TY - JOUR
T1 - Impacts of pembrolizumab therapy on immune phenotype in patients with high-grade neuroendocrine neoplasms
AU - MacFarlane, Alexander W.
AU - Yeung, Ho Man
AU - Alpaugh, R. Katherine
AU - Dulaimi, Essel
AU - Engstrom, Paul F.
AU - Dasari, Arvind
AU - Campbell, Kerry S.
AU - Vijayvergia, Namrata
N1 - Funding Information:
These studies were supported by research grant MISP#53956 from Merck, NCI Comprehensive Cancer Center Support Grant CA06927 (FCCC), an appropriation from the Commonwealth of Pennsylvania, and philanthropic support to FCCC research from the In Vino Vita fundraiser, Bucks County and Main Line Boards of Associates, the C.W.A. Local 13000 Jim Willer Golf Tournament, and the Dragon Boat Team fundraising event. Acknowledgments
Funding Information:
The authors thank all the patients that participated in this study. They also thank Irina Shchaveleva, Dr. Chun Zhou, and Judy Fang from the FCCC Immune Monitoring Facility, Dr. Greg Cesarone from QualTek Molecular Laboratories, FCCC Biostatistics & Bioinformatics Facility, especially Karen Ruth, and FCCC Cell Culture Facility for technical support, Dr. Shafat Quadri, Medical Science Liaison at Merck for coordination of the clinical trial, Drs. Matthew Zibelman and Phillip Abbosh for critical evaluation of the manuscript, and financial support from Merck Research Laboratories, the FCCC In Vino Vita philanthropic event, FCCC Bucks County and Mainline Boards of Associates, the C.W.A. Local 13000 Jim Willer Golf Tournament, and the FCCC Dragon Boat Team.
Publisher Copyright:
© 2021, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2021/7
Y1 - 2021/7
N2 - High grade neuroendocrine neoplasms (G3 NENs) are rare aggressive tumors with limited treatment options. Twenty-one previously treated patients with metastatic extra-pulmonary G3 NENs were treated with pembrolizumab. Baseline tumor samples were assessed for PD-L1 and tumor infiltrating lymphocytes (TIL). Peripheral blood samples drawn pre-treatment, prior to cycle three, and at disease progression were analyzed by flow cytometry. One patient achieved partial response, two had stable disease, and 18 exhibited progressive disease. The partially responding patient did not progress after 392 days, and the median progression-free survival (PFS) was 59 days. Longer PFS correlated independently with higher pre-treatment peripheral blood T-cell counts and lower pre-treatment activation state (CD69 expression) of naïve T cells and NK cells. Peripheral T-cell viability was reduced in patients with greater TILs. Post-treatment, T cells had reduced numbers of CD4+ cells, reduced PD-1 expression, increased activation of effector (CD62L−) cells, and increased expression of TIGIT. Baseline TIGIT expression on peripheral T cells also correlated positively with Ki67 in tumor. Patients with higher baseline T-cell expression of TIM-3 had shorter PFS. Despite limited activity of pembrolizumab, this study highlights the immune phenotype in this rare tumor type before and after treatment. High baseline peripheral T-cell count and reduced activation of T and NK cell subsets were associated with improved outcomes. Furthermore, increased post-treatment TIGIT and elevated baseline TIM-3 expression suggest that these may limit the efficacy of pembrolizumab, providing a rationale for combination immunotherapy (PD-1 with TIGIT and/or TIM-3 antibodies) to treat extra-pulmonary G3 NENs.
AB - High grade neuroendocrine neoplasms (G3 NENs) are rare aggressive tumors with limited treatment options. Twenty-one previously treated patients with metastatic extra-pulmonary G3 NENs were treated with pembrolizumab. Baseline tumor samples were assessed for PD-L1 and tumor infiltrating lymphocytes (TIL). Peripheral blood samples drawn pre-treatment, prior to cycle three, and at disease progression were analyzed by flow cytometry. One patient achieved partial response, two had stable disease, and 18 exhibited progressive disease. The partially responding patient did not progress after 392 days, and the median progression-free survival (PFS) was 59 days. Longer PFS correlated independently with higher pre-treatment peripheral blood T-cell counts and lower pre-treatment activation state (CD69 expression) of naïve T cells and NK cells. Peripheral T-cell viability was reduced in patients with greater TILs. Post-treatment, T cells had reduced numbers of CD4+ cells, reduced PD-1 expression, increased activation of effector (CD62L−) cells, and increased expression of TIGIT. Baseline TIGIT expression on peripheral T cells also correlated positively with Ki67 in tumor. Patients with higher baseline T-cell expression of TIM-3 had shorter PFS. Despite limited activity of pembrolizumab, this study highlights the immune phenotype in this rare tumor type before and after treatment. High baseline peripheral T-cell count and reduced activation of T and NK cell subsets were associated with improved outcomes. Furthermore, increased post-treatment TIGIT and elevated baseline TIM-3 expression suggest that these may limit the efficacy of pembrolizumab, providing a rationale for combination immunotherapy (PD-1 with TIGIT and/or TIM-3 antibodies) to treat extra-pulmonary G3 NENs.
KW - G3 NEN
KW - NK cells
KW - Neuroendocrine
KW - PD-1
KW - Pembrolizumab
KW - T cells
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U2 - 10.1007/s00262-020-02811-5
DO - 10.1007/s00262-020-02811-5
M3 - Article
C2 - 33398390
AN - SCOPUS:85098659299
SN - 0340-7004
VL - 70
SP - 1893
EP - 1906
JO - Cancer Immunology, Immunotherapy
JF - Cancer Immunology, Immunotherapy
IS - 7
ER -