001. Once the tumor microenvironment becomes more immunogenic, the inhibition of PD-1 should allow the T cells to more effectively kill the cancer cells, the researchers hypothesize.
The trial is testing varying doses of CMP-001 in combination with pembrolizumab in patients with metastatic melanoma who are resistant to PD-1 inhibition. The researchers reported an objective response rate of 22 percent in evaluable patients.
Mohammed Milhem, MBBS
“Additional larger studies in this patient population will need to be conducted to further evaluate the clinical benefit, but if the current results are confirmed, it appears that this combination could offer a new treatment option for patients with advanced melanoma who are not responsive to pembrolizumab,” said Milhem.
Combining PD-1 and HDAC inhibition
Tumors can have an aberrant epigenome – irregular modifications to the packaging of DNA that can affect gene expression – which results in the altered transcription of tumor suppressors and oncogenes, helping cancer cells to survive. As such, epigenetic mechanisms have been a therapeutic target for cancer treatment for more than a decade
One class of epigenetic modulators are histone deacetylases (HDACs). By removing acetyl groups from histone proteins and other substrates, HDACs can modulate the expression of target genes.
Research has shown that HDAC inhibitors can reduce the viability of granulocytic myeloid-derived suppressor cells (MDSCs), which are immunosuppressive, isolated from tumor-bearing mice, and that combining HDAC inhibitors with checkpoint inhibition eliminated primary tumors and metastasis in mice.
Anthony Tolcher, MD, FRCP(C), the director of Clinical Research at South Texas Accelerated Research Therapeutics (START), presented data from a phase I trial investigating the combination of the HDAC inhibitor entinostat with pembrolizumab in patients with advanced solid tumors. Tolcher and colleagues found a reduction in monocytic MDSCs across all treatment arms. Of the 26 patients enrolled in the study, three had a partial response and two had stable disease; four patients are continuing treatment beyond 40 weeks.
Combining PD-1 inhibition with personalized neoantigen vaccines
While still somewhat early in development, personalized cancer vaccines are an exciting area of cancer drug discovery. By sequencing a patient’s tumor, scientists are attempting to identify neoantigens and develop personalized vaccines to stimulate tumor-specific T cells.
Previous work has investigated this approach in patients with advanced melanoma who received a personalized neoantigen vaccine along with the immunostimulant Poly-ICLC following surgery. Anti-PD-1 treatment resulted in a complete response in all patients who had recurrent disease. Furthermore, the researchers observed that the patients’ T cells responded to novel targets following treatment with checkpoint inhibition. A clinical trial was initiated to study the combination of the checkpoint inhibitor nivolumab and the personalized neoantigen vaccine, NEO-PV-01, for patients with a wide variety of cancers.
In this phase I clinical trial, patients received nivolumab biweekly as a monotherapy. After 12 weeks, following the generation of the personalized vaccine, patients received NEO-PV-01 along with Poly-ICLC. The study presented by Patrick Ott, MD, PhD of Dana-Farber Cancer Institute, reported that of the 14 patients who had completed their vaccination schedule, five patients saw a partial response, five patients had stable disease, and four patients had progressive disease.
The researchers also observed T-cell responses to neoantigens identified within the tumor but not included in the vaccine (epitope spreading) in half of the patients analyzed.
Further combinations?
While this post only touched on a few of the immunotherapy combinations discussed at the AACR Annual Meeting 2018, many more talks, including a plenary session focusing on immunotherapy combinations in lung cancer, covered in detail in this post, highlight the excitement surrounding immune checkpoint inhibition. Indeed, the phase III clinical trial Keynote-189 presented at the meeting evaluating the combination of pembrolizumab plus chemotherapy was covered by The New York Times.
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