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Magnitude and duration of immune checkpoint up-regulation and changes in the immune microenvironment post chemo-radiation (CRT) in esophageal cancer.

Publication ,  Conference
Kelly, RJ; Zaidi, AH; Smith, MA; Omstead, AN; Kosovec, JE; Matsui, D; Martin, SA; DiCarlo, C; Werts, ED; Silverman, JF; Wang, DH; Jobe, BA
Published in: Journal of Clinical Oncology
May 20, 2017

4060 Background: PD-1 inhibitors in metastatic gastroesophageal cancer have demonstrated response rates of approximately 25%. Unfortunately, the majority of patients do not respond. Therefore, a rationale strategy of combining immunotherapeutic agents with CRT in earlier stage esophageal cancer may prevent metastatic disease in a greater proportion of patients. This study assessed the impact of CRT on the immune microenvironment and the expression patterns of multiple immune checkpoints to optimally design neoadjuvant clinical trials. Methods: To determine the effects of CRT on resected esophageal adenocarcinomas (EAC), we examined the immune microenvironment pre and post CRT using IHC, LCM followed by qRT-PCR, and functional analysis of tumor-infiltrating lymphocytes. Additionally, to assess the duration and dependency of radiation-induced PD-L1 sensitization, esophagojejunostomy were performed on rats to induce gastroduodenoesophageal reflux and EAC formation. First, tumor bearing animals were dosed with single fraction 13 Gy or 16 Gy radiation to determine safety, dose correlation, and PD-L1 sensitization using qRT-PCR post-radiation. Next, longitudinal PD-L1 expression levels within individual tumor bearing animals were determined using serial endoscopic biopsies at baseline, 1, 5 and 9 weeks post 16 Gy radiation. Results: The majority of cancers displayed enhanced interferon γ and activated CD8+ T lymphocytes at the tumor stroma interface. These tumors also demonstrated enhanced upregulation of PD-L1 and multiple other immune checkpoints including – TIM3, GITR, IDO1, LAG3, CD137, OX40 and KIR. The animal model results indicated PD-L1 upregulation is dose dependent and transiently elevated post radiation exposure. Conclusions: Collectively, these findings provide insights into the evolving immune landscape after CRT and have significant implications for future neoadjuvant trial designs that will combine radiotherapy with immune checkpoint inhibitors. Currently, we are conducting a neoadjuvant trial assessing Nivolumab or Nivolumab/Ipilimumab in combination with CRT in stage II/III operable esophageal cancer.

Duke Scholars

Published In

Journal of Clinical Oncology

DOI

EISSN

1527-7755

ISSN

0732-183X

Publication Date

May 20, 2017

Volume

35

Issue

15_suppl

Start / End Page

4060 / 4060

Publisher

American Society of Clinical Oncology (ASCO)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 1112 Oncology and Carcinogenesis
  • 1103 Clinical Sciences
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Kelly, R. J., Zaidi, A. H., Smith, M. A., Omstead, A. N., Kosovec, J. E., Matsui, D., … Jobe, B. A. (2017). Magnitude and duration of immune checkpoint up-regulation and changes in the immune microenvironment post chemo-radiation (CRT) in esophageal cancer. In Journal of Clinical Oncology (Vol. 35, pp. 4060–4060). American Society of Clinical Oncology (ASCO). https://doi.org/10.1200/jco.2017.35.15_suppl.4060
Kelly, Ronan Joseph, Ali Hussainy Zaidi, Matthew A. Smith, Ashten N. Omstead, Juliann E. Kosovec, Daisuke Matsui, Samantha A. Martin, et al. “Magnitude and duration of immune checkpoint up-regulation and changes in the immune microenvironment post chemo-radiation (CRT) in esophageal cancer.” In Journal of Clinical Oncology, 35:4060–4060. American Society of Clinical Oncology (ASCO), 2017. https://doi.org/10.1200/jco.2017.35.15_suppl.4060.
Kelly RJ, Zaidi AH, Smith MA, Omstead AN, Kosovec JE, Matsui D, et al. Magnitude and duration of immune checkpoint up-regulation and changes in the immune microenvironment post chemo-radiation (CRT) in esophageal cancer. In: Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO); 2017. p. 4060–4060.
Kelly, Ronan Joseph, et al. “Magnitude and duration of immune checkpoint up-regulation and changes in the immune microenvironment post chemo-radiation (CRT) in esophageal cancer.Journal of Clinical Oncology, vol. 35, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2017, pp. 4060–4060. Crossref, doi:10.1200/jco.2017.35.15_suppl.4060.
Kelly RJ, Zaidi AH, Smith MA, Omstead AN, Kosovec JE, Matsui D, Martin SA, DiCarlo C, Werts ED, Silverman JF, Wang DH, Jobe BA. Magnitude and duration of immune checkpoint up-regulation and changes in the immune microenvironment post chemo-radiation (CRT) in esophageal cancer. Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO); 2017. p. 4060–4060.

Published In

Journal of Clinical Oncology

DOI

EISSN

1527-7755

ISSN

0732-183X

Publication Date

May 20, 2017

Volume

35

Issue

15_suppl

Start / End Page

4060 / 4060

Publisher

American Society of Clinical Oncology (ASCO)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 1112 Oncology and Carcinogenesis
  • 1103 Clinical Sciences