Study protocol of a phase II study to evaluate safety and efficacy of neo-adjuvant pembrolizumab and radiotherapy in localized rectal cancer.
Pembrolizumab
Radiotherapy
Rectal cancer
T cell infiltration
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
15 Jul 2022
15 Jul 2022
Historique:
received:
06
12
2021
accepted:
24
06
2022
entrez:
15
7
2022
pubmed:
16
7
2022
medline:
20
7
2022
Statut:
epublish
Résumé
Reshaping the tumor microenvironment by novel immunotherapies represents a key strategy to improve cancer treatment. Nevertheless, responsiveness to these treatments is often correlated with the extent of T cell infiltration at the tumor site. Remarkably, microsatellite stable rectal cancer is characterized by poor T cell infiltration and, therefore, does not respond to immune checkpoint blockade. To date, the only available curative option for these patients relies on extensive surgery. With the aim to broaden the application of promising immunotherapies, it is necessary to develop alternative approaches to promote T cell infiltration into the tumor microenvironment of these tumors. In this regard, recent evidence shows that radiotherapy has profound immunostimulatory effects, hinting at the possibility of combining it with immunotherapy. The combination of long-course chemoradiotherapy and immune checkpoint inhibition was recently shown to be safe and yielded promising results in rectal cancer, however short-course radiotherapy and immune checkpoint inhibition have never been tested in these tumors. Our clinical trial investigates the clinical and biological impact of combining pembrolizumab with short-course radiotherapy in the neo-adjuvant treatment of localized rectal cancer. This phase II non-randomized study will recruit 25 patients who will receive short-course preoperative radiotherapy (5 Gy × 5 days) and four injections of pembrolizumab starting on the same day and on weeks 4, 7 and 10. Radical surgery will be performed three weeks after the last pembrolizumab injection. Our clinical trial includes an extensive translational research program involving the transcriptomic and proteomic analysis of tumor and blood samples throughout the course of the treatment. Our study is the first clinical trial to combine short-course radiotherapy and immune checkpoint inhibition in rectal cancer, which could potentially result in a major breakthrough in the treatment of this cancer. Additionally, the translational research program will offer insights into immunological changes within the tumor and blood and their correlation with patient outcome. Taken together, our work will help optimizing future treatment combinations and, possibly, better selecting patients. This study was registered with www. gov : NCT04109755 . Registration date: June, 2020.
Sections du résumé
BACKGROUND
BACKGROUND
Reshaping the tumor microenvironment by novel immunotherapies represents a key strategy to improve cancer treatment. Nevertheless, responsiveness to these treatments is often correlated with the extent of T cell infiltration at the tumor site. Remarkably, microsatellite stable rectal cancer is characterized by poor T cell infiltration and, therefore, does not respond to immune checkpoint blockade. To date, the only available curative option for these patients relies on extensive surgery. With the aim to broaden the application of promising immunotherapies, it is necessary to develop alternative approaches to promote T cell infiltration into the tumor microenvironment of these tumors. In this regard, recent evidence shows that radiotherapy has profound immunostimulatory effects, hinting at the possibility of combining it with immunotherapy. The combination of long-course chemoradiotherapy and immune checkpoint inhibition was recently shown to be safe and yielded promising results in rectal cancer, however short-course radiotherapy and immune checkpoint inhibition have never been tested in these tumors.
METHODS
METHODS
Our clinical trial investigates the clinical and biological impact of combining pembrolizumab with short-course radiotherapy in the neo-adjuvant treatment of localized rectal cancer. This phase II non-randomized study will recruit 25 patients who will receive short-course preoperative radiotherapy (5 Gy × 5 days) and four injections of pembrolizumab starting on the same day and on weeks 4, 7 and 10. Radical surgery will be performed three weeks after the last pembrolizumab injection. Our clinical trial includes an extensive translational research program involving the transcriptomic and proteomic analysis of tumor and blood samples throughout the course of the treatment.
DISCUSSION
CONCLUSIONS
Our study is the first clinical trial to combine short-course radiotherapy and immune checkpoint inhibition in rectal cancer, which could potentially result in a major breakthrough in the treatment of this cancer. Additionally, the translational research program will offer insights into immunological changes within the tumor and blood and their correlation with patient outcome. Taken together, our work will help optimizing future treatment combinations and, possibly, better selecting patients.
TRIAL REGISTRATION
BACKGROUND
This study was registered with www.
CLINICALTRIAL
BACKGROUND
gov : NCT04109755 . Registration date: June, 2020.
Identifiants
pubmed: 35840912
doi: 10.1186/s12885-022-09820-w
pii: 10.1186/s12885-022-09820-w
pmc: PMC9288067
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Immune Checkpoint Inhibitors
0
pembrolizumab
DPT0O3T46P
Banques de données
ClinicalTrials.gov
['NCT04109755']
Types de publication
Clinical Trial Protocol
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
772Informations de copyright
© 2022. The Author(s).
Références
Science. 2006 Sep 29;313(5795):1960-4
pubmed: 17008531
J Natl Compr Canc Netw. 2017 Mar;15(3):401-410
pubmed: 28275038
Br J Surg. 2015 Jul;102(8):972-8; discussion 978
pubmed: 26095256
J Clin Oncol. 2012 Nov 1;30(31):3827-33
pubmed: 23008301
J Clin Invest. 2014 Feb;124(2):687-95
pubmed: 24382348
Am Soc Clin Oncol Educ Book. 2018 May 23;38:239-247
pubmed: 30231358
Lancet Oncol. 2017 Sep;18(9):1182-1191
pubmed: 28734759
CA Cancer J Clin. 2018 Nov;68(6):394-424
pubmed: 30207593
J Clin Invest. 2015 Sep;125(9):3335-7
pubmed: 26325031
Eur J Cancer. 2009 Jan;45(2):228-47
pubmed: 19097774
Lancet Oncol. 2005 Jul;6(7):520-8
pubmed: 15992701
Br J Surg. 2006 Oct;93(10):1215-23
pubmed: 16983741
Clin Cancer Res. 2017 Sep 15;23(18):5514-5526
pubmed: 28533222
J Natl Compr Canc Netw. 2014 Apr;12(4):513-9
pubmed: 24717570
Gut. 2017 Apr;66(4):683-691
pubmed: 26818619
J Clin Oncol. 2010 Oct 10;28(29):4531-8
pubmed: 20516428
Nat Med. 2020 Apr;26(4):566-576
pubmed: 32251400
Int J Cancer. 2019 Apr 15;144(8):1941-1953
pubmed: 30350310
Cancer Res. 2011 Feb 15;71(4):1263-71
pubmed: 21303976
Lancet Oncol. 2020 Sep;21(9):e419-e430
pubmed: 32888471
Nat Rev Cancer. 2012 Mar 22;12(4):252-64
pubmed: 22437870
Cancer Res. 2014 Oct 1;74(19):5458-68
pubmed: 25274032