Talactoferrin Alfa (TLF):母亲的奶，治疗癌症

jimmy112199 · 发表于 2008-4-5 03:15:46

<div id="post-1014" class="title" style="margin-top: 10px;"><a rel="bookmark" href="http://onctalk.com/2008/01/26/tlf-for-nsclc/" class="lt" style="color: rgb(136, 136, 136); text-decoration: none; font-size: 14px; font-weight: bold;">Talactoferrin Alfa (TLF): Mother’s Milk Becomes Cancer Treatment</a></div>

  
We’ve covered several novel agents for treating lung cancer, but a new
one that has shown promise in early studies and now is the subject of
larger phase III trials is a drug called talactoferrin alfa (TLF), from
a small company based in Houston called Agennix.  I think it’s possible
that much of the reason there hasn’t been much buzz behind this
treatment, despite the very intriguing results, is that this agent is
so different from the mechanisms we know well already, like blocking
angiogenesis, inhibiting EGFR, combining these approaches, etc.  And
the fact that this is a small company far from the big pharma and
biotech hubs like New Jersey and the Bay Area probably contribute; in
addition, all of the results thus far have been generated out of India,
which has many lung cancer patients but few recognized leaders in the
field, so there hasn’t been an identifiable spokesperson to introduce
the lung cancer world to the novel agent and concept of TLF.  But let’s
try to remedy this situation, because I’m inclined to keep my eye on it
for the next few years. 
  
   TLF is an oral protein that is a <a target="_blank" href="http://www.google.com/search?hl=en&defl=en&q=define:recombinant&sa=X&oi=glossary_definition&ct=title" title="web def recombinant ">recombinant</a>
product that is structurally identical in all material respects to
human lactoferrin, an important immunomodulatory product that is
expressed throughout the body in immune cells.  As the name implies, it
is found in highest concentration in breast milk, and it is important
in contributing to the development of an infant’s immune system.  The
largest component of the immune system is actually the “<a target="_blank" href="http://en.wikipedia.org/wiki/Gut_associated_lymphoid_tissue" title="wikipedia entry for GALT">gut-associated lymphoid tissue</a>”
(GALT), where the cells of the immune system interface with vast
amounts of new proteins from the outside world (food).  TLF is
purported to work by getting taken up by the immune cell centers of the
gut, called <a target="_blank" href="http://en.wikipedia.org/wiki/Peyer%27s_patches" title="

eyer's patches">

eyer’s patches</a>, where they induce immature <a target="_blank" href="http://en.wikipedia.org/wiki/Dendritic_cells" title="wikipedia dendritic cells">dendritic cells</a>,
which are some of the heavy lifters teaching the rest of the immune
cells what to focus on and what to ignore, to mature.  Although the
immune system is very complicated, the end result is that TLF can
activate dendritic cells of the immune system and thereby lead to
increased immune function against tumor cells. 
<a href="http://onctalk.com/wp-content/uploads/2008/01/tlf-moa.jpg" title="Talactoferrin MOA" class="imagelink"><img width="396" height="243" src="http://onctalk.com/wp-content/uploads/2008/01/tlf-moa.jpg" alt="Talactoferrin MOA" id="image1011" style="width: 396px; height: 243px;"/></a>
 (Click on image to enlarge)  Please don’t worry if you don’t “get”
these immune system principle: I show the figure in case people are
interested, but it’s not on the quiz.   Your immune system is like your
television  — you don’t need to know how it works to be able to use
it.  Suffice it to say that there are several lab-based studies with
animal models of cancer that support this immunostimulatory role for
TLF.  But the real issue is what it does in humans.
    Importantly, with approximately 500 patients receiving TLF over
the past several years, no obvious side effects have been noted, in
contrast with other “targeted approaches” in which side effects ranging
from a serious rash to life-threatening bleeding are ongoing
challenges.  The phase I (safety) work in humans gave some signals of
activity among NSCLC patients, among whom several had a prolonged
survival of a year or longer despite having progressed on prior
treatment (<a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed/16193240?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum" title="phase I TLF report">abstract here</a>). 
  
   But in the last couple of years the results of two phase II
randomized trials in advanced NSCLC have been reported, and they both
appear provocative.  At ASCO 2006, one study by Wang and colleagues (<a target="_blank" href="http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=40&abstractID=34470" title="Yang TLF first line with Carbo taxol">abstract here</a>)
reported the results of a randomized phase II trial of standard
first-line chemo with carbo/taxol every three weeks along with either
TLF daily or placebo.  It was a “double-blinded trial”, so neither the
physicians nor the patients knew whether they were receiving the
active drug or placebo.  A total of 110 patients were enrolled, among
whom 100 had a scan six weeks (2 cycles) later to assess response.  In
this study, response rate (RR) was the primary endpoint, and this
was strikingly higher in the recipients of TLF combined with chemo
compared with chemo and placebo:
<a href="http://onctalk.com/wp-content/uploads/2008/01/tlf-chemo-rr-results.jpg" title="TLF chemo RR results" class="imagelink"><img width="394" height="187" src="http://onctalk.com/wp-content/uploads/2008/01/tlf-chemo-rr-results.jpg" alt="TLF chemo RR results" id="image1012" style="width: 394px; height: 187px;"/></a>
The bars on the left include all patients who started the trial (for
which the results were not quite statistically significantly different,
p < 0.08), but when only the patients who got to their first
follow-up scan were included (the evaluable patients), the
differences were more pronounced and actually statistically significant
(p < 0.05).  And progression-free and overall survival also appeared
notably superior with TLF added to chemo.
   When you add a third agent to a standard chemo doublet like
carbo/paclitaxel, it generally adds side effects, whether that’s adding
avastin, or erbitux, a third conventional chemo agent, or whatever else
you’re interested in.  One of the curious findings in this trial with
TLF was that the side effects (typically referred to as toxicity or
adverse events) were actually lower in the recipients of active TLF compared with placebo recipients, looking at
all reported adverse events/side effects (left) or just the more serious (grade 3 or 4) ones (right):
<a href="http://onctalk.com/wp-content/uploads/2008/01/tlf-chemo-side-effects-asco-2006.jpg" title="TLF chemo side effects" class="imagelink"><img width="397" height="261" src="http://onctalk.com/wp-content/uploads/2008/01/tlf-chemo-side-effects-asco-2006.jpg" alt="TLF chemo side effects" id="image1013" style="width: 397px; height: 261px;"/></a>
Very curious.  Presumably, enhancing immune function translates to fewer side effects from standard chemo. 
   While these results are impressive, this trial was presented as
just a poster at the ASCO meeting in 2006, and it didn’t receive much
attention when many physicians and the media focused on multitargeted
agents like sutent and nexavar, and we tried to figure out how best to
use drugs like tarceva and avastin.  This was only a 110 patient study,
but if the TLF results were true, this approach could have a real
impact. 
   We got more information from another trial this past year, so
I’ll continue with that along with the future plans for TLF in my next
post.

jimmy112199 · 发表于 2008-4-5 03:20:57

回应" talactoferrin （ tlf ）：母亲的奶，治疗癌症"       1 。       一        andygavanna内容为：        2008年1月31日在下午6时55分          哇！我是哺乳顾问，所以我很熟悉，对研究，在过去十年关于潜在癌症死亡性能的乳汁。我很高兴地看到，它要到下一级。我的父亲曾第四阶段肺癌（脑会晤）在 12年前（我已张贴他的故事，在此之前），现在还活着，并脚踢-非执行董事为10年（他现在有膀胱癌，现在虽然） 。这听起来可能有点陌生和毛很多人，但是当他收到他的化疗（卡铂/紫杉醇）和辐射的TX他经常喝我的抽母乳（我有一个六个月大孩子   ） 。在当时，有不少的研究来了解免疫因素在骨髓，所以我们认为它不能伤害，它可能提高他的免疫系统。他的混合，它与酸奶，使之赏心乐事。他仍然相当健康，在 他的TX ，所以我想认为，牛奶有一些东西需要做这一点。当然，与这些新的事态发展，也许牛奶部分的处理过于！有趣的是，最近我读到一篇有关癌症病人使用牛奶人乳银 行作为alternitive疗法。一，先生们在文章中，甚至谈到混合，它与酸奶。我想我们都是领先于我们的时候。丹尼斯 One Response to “Talactoferrin Alfa (TLF): Mother’s Milk Becomes Cancer Treatment”       1       andygavanna Says:       January 31st, 2008 at 6:55 pm       Wow! I’m a lactation consultant so I am well versed on the studies in the past ten years regarding the potential cancer killing properties of breastmilk. It is nice to see it going to the next level. My father had Stage IV lung cancer (brain met) 12 years ago (I have posted his story here before) and is still alive and kicking -NED for 10 years (he now has bladder cancer now though). This may sound a bit strange and gross to many people but when he received his chemo (carboplatin/taxol) and radiation tx he regularly drank my pumped breastmilk (I had a 6 month old). At that time a lot of research had come out about the immunological factors in BM so we thought that it couldn’t hurt and that it might boost his immune system. He mixed it with yogurt to make it palatable. He remained quite healthy during his tx so I would like to think that the milk had something to do with that. Of course with these new developments perhaps the milk was part of the treatment too! Interestingly, I recently read an article about cancer patients using milk from human milk banks as an alternitive therapy. One gentlemen in the article even spoke about mixing it with yogurt. I suppose we were ahead of our time. Denise

[此贴子已经被作者于2008-4-5 3:30:32编辑过]

白菜头 · 发表于 2008-4-6 16:34:02

母乳?不知道能不能治病,但是我确信它一定能提高免疫力.

jimmy112199 · 发表于 2008-4-7 08:10:12

第一期试验: 口服talactoferrin alfa 治疗难治性实体瘤 Teresa G. Hayes1, 2 Contact Information, Gerald F. Falchook1, Gauri R. Varadhachary1, Dori P. Smith1, Lisa D. Davis1, Hari M. Dhingra1, Benjamin P. Hayes1 and Atul Varadhachary1 (1)      Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas, USA (2)      VA 111H, Michael E. DeBakey VA Medical Center, 2002 Holcombe Blvd., Houston, TX 77030, USA 简要背景： 乳铁蛋白是一种铁结合糖蛋白,作为一种蛋白质产物,首次发现于母乳的乳腺上皮细胞中。其免疫调节功能，包括活化的NK细胞和淋巴因子激活的杀伤细胞， 并增强中性粒细胞和巨噬细胞的细胞毒作用。 研究目的: talactoferrin alfa（ talactoferrin ; tlf ）在动物模型中已显示出大有希望的抗癌活性。本研究的目的是在人类，以及药代动力学和药效学，评价安全性和耐受性。 方法： 10例成人患者，具有常规化疗失败后已进展的晚期实体肿瘤，口服talactoferrin alfa，剂量由1.5至9克/日，用服药2周， 停药2周时间安排。，从   药物毒性，肿瘤的生长速度， talactoferrin药动学和细胞因子的标志物，对患者进行了评价。 结果： talactoferrin很很好的耐受性。没有血液，肝，肾毒性的报道。一个有病人二级腹泻，并有没有三级或4不良反应。继口服，在相当程度上 talactoferrin被undetectable流通中，但统计上的显着增加，在循环白细胞介素-18 ，药效学指标talactoferrin活动进行了观察。在上述 8例中，用胸片评估， 5 人（ 63 ％ ）在开始治疗后两个月，按照recist准则，病情稳定，(其中包括1名病人有少量的响应)。七名病人（( 88 ％） ，的肿瘤生长速度减少了。其中三名非小细胞肺癌（ NSCLC ）患者成活率，在    开始talactoferrin治疗后，至少一年 结论： talactoferrin是一种很有前途的，耐受性良好新的代理人选进行评估应进一步治疗难治性转移性癌。

hase I trial of oral talactoferrin alfa in refractory solid tumors Teresa G. Hayes1, 2 Contact Information, Gerald F. Falchook1, Gauri R. Varadhachary1, Dori P. Smith1, Lisa D. Davis1, Hari M. Dhingra1, Benjamin P. Hayes1 and Atul Varadhachary1 (1)      Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas, USA (2)      VA 111H, Michael E. DeBakey VA Medical Center, 2002 Holcombe Blvd., Houston, TX 77030, USA

ublished online: 20 September 2005 Summary  Background: Lactoferrin is an iron-binding glycoprotein first identified in breast milk as a protein product of mammary epithelial cells. Its immunomodulatory functions include activation of NK and lymphokine-activated killer cells and enhancement of PMN and macrophage cytotoxicity. Studies in animal models have shown promising anti-cancer activity. The purpose of the present study was to evaluate the safety and tolerability of talactoferrin alfa (talactoferrin; TLF) in humans, as well as pharmacokinetics and pharmacodynamics. Methods: Ten adult patients with progressive advanced solid tumors who had failed conventional chemotherapy were administered oral TLF at doses from 1.5 to 9 g/day, using a 2 weeks on, 2 weeks off schedule. Patients were evaluated for drug toxicity, tumor growth rate, talactoferrin pharmacokinetics and cytokine markers. Results: Talactoferrin was very well tolerated. No hematological, hepatic, or renal toxicities were reported. A single patient had Grade 2 diarrhea, and there were no Grade 3 or 4 toxicities. Following oral administration, significant levels of talactoferrin were undetectable in circulation, but a statistically significant increase in circulating IL-18, a pharmacodynamic indicator of talactoferrin activity, was observed. Of the eight patients who were radiologically evaluable, five (63%) had stable disease by RECIST criteria two months after start of therapy, including one patient with a minor response. Seven patients (88%) had a decrease in their tumor growth rate. The three patients with non-small cell lung cancer (NSCLC) all survived for at least one year following the start of talactoferrin monotherapy. Conclusions: Talactoferrin is a promising, well-tolerated new agent that should be evaluated further in patients with refractory metastatic cancer. Key Words  talactoferrin - nonsmall cell lung cancer - refractory cancer Research supported by Agennix, Inc., Houston, Texas.

resented previously in part: Proc. ASCO, Vol. 22, Abstract 947, 2003 and Proc. ASCO, Vol. 23, Abstract 3140, 2004.

[此贴子已经被作者于2008-4-11 7:04:48编辑过]

jimmy112199 · 发表于 2008-4-7 08:16:55

加入口服talactoferrin到一线非小细胞肺癌化疗的安全增强疗效的随机试验。 子类别：非小细胞肺癌 类别： 肺癌会议： 2006年的ASCO年度会议 摘要： 7095 引文： 日刊临床肿瘤学， 2006年的ASCO年度会议程序的第一部分卷24 ，第18 （ 6月20日补充）， 2006年： 7095 作者（号）： Y. Wang, D. Raghunadharao, G. Raman, D. Doval, S. Advani, P. Julka, P. Parikh, S. Patil, S. Nag, J. Madhavan, A. Varadhachary  摘要： 背景： talactoferrin alfa（ TLF ），是一种口服的免疫调节蛋白与一种新型的药制剂。 TLF在早期临床实验中，无论是单独用药，或联合化疗，都展示了抗癌性。在第一/第二期临床试验，TLF在非小细胞肺癌（ NSCLC ）是安全的，明显的单剂抗癌性。 方法： 110个晚期或转移性非小细胞肺癌患者在多个中心接受了化疗治疗试验， ），以卡   铂/紫杉醇（  CP ）治疗，按1：1比例，要么加TLF或安慰剂。开始后的第二天，碳/磷（三： AUC为5毫克/毫升/分钟;市民： 175水化），在化疗周期1 ，第3和第5 ，口腔tlf （ 1.5克竞投者）或安慰剂是在经管的35天周期长达3个周期，或直至进展。主要终点证实反应率（ Rr ;公关+ CR ）的经CT用recist 。次要目标包括级数无瘤生存（油站）和总生存期（ OS ）的。结果：基线病人和疾病特征的可比在这两个群体。所有110例患者包括在意向治疗（ ITT工业）的人口。 100名患者至少有一名CT扫描后开始治疗的前瞻性定义为可评价的人口。加入口腔tlf以碳/磷提高疗效所有的端点审查包括居民代表，油站和OS 。居民证实，在100名可评估的病人明显增加，从29 ％至47 ％（ P值0.05 ）。居民证实，在110 ITT工业患者改善，由27 ％提高至42 ％（ P值0.08 ）。位数的加油站，在两可评估和ITT工业患者改善了2.8个月（ 67 ％）。操作系统中位数提高31 ％和18 ％，在可评价和ITT工业患者，分别为一项划时代的分析比较，病人的存活率并没有一个公关表现出显着差异（ P < 0.01 ） ，暗示一个强大公会之间的RR和生存。 tlf看来是非常安全的，耐受性好，没有任何与毒品有关的更美好。更少的AES观察，在tlf手臂比安慰剂的手臂， 346和432的AES ，水平（

= 0.0023 ）。数量级3 / 4 AES公司还较低，在tlf手臂， 60银两91 （ P值0.0144 ） 。结论：加入口腔tlf标准碳/磷化疗在非小细胞肺癌是安全和提高疗效的随机，多中心，双盲，安慰剂对照试验，以明显改善，居民代表，油站和OS 。结果与tlf媲美其他防癌剂。口腔tlf将进一步评估，在第三阶段试验。 Adding oral talactoferrin to first-line NSCLC chemotherapy safely enhanced efficacy in a randomized trial.  Sub-category: Non-Small Cell Lung Cancer Category: Lung Cancer Meeting: 2006 ASCO Annual Meeting

rinter Friendly E-Mail Article Abstract No: 095 Citation:     Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 7095 Author(s):     Y. Wang, D. Raghunadharao, G. Raman, D. Doval, S. Advani, P. Julka, P. Parikh, S. Patil, S. Nag, J. Madhavan, A. Varadhachary Abstract:     Background: Talactoferrin alfa (TLF) is an oral immunomodulatory protein with a novel mechanism. TLF showed preclinical anti-cancer activity alone and in combination with chemotherapy. In Phase I/II trials, TLF was safe with apparent single-agent anti-cancer activity in non-small cell lung cancer (NSCLC). Methods: 110 chemo-naive patients with advanced or metastatic NSCLC were randomized (1:1) in a multi-center trial to carboplatin/paclitaxel (C/P) therapy plus either TLF or placebo. Starting the day after C/P (C:AUC 5 mg/mL/min; P:175 mg/m2) in chemo-cycles 1, 3 and 5, oral TLF (1.5 g BID) or placebo was administered in 35-day cycles for up to three cycles or until progression. Primary endpoint was Confirmed Response Rate (RR; PR+CR) by CT using RECIST. Secondary endpoints included Progression Free Survival (PFS) and Overall Survival (OS). Results: Baseline patient and disease characteristics were comparable in both groups. All 110 patients were included in the Intent To Treat (ITT) population. 100 patients with at least one CT scan after starting treatment were prospectively defined as the Evaluable population. Adding oral TLF to C/P enhanced efficacy on all endpoints examined including RR, PFS and OS. Confirmed RR in the 100 evaluable patients significantly increased from 29% to 47% (P = 0.05). Confirmed RR in the 110 ITT patients improved from 27% to 42% (P = 0.08). Median PFS in both evaluable and ITT patients improved by 2.8 months (67%). Median OS improved by 31% and 18% in evaluable and ITT patients, respectively. A landmark analysis comparing survival in patients with and without a PR showed a significant difference (P < 0.01), suggesting a strong association between RR and survival. TLF appeared to be very safe and well tolerated with no drug-related SAEs. Fewer AEs were observed in the TLF arm than in the placebo arm, 346 and 432 AEs, respectively (P = 0.0023). The number of Grade 3/4 AEs was also lower in the TLF arm, 60 versus 91 (P = 0.0144). Conclusions: Adding oral TLF to standard C/P chemotherapy in NSCLC was safe and increased efficacy in a randomized, multi-center, double-blind, placebo-controlled trial, with apparent improvements in RR, PFS and OS. Results with TLF compare favorably to other anti-cancer agents. Oral TLF will be further evaluated in a Phase III trial.

[此贴子已经被作者于2008-4-11 7:22:57编辑过]

超越死亡 · 发表于 2014-12-1 18:12:49

Agennix肺癌药物talactoferrin三期实验失败 2012年8月7日
该公司的免疫治疗药物talactoferrin最终未能达到预期的主要目标。在服用安慰剂的肺癌患者平均生存时间为7.7个月的前提下，服用这一实验性蛋白质药物的患者组仅有平均7.5个月的生存期。根据Agennix的对外声明，公司正准备采取行动来降低研发成本，并已经在着手一个新的研究路线。
倒在三期，非常可惜！

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