Abstract
A prospective non-randomized phase I trial of dendritic cell–based cryoimmunotherapy combined with checkpoint inhibitors in mCRPC.
Author
person
Liv Cecilie Vestrheim Thomsen
Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway
info_outline
Liv Cecilie Vestrheim Thomsen, Alfred Honoré, Bjorn T. Gjertsen, Astrid Børretzen, Lars Anders Reisæter, Bjarte Almås, Svein Inge Helle, Kristina Førde, Martin Biermann, Waqas Azeem, Benjamin Gabriel, Stian Knappskog, Ole Johan Halvorsen, Lars Akslen, Klaus Pantel, Sabine Riethdorf, Anne Margrete Øyan, Karl-Henning Kalland, Christian Beisland
Full text
Authors
person
Liv Cecilie Vestrheim Thomsen
Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway
info_outline
Liv Cecilie Vestrheim Thomsen, Alfred Honoré, Bjorn T. Gjertsen, Astrid Børretzen, Lars Anders Reisæter, Bjarte Almås, Svein Inge Helle, Kristina Førde, Martin Biermann, Waqas Azeem, Benjamin Gabriel, Stian Knappskog, Ole Johan Halvorsen, Lars Akslen, Klaus Pantel, Sabine Riethdorf, Anne Margrete Øyan, Karl-Henning Kalland, Christian Beisland
Organizations
Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway, Dept. of Urology, Haukeland University Hospital, Bergen, Norway, Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway, Dept. of Pathology, Haukeland University Hospital, Bergen, Norway, Dept. of Radiology, Haukeland University Hospital, Bergen, Norway, Dept. of Oncology, Haukeland University Hospital, Bergen, Norway, Centre for Cancer Biomarkers CCBIO, Dept. of Clinical Science, University of Bergen, Bergen, Norway, K.G. Jebsen Centre for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway, Centre for Cancer Biomarkers CCBIO, Dept. of Clinical Medicine, University of Bergen, Bergen, Norway, Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany, University Medical Center HH-Eppendorf, Hamburg, Germany, Dept. of Clinical Science, University of Bergen, Bergen, Norway
Abstract Disclosures
Research Funding
Other
Helse Vest and Helse Vest Strategic grants for Personalized Therapy, Bergen Stem Cell Consortium, Research Council of Norway through its Centres of Excellence funding scheme (project number 223250), the Research Council of Norway NFR BEHANDLING programme (project number 287829), the Norwegian Cancer Society (project number 204947), and the Bergen Research Foundation/Trond Mohn Stiftelse
Background:
Despite improvements, metastatic castration-resistant prostate cancer (mCRPC) still has dismal overall survival (OS). We treated 18 mCRPC patients with dendritic cell (DC)-based cryoimmunotherapy (CryoIT) as monotherapy or combined with checkpoint inhibitors to determine safety and immune response.
Methods:
mCRPC patients were biopsied before cryoablation, and subsequently injected intratumorally with autologous immature DCs. DC doses were escalated in a 3+3 design (n=9) followed by dose expansion combined with either ipilimumab (n=6) or pembrolizumab (n=3). The disease burden was assessed by PSA values, iRECISTv1.1 (PET/CT, MRI and bone scintigraphy at baseline, 14, 22 and 46 weeks) and circulating tumor cells (CTC; CellSearch). Immune response was monitored by ultradeep T-cell receptor sequencing.
Results:
The patients had aggressive cancer, with ISUP grade group 4 and 5 in 72% (13/18) at diagnosis and in 100% at inclusion. At baseline, higher ALP correlated with higher regulatory T cells (p=0.047), FoxP3+/CD3+ratios (p=0.014) and FoxP3+/CD8+ratios (p=0.004) in tissues. Median OS and progression-free survival (PFS) were 40.7 and 10.5 months, respectively. Of the 8 patients alive 43 to 85 months post-CryoIT, 7 had progressed and received other treatment. Early decreases in PSA (p=0.002) and LDH (p=0.01) levels 6 weeks after CryoIT indicated better outcomes at 22 weeks. Longer OS correlated with lower tissue ratios of CD4+/CD3+cells (p=0.002) and CD4+/CD8+cells (p=0.007). All patients with increased numbers of new T-cell clonotypes after CryoIT and CTC at the pretreatment level of 1-4 cells/ 7.5 mL blood changed to negative during follow-up up to 72 weeks.
Conclusions:
CryoIT demonstrates non-inferior OS and PFS compared to other mCRPC trials, and therapy response was suggested by decreased CTCs and induction of new T-cell clonotypes post-CryoIT. Lower CD4
+
cell fractions of lymphocytes in the TME indicate better OS after CryoIT. CryoIT appears not to decrease effects of post-treatment recurrence therapies. Clinical trial information: NCT02423928.
Adverse event
Grade 1-2 (n)
Grade 3 (n)
Urinary tract
11
1
Hematologic
1
0
Gastrointestinal
7
0
Pain
3
0
Influenza/common cold
5
0
Osteomyelitis
0
1
Rash
1
0
Other
4
0
Clinical status
Clinical
13 organizations
3 drugs
3 targets
Organization
Centre for Cancer Biomarkers CCBIOOrganization
University of BergenOrganization
Dept. of UrologyOrganization
Haukeland University HospitalOrganization
Dept. of PathologyOrganization
Dept. of RadiologyOrganization
Dept. of Oncology IRCCS-'Mario Negri' InstituteOrganization
Dept. of Clinical MedicineOrganization
Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, GermanyOrganization
University Medical Center HH-EppendorfOrganization
Dept. of Clinical ScienceDrug
ipilimumabDrug
pembrolizumabTarget
CTLA-4Target
dendritic cells