Modulation of the immune microenvironment of high-risk ductal carcinoma in situ by intralesional pembrolizumab injection

Abstract Ductal carcinoma in situ (DCIS) is a risk factor for the subsequent development of invasive breast cancer. High-risk features include age <45 years, size >5 cm, high-grade, palpable mass, hormone receptor negativity, and HER2 positivity. We have previously shown that immune infiltrate...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Alexa C. Glencer, Jasmine M. Wong, Nola M. Hylton, Gregor Krings, Emma McCune, Harriet T. Rothschild, Tristan A. Loveday, Michael D. Alvarado, Laura J. Esserman, Michael J. Campbell
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/5a661047542045b0add0bdcad86a3bf3
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:5a661047542045b0add0bdcad86a3bf3
record_format	dspace
spelling	oai:doaj.org-article:5a661047542045b0add0bdcad86a3bf32021-12-02T16:53:05ZModulation of the immune microenvironment of high-risk ductal carcinoma in situ by intralesional pembrolizumab injection10.1038/s41523-021-00267-z2374-4677https://doaj.org/article/5a661047542045b0add0bdcad86a3bf32021-05-01T00:00:00Zhttps://doi.org/10.1038/s41523-021-00267-zhttps://doaj.org/toc/2374-4677Abstract Ductal carcinoma in situ (DCIS) is a risk factor for the subsequent development of invasive breast cancer. High-risk features include age <45 years, size >5 cm, high-grade, palpable mass, hormone receptor negativity, and HER2 positivity. We have previously shown that immune infiltrates are positively associated with these high-risk features, suggesting that manipulating the immune microenvironment in high-risk DCIS could potentially alter disease progression. Patients with high-risk DCIS were enrolled in this 3 × 3 phase 1 dose-escalation pilot study of 2, 4, and 8 mg intralesional injections of the PD-1 immune checkpoint inhibitor, pembrolizumab. Study participants received two intralesional injections, three weeks apart, prior to surgery. Tissue from pre-treatment biopsies and post-treatment surgical resections was analyzed using multiplex immunofluorescence (mIF) staining for various immune cell populations. The intralesional injections were easily administered and well-tolerated. mIF analyses demonstrated significant increases in total T cell and CD8+ T cell percentages in most patients after receiving pembrolizumab, even at the 2 mg dose. T cell expansion was confined primarily to the stroma rather than within DCIS-containing ducts. Neither cleaved caspase 3 (CC3) staining, a marker for apoptosis, nor DCIS volume (as measured by MRI) changed significantly following treatment. Intralesional injection of pembrolizumab is safe and feasible in patients with DCIS. Nearly all patients experienced robust total and CD8+ T cell responses. However, we did not observe evidence of cell death or tumor volume decrease by MRI, suggesting that additional strategies may be needed to elicit stronger anti-tumor immunity.Alexa C. GlencerJasmine M. WongNola M. HyltonGregor KringsEmma McCuneHarriet T. RothschildTristan A. LovedayMichael D. AlvaradoLaura J. EssermanMichael J. CampbellNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Breast Cancer, Vol 7, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Alexa C. Glencer Jasmine M. Wong Nola M. Hylton Gregor Krings Emma McCune Harriet T. Rothschild Tristan A. Loveday Michael D. Alvarado Laura J. Esserman Michael J. Campbell Modulation of the immune microenvironment of high-risk ductal carcinoma in situ by intralesional pembrolizumab injection
description	Abstract Ductal carcinoma in situ (DCIS) is a risk factor for the subsequent development of invasive breast cancer. High-risk features include age <45 years, size >5 cm, high-grade, palpable mass, hormone receptor negativity, and HER2 positivity. We have previously shown that immune infiltrates are positively associated with these high-risk features, suggesting that manipulating the immune microenvironment in high-risk DCIS could potentially alter disease progression. Patients with high-risk DCIS were enrolled in this 3 × 3 phase 1 dose-escalation pilot study of 2, 4, and 8 mg intralesional injections of the PD-1 immune checkpoint inhibitor, pembrolizumab. Study participants received two intralesional injections, three weeks apart, prior to surgery. Tissue from pre-treatment biopsies and post-treatment surgical resections was analyzed using multiplex immunofluorescence (mIF) staining for various immune cell populations. The intralesional injections were easily administered and well-tolerated. mIF analyses demonstrated significant increases in total T cell and CD8+ T cell percentages in most patients after receiving pembrolizumab, even at the 2 mg dose. T cell expansion was confined primarily to the stroma rather than within DCIS-containing ducts. Neither cleaved caspase 3 (CC3) staining, a marker for apoptosis, nor DCIS volume (as measured by MRI) changed significantly following treatment. Intralesional injection of pembrolizumab is safe and feasible in patients with DCIS. Nearly all patients experienced robust total and CD8+ T cell responses. However, we did not observe evidence of cell death or tumor volume decrease by MRI, suggesting that additional strategies may be needed to elicit stronger anti-tumor immunity.
format	article
author	Alexa C. Glencer Jasmine M. Wong Nola M. Hylton Gregor Krings Emma McCune Harriet T. Rothschild Tristan A. Loveday Michael D. Alvarado Laura J. Esserman Michael J. Campbell
author_facet	Alexa C. Glencer Jasmine M. Wong Nola M. Hylton Gregor Krings Emma McCune Harriet T. Rothschild Tristan A. Loveday Michael D. Alvarado Laura J. Esserman Michael J. Campbell
author_sort	Alexa C. Glencer
title	Modulation of the immune microenvironment of high-risk ductal carcinoma in situ by intralesional pembrolizumab injection
title_short	Modulation of the immune microenvironment of high-risk ductal carcinoma in situ by intralesional pembrolizumab injection
title_full	Modulation of the immune microenvironment of high-risk ductal carcinoma in situ by intralesional pembrolizumab injection
title_fullStr	Modulation of the immune microenvironment of high-risk ductal carcinoma in situ by intralesional pembrolizumab injection
title_full_unstemmed	Modulation of the immune microenvironment of high-risk ductal carcinoma in situ by intralesional pembrolizumab injection
title_sort	modulation of the immune microenvironment of high-risk ductal carcinoma in situ by intralesional pembrolizumab injection
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/5a661047542045b0add0bdcad86a3bf3
work_keys_str_mv	AT alexacglencer modulationoftheimmunemicroenvironmentofhighriskductalcarcinomainsitubyintralesionalpembrolizumabinjection AT jasminemwong modulationoftheimmunemicroenvironmentofhighriskductalcarcinomainsitubyintralesionalpembrolizumabinjection AT nolamhylton modulationoftheimmunemicroenvironmentofhighriskductalcarcinomainsitubyintralesionalpembrolizumabinjection AT gregorkrings modulationoftheimmunemicroenvironmentofhighriskductalcarcinomainsitubyintralesionalpembrolizumabinjection AT emmamccune modulationoftheimmunemicroenvironmentofhighriskductalcarcinomainsitubyintralesionalpembrolizumabinjection AT harriettrothschild modulationoftheimmunemicroenvironmentofhighriskductalcarcinomainsitubyintralesionalpembrolizumabinjection AT tristanaloveday modulationoftheimmunemicroenvironmentofhighriskductalcarcinomainsitubyintralesionalpembrolizumabinjection AT michaeldalvarado modulationoftheimmunemicroenvironmentofhighriskductalcarcinomainsitubyintralesionalpembrolizumabinjection AT laurajesserman modulationoftheimmunemicroenvironmentofhighriskductalcarcinomainsitubyintralesionalpembrolizumabinjection AT michaeljcampbell modulationoftheimmunemicroenvironmentofhighriskductalcarcinomainsitubyintralesionalpembrolizumabinjection
_version_	1718382859987714048

Modulation of the immune microenvironment of high-risk ductal carcinoma in situ by intralesional pembrolizumab injection

Ejemplares similares