Immune checkpoint inhibitor (ICI) treatment has produced striking results in patients with colorectal cancer (CRC) of the subtype deficient mismatch repair (dMMR). The majority of patients, however, have proficient MMR (pMMR) tumors, with limited effect of ICIs. The key difference between dMMR and pMMR tumors is the infiltration of cytotoxic T-cells. dMMR tumors have increased infiltration and thus increased efficacy from ICI treatment. The investigators conducted a proof of concept study where the investigators applied an intratumoral (IT) unaltered flu vaccine in ten patients with non-metastatic pMMR CRC. The intervention increased infiltration of cytotoxic T-cells and the immune checkpoint PD-L1, suggesting that IT flu vaccine primes pMMR tumors to ICI treatment. The investigators aim to test the combination of IT flu vaccine and ICI treatment in patients with non-metastatic pMMR CRC in a new trial. The hypothesis is that IT flu vaccine and ICI treatment will synergistically to induce cancer cell death.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
21
Intratumoral influenza vaccine treatment, administered via endoscopic procedure
Single dose pembrolizumab treatment
Center for Surgical Science, Department of Surgery, Zealand University Hospital
Koege, Region Sjælland, Denmark
Pathological response
The primary endpoint will be the percent of viable tumor cells in the resected specimen. Partial response will be defined as at least 30% tumor regression and major pathological response (MPR) will be defined as \< 10 % viable cells corresponding to Mandard tumor regression grade 1-2
Time frame: Day 30-35
Number of participants with specific treatment-related adverse events as assessed by CTCAE v4.0"
Intratumoral flu vaccine treatment: The specific safety endpoint is perforation at tumor site due to intratumoral flu vaccine treatment Pembrolizumab treatment: Postponement of surgery, and surgical complication that leads to reoperation The Departments of Surgery are responsible for assessment of the "Before pembrolizumab treatment" safety endpoint, while Department of Surgery and Oncology are responsible for assessment of the remaining safety endpoints. Causality assessment will be done by investigators or delegates with relevant experience by use of the WHO-UMC causality assessment system.
Time frame: Day 0-365
Tumor microenvironment
Immunohistochemical analysis of CD3+ and CD8+ T cells, spatial protein expression analyses of immune-infiltrated regions of tumors at the different time points, flow cytometry, and full transcriptomic analyses including single cell analysis.
Time frame: Day 0-35
Analysis of perturbations in the immune activity with a focus on effector and memory CD8+ T cells
Flow cytometry and full transcriptomic analyses including single cell analysis of effector and memory CD8+ T cells
Time frame: Day 0-35
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