Global S&T Development Trend Analysis Platform of Resources and Environment
| DOI | 10.1126/science.abg2904 |
| Modulating gut microbiota to treat cancer | |
| Christopher H. Woelk; Alexandra Snyder | |
| 2021-02-05 | |
| 发表期刊 | Science
 |
| 出版年 | 2021 |
| 英文摘要 | In the fourth century, a Chinese practitioner reportedly used the stool of healthy subjects to treat patients with diarrhea ([ 1 ][1]). In 1958, fecal microbiota transplantation (FMT) was reported as a treatment for Clostridium difficile infection that was resistant to antibiotics ([ 2 ][2]). FMT became an option for routine treatment for such infections in 2013, after a clinical trial demonstrated a higher response rate in C. difficile –infected patients treated with FMT (81%) compared to those treated with an antibiotic (31%) ([ 3 ][3]). Since then, interest in FMT has evolved in diverse clinical settings. In cancer, studies on hematopoietic stem cell transplantation, arguably the first immunotherapy of the modern cancer era, have suggested a role for the gut microbiota in clinical outcomes ([ 4 ][4]). On pages 602 and 595 of this issue, Baruch et al. ([ 5 ][5]) and Davar et al. ([ 6 ][6]), respectively, report that manipulating the gut microbiota may allow cancer patients to overcome resistance to immunotherapy.
Cancer immunotherapy for solid tumors experienced a rebirth in the 2010s with the approval of checkpoint inhibitors (CPIs) that block cytotoxic T lymphocyte–associated protein-4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1). These proteins act as cellular “brakes” to control immune responses; thus, CPIs release this restraint. Biomarkers of response and resistance to CPIs include tumor-specific attributes (such as PD-L1 expression and mutation burden). Earlier studies reported that mice subjected to FMT or oral gavage with specific bacteria showed greater sensitivity to CPIs ([ 7 ][7], [ 8 ][8]). Subsequent studies described associations between the gut microbiota and outcomes in cancer patients treated with CPIs ([ 9 ][9], [ 10 ][10]).
Baruch et al. and Davar et al. attempt to bridge association to causation, suggesting that altering the gut microbiota may restore sensitivity to CPIs in patients with advanced cancer. Baruch et al. treated 10 melanoma patients with FMT from two donors who had exhibited a complete response (disappearance of cancer as determined by imaging) to CPIs. Eligible transplant recipients had to have shown progressive disease during or after prior CPI therapy. These patients were then treated with antibiotics to deplete their existing gut microbiota, a process thought to aid subsequent microbiota engraftment. This was followed by FMT administered by colonoscopy every 14 days, together with standard dosing of a CPI targeting PD-1 (nivolumab). Three of the 10 patients showed a radiographic response (shrinking of tumor size as determined by imaging). Of the three patients, one (who had no prior response to CPIs) showed a complete response to FMT when it was given 66 days after the last dose of a previous CPI treatment. This suggests a true de novo response. However, the other two patients showed only a partial response to FMT. They exhibited some response to immunotherapy early on but over time eventually showed disease progression and were therefore considered immunotherapy nonresponsive. Yet, after 119 and 204 days had passed, they then responded to CPI-FMT therapy. Thus, responses to a CPI-FMT combination may have been due to retreatment with CPI alone rather than from a new effect of added FMT, although a role for FMT cannot be excluded. Notably, two of these three responding patients experienced pseudoprogression (when imaging suggests an apparent worsening of a cancer that is followed by subsequent improvement) at a rate much higher than typically seen in patients with melanoma ([ 11 ][11]). The three responding patients also showed increased expression of immune-related genes in the lamina propria (part of the lining of the gastrointestinal tract) and in their tumors. These changes may reflect biological processes associated with clinical response.
The melanoma patients treated by Davar et al. met a stricter definition of resistance to immunotherapy, as they were required to demonstrate no response to prior CPI treatment as well as progressive disease. Stool was collected from seven patients with partial or complete response to CPIs. Patients who were previously refractory to CPIs were initially treated with FMT (stool selected from any one of the seven donors) in combination with a CPI (pembrolizumab), followed by CPI alone every 3 weeks until cancer progression was observed. Three of 15 FMT-treated patients demonstrated a partial response (as determined by imaging of tumor burden), and a further three patients showed stable disease for more than 12 months.
The observations of Baruch et al. and Davar et al. suggest a possible therapeutic effect of FMT in CPI-treated patients. However, several clinical, regulatory, and scientific questions need to be addressed for this approach to become an approved treatment. Notably, a subset of patients who are treated beyond progression with CPIs may experience benefit ([ 12 ][12]), and larger studies in a defined post-CPI population are needed to show FMT efficacy. In addition, across all the patients studied, neither study reported PD-L1 expression or tumor mutation burden, two biomarkers of CPI response. This information is important to determine whether patients require a preexisting adaptive immune response to respond to microbiotamodulating therapy. The studies of Baruch et al. and Davar et al. were each conducted at a single facility, where patients are more likely to have a similar diet and microbiota profiles than at the diverse sites accrued during a phase 2 or 3 clinical trial. Future work is needed to better understand which response profiles for sourcing donor FMT, engraftment procedures, and recipient phenotypes are required for successful CPI-FMT combination therapy.
From a regulatory perspective, challenges in the post-CPI setting include defining the proportion of activity attributable to each part of a combination therapy, defining a CPI-refractory population, and positioning FMT intervention in the context of cancer therapies. Furthermore, because FMT is considered a live biological product and a drug by the U.S. Food and Drug Administration ([ 13 ][13]), FMT combinations with CPIs are likely to encounter regulatory challenges similar to those experienced by FMT for C. difficile infection, which has no clinical approval to date. The regulatory reality for this combination therapy is linked to the scientific challenges of this field; unlike other anticancer therapies being developed for post-CPI use, the “active ingredient” in FMT and its mechanism(s) are unknown. Recent advances in treating C. difficile infection may overcome regulatory hurdles, as illustrated by ECOSPOR III, a phase 3 clinical trial in which capsules containing purified bacterial spores were administered to patients (thought to be potentially safer and more consistent than FMT) ([ 14 ][14]). Different cancer studies have used different DNA sequencing and bioinformatic strategies, attribute the salutary effects of FMT to different bacteria ([ 7 ][7]–[ 10 ][10]), and have not resolved whether general diversity of the microbiota, particular bacterial species, a specific bacterial metabolite, or some other interaction between the host and donor microbiota is the dominant factor in patient response to FMT. Although Baruch et al. and Davar et al. agree that bacteria belonging to the phylum Firmicutes may be associated with response to CPI-FMT therapy, wellpowered studies need to robustly show a clear association between specific taxa and clinical response. Shifting from comparisons of bacterial taxonomy to comparisons of functional metabolic profiles, as performed by Baruch et al. , may provide better mechanistic insights.
Future studies should consider integrating microbiota-related data with tumor-and patient-intrinsic factors that affect outcomes to CPI. Baruch et al. and Davar et al. indicate an acceptable safety profile and potential efficacy for CPI-FMT therapy in advanced melanoma patients. In addition, several companies have live biological products in clinical trials with CPIs in patients with solid tumors (e.g., NCT03817125, NCT04208958, NCT03637803). Large-scale studies should better define efficacy and answer outstanding regulatory and scientific questions.
1. [↵][15]1. J. Stripling,
2. M. Rodriguez
, Am. J. Med. Sci. 356, 424 (2018).
[OpenUrl][16]
2. [↵][17]1. B. Eiseman et al
., Surgery 44, 854 (1958).
[OpenUrl][18][PubMed][19][Web of Science][20]
3. [↵][21]1. E. van Nood et al
., N. Engl. J. Med. 368, 407 (2013).
[OpenUrl][22][CrossRef][23][PubMed][24][Web of Science][25]
4. [↵][26]1. J. U. Peled et al
., J. Clin. Oncol. 35, 1650 (2017).
[OpenUrl][27][CrossRef][28][PubMed][29]
5. [↵][30]1. E. N. Baruch et al
., Science 371, 602 (2021).
[OpenUrl][31][Abstract/FREE Full Text][32]
6. [↵][33]1. D. Davar et al
., Science 371, 595 (2021).
[OpenUrl][34][Abstract/FREE Full Text][35]
7. [↵][36]1. M. Vétizou et al
., Science 350, 1079 (2015).
[OpenUrl][37][Abstract/FREE Full Text][38]
8. [↵][39]1. A. Sivan et al
., Science 350, 1084 (2015).
[OpenUrl][40][Abstract/FREE Full Text][41]
9. [↵][42]1. V. Gopalakrishnan et al
., Science 359, 97 (2018).
[OpenUrl][43][Abstract/FREE Full Text][44]
10. [↵][45]1. B. Routy et al
., Science 359, 91 (2018).
[OpenUrl][46][Abstract/FREE Full Text][47]
11. [↵][48]1. F. S. Hodi et al
., J. Clin. Oncol. J. Clin. Oncol., 1510 (2016).
12. [↵][49]1. J. A. Beaver et al
., Lancet Oncol. Lancet Oncol., 229 (2018).
13. [↵][50]FDA, Fed. Reg. 84, 47911 (2011); |
| 领域 | 气候变化 ; 资源环境 |
| URL | 查看原文 |
| 引用统计 | |
| 文献类型 | 期刊论文 |
| 条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/314037 |
| 专题 | 气候变化 资源环境科学 |
| 推荐引用方式 GB/T 7714 | Christopher H. Woelk,Alexandra Snyder. Modulating gut microbiota to treat cancer[J]. Science,2021. |
| APA | Christopher H. Woelk,&Alexandra Snyder.(2021).Modulating gut microbiota to treat cancer.Science. |
| MLA | Christopher H. Woelk,et al."Modulating gut microbiota to treat cancer".Science (2021). |
| 条目包含的文件 | 条目无相关文件。 | |||||
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。
修改评论