The ambition of the Marleen Kok Group is two-fold: 1). To develop predictive tests that can be utilized to select breast cancer patients who will benefit from immunotherapy. Both learning lesions from research in more immunogenic tumors such as melanoma as well as unraveling the breast tumor microenvironment will be crucial to accomplish this; 2). To explore how we should combine immunotherapy with conventional treatments that can be immunostimulatory such as certain chemotherapies, targeted therapies or irradiation. Via team-science these ambitions will hopefully lead to future personalized breast cancer immunotherapy and subsequently to the reduction of toxic chemotherapy.
The group of Marleen Kok works in close collaboration with the group of Karin de Visser to dissect the systemic immune components and study breast cancer-immune interactions.
There is now abundant clinical evidence that the T cells can control the growth of human cancers, however so far only a small subgroup of breast cancer patients seems to have benefit from immunotherapeutic agents such as anti-PD1. Our ambition is two-fold: 1). To develop predictive tests that can be utilized to select breast cancer patients who will benefit from immunotherapy. We strongly belief that both learning lesions from research in more immunogenic tumors such as melanoma as well as unraveling the breast tumor microenvironment and the systemic immune components (in close collaboration with de Visser lab) will be crucial to accomplish this; 2). To explore how we should combine immunotherapy with conventional treatments that can be immunostimulatory such as certain chemotherapies, targeted therapies or irradiation. Via team-science these ambitions will hopefully lead to future personalized breast cancer immunotherapy.
The response rate of triple negative breast cancer (TNBC) patients to PD-1 blockade is low, highlighting an urgent clinical need for strategies that render the TNBC tumor microenvironment (TME) more sensitive to PD-1 blockade. Immunomodulatory mechanisms have been proposed for both chemotherapy and irradiation, but it has not been established whether these therapies may improve efficacy of PD-1 blockade by favorably changing the TME. Patients with metastatic TNBC were randomized to anti-PD1 without induction or to one of four induction treatments, consisting of irradiation or a two- week low-dose regimen of cyclophosphamide, cisplatin or doxorubicin, all followed by anti-PD-1. The majority of clinical responses were observed on anti-PD1 in the cisplatin and doxorubicin induction cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes, involved in PD-1/PD-L1, and T-cell cytotoxicity pathways. This was supported by enrichment among upregulated genes related to inflammation, JAK-STAT and TNFα-signaling after doxorubicin. In addition, we observed a trend towards increased T-cell infiltration, measured using T-cell receptor (TCR) sequencing, after doxorubicin. Together, the data suggest that short-term doxorubicin and cisplatin may induce a more favorable TME and increase the likelihood of response to PD-1 blockade in TNBC. Results have been presented at ESMO 2017, ASCO 2018 and recently published in Nature Medicine (Voorwerk et al.)
Recently, genomic profiling showed that within invasive lobular breast cancer (ILC) an 'immune-related' subtype exists of tumors with higher expression of immune-related genes. Besides, in a previously established mouse model for mILC, a synergistic effect of platinum and checkpoint inhibitors was observed (dr Karin de Visser group, NKI). Currently we are investigating the efficacy and immunomodulatory capacity of PD-1 blockade in combination with platinum agents in patients with metastatic ILC.
There is now substantial evidence from preclinical studies that suppressive immune cells and soluble immune mediators can blunt the anti-cancer T cells response. Right now the key question is whether this immunosuppressive phenomenon is present in breast cancer patients and whether it is important for response to immunotherapy. In collaboration with the group of dr Karin de Visser we have set-up a pipeline for comprehensive analyses of these systemic immunosuppressive components using high-dimensional flow cytometry combined with functional assays on fresh material from breast cancer patients.