Rolf Kiessling's Group
Using the immune system to treat cancer.
General Area of Research
Immunotherapy is making major progress in the clinic and treatment with checkpoint inhibition (CI) results in significant increase in the overall survival among patients with advanced malignant melanoma. Yet, the majority (>50 %) of patients are not helped, why there is a need for improvements by novel combinations and by predictive biomarkers. Administration of tumor infiltrating lymphocytes (TIL) combined with after low dose chemotherapy has been reported to result in long-lasting clinical responses in 20% of the treated patients in patients with metastatic melanoma.
Ongoing research projects; A Phase I study with TIL combined with a Dendritic cell (DC) vaccine in advanced malignant melanoma patients is ongoing as an improved continuation of our published “First-in-man” pilot study. Several complete and long-lasting responses according to RECIST 1.1 have been observed, motivating an analysis of the responsible T cell clones and a search for antigens recognized by infused T cells, focusing on the role of missense mutations as “neoantigens”. A search for predictive biomarkers has shown promising results, and the presence of monocytic Myeloid Derived Suppressor Cells (moMDSC) was shown to predict poor response to CI.
Conclusion from our research: Cell therapy can result in complete clinical responses also in patients who are not responding any longer to checkpoint therapy. Our project has revealed a critical role for moMDSC in conferring resistance to immunotherapy and as predictive biomarkers for clinical response.
- The Swedish Cancer Society
- Swedish Medical Research Council
- ALF-Project grant from the Stockholm City Council
- Cancer Society in Stockholm
- Knut and Alice Wallenberg foundation
- Torsten Söderbergs Stiftelse
Rolf Kiessling, MD, PhD, Professor, Group leader
Stina Wickström, PhD, Assistant professor
Jeroen Melief, PhD, Assistant professor
Stefanie Renken, PhD student
Lucas Baldran, PhD student
Ulrika Edbäck, Medical Laboratory Scientist
Janin Kaper, head of GMP-CCK
Takuro Matsumoto, MD, Postdoctoral fellow
PD-1 checkpoint blockade in advanced melanoma patients: NK cells, monocytic subsets and host PD-L1 expression as predictive biomarker candidates.
Pico de Coaña Y, Wolodarski M, van der Haar Àvila I, Nakajima T, Rentouli S, Lundqvist A, et al
Oncoimmunology 2020 08;9(1):1786888
High expression of ID1 in monocytes is strongly associated with phenotypic and functional MDSC markers in advanced melanoma.
Melief J, Pico de Coaña Y, Maas R, Fennemann FL, Wolodarski M, Hansson J, et al
Cancer Immunol Immunother 2020 Apr;69(4):513-522
Complete and long-lasting clinical responses in immune checkpoint inhibitor-resistant, metastasized melanoma treated with adoptive T cell transfer combined with DC vaccination.
Lövgren T, Wolodarski M, Wickström S, Edbäck U, Wallin M, Martell E, et al
Oncoimmunology 2020 07;9(1):1792058
Cancer Neoepitopes for Immunotherapy: Discordance Between Tumor-Infiltrating T Cell Reactivity and Tumor MHC Peptidome Display.
Wickström SL, Lövgren T, Volkmar M, Reinhold B, Duke-Cohan JS, Hartmann L, et al
Front Immunol 2019 ;10():2766
Self-Delivering RNAi Targeting PD-1 Improves Tumor-Specific T Cell Functionality for Adoptive Cell Therapy of Malignant Melanoma.
Ligtenberg MA, Pico de Coaña Y, Shmushkovich T, Yoshimoto Y, Truxova I, Yang Y, et al
Mol Ther 2018 06;26(6):1482-1493
Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-γ and multiple toll-like receptor agonists.
Lövgren T, Sarhan D, Truxová I, Choudhary B, Maas R, Melief J, et al
Cancer Immunol Immunother 2017 Oct;66(10):1333-1344
Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma.
de Coaña YP, Wolodarski M, Poschke I, Yoshimoto Y, Yang Y, Nyström M, et al
Oncotarget 2017 Mar;8(13):21539-21553
Targeting Suppressive Myeloid Cells Potentiates Checkpoint Inhibitors to Control Spontaneous Neuroblastoma.
Mao Y, Eissler N, Blanc KL, Johnsen JI, Kogner P, Kiessling R
Clin Cancer Res 2016 08;22(15):3849-59
A phase I clinical trial combining dendritic cell vaccination with adoptive T cell transfer in patients with stage IV melanoma.
Poschke I, Lövgren T, Adamson L, Nyström M, Andersson E, Hansson J, et al
Cancer Immunol Immunother 2014 Oct;63(10):1061-71
Melanoma-educated CD14+ cells acquire a myeloid-derived suppressor cell phenotype through COX-2-dependent mechanisms.
Mao Y, Poschke I, Wennerberg E, Pico de Coaña Y, Egyhazi Brage S, Schultz I, et al
Cancer Res 2013 Jul;73(13):3877-87