Preoperative liquid biopsy for optimal patient selection in metastatic colorectal cancer.

OBJECTIVE: In this pilot study, we sought to determine if preoperative circulating tumor DNA could be a useful predictor to avoid futile metastasectomy, predict early postoperative recurrence, and determine optimal chemotherapy duration during the management of patients with resectable metastatic colorectal cancer. METHODS: Patients from 2021 to 2023 were enrolled prospectively and evaluated with circulating tumor DNA preoperatively and postoperatively for detection of recurrence. Clinicopathologic and treatment factors as well as disease-free survival were compared between those with undetectable versus detectable preoperative circulating tumor DNA. RESULTS: Twenty-eight patients were evaluated, with a median follow-up time of 24 months. The median preoperative circulating tumor DNA level was 0.16 MTM/mL [0.00, 2.30]. Of the 10 patients (40%) with a preoperative circulating tumor DNA level of zero, 5 patients (50%) recurred between 4 and 18 months postoperatively. Among the 18 patients whose disease recurred, 10 patients (56%) had circulating tumor DNA detected postoperatively. Median change between preoperative and postoperative circulating tumor DNA levels was 0.00 [-0.02, 0.05] in those who did not recur and 0.00 [-7.04, 0.00] in those who recurred. When disease-free survival was evaluated by detectable versus undetectable preoperative circulating tumor DNA levels, there was no difference in disease-free survival estimates (P value = .11). On univariate Cox proportional hazards analysis, the preoperative circulating tumor DNA level, change between preoperative and postoperative circulating tumor DNA levels, and postoperative circulating tumor DNA levels did not influence disease-free survival. However, those with detectable postoperative circulating tumor DNA were 3.96 (95% confidence interval 1.30-12.06) times as likely to recur compared to those with undetectable postoperative circulating tumor DNA. CONCLUSION: New technologies including use of circulating tumor DNA may help better predict which patients with colorectal liver metastases will undergo futile surgery. Our preliminary findings suggest that postoperative, and not preoperative, circulating tumor DNA is predictive of recurrence following metastasectomy. Use of circulating tumor DNA in guiding operative management should be done in conjunction with high-quality imaging and other serologic markers to determine which patients with colorectal liver metastases are likely to receive durable benefit from operative intervention.

Irreversible electroporation augments ß-glucan induced trained innate immunity for the treatment of pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic cancer (PC) is a challenging diagnosis that is yet to benefit from the advancements in immuno-oncologic treatments. Irreversible electroporation (IRE), a non-thermal method of tumor ablation, is used in treatment of select patients with locally-advanced unresectable PC and has potentiated the effect of certain immunotherapies. Yeast-derived particulate ß-glucan induces trained innate immunity and successfully reduces murine PC tumor burden. This study tests the hypothesis that IRE may augment ß-glucan induced trained immunity in the treatment of PC. METHODS: ß-Glucan-trained pancreatic myeloid cells were evaluated ex vivo for trained responses and antitumor function after exposure to ablated and unablated tumor-conditioned media. ß-Glucan and IRE combination therapy was tested in an orthotopic murine PC model in wild-type and Rag-/- mice. Tumor immune phenotypes were assessed by flow cytometry. Effect of oral ß-glucan in the murine pancreas was evaluated and used in combination with IRE to treat PC. The peripheral blood of patients with PC taking oral ß-glucan after IRE was evaluated by mass cytometry. RESULTS: IRE-ablated tumor cells elicited a potent trained response ex vivo and augmented antitumor functionality. In vivo, ß-glucan in combination with IRE reduced local and distant tumor burden prolonging survival in a murine orthotopic PC model. This combination augmented immune cell infiltration to the PC tumor microenvironment and potentiated the trained response from tumor-infiltrating myeloid cells. The antitumor effect of this dual therapy occurred independent of the adaptive immune response. Further, orally administered ß-glucan was identified as an alternative route to induce trained immunity in the murine pancreas and prolonged PC survival in combination with IRE. ß-Glucan in vitro treatment also induced trained immunity in peripheral blood monocytes obtained from patients with treatment-naïve PC. Finally, orally administered ß-glucan was found to significantly alter the innate cell landscape within the peripheral blood of five patients with stage III locally-advanced PC who had undergone IRE. CONCLUSIONS: These data highlight a relevant and novel application of trained immunity within the setting of surgical ablation that may stand to benefit patients with PC.

A phase 1b trial of concurrent immunotherapy and irreversible electroporation in the treatment of locally advanced pancreatic adenocarcinoma.

BACKGROUND: Combining immune checkpoint blockade therapy with operative disruptive immunomodulation using irreversible electroporation may overcome the resistance to systemic therapy found in patients with locally advanced, unresectable pancreatic cancer. We describe the safety profile and efficacy of IRE with nivolumab. METHODS: In the preclinical phase of study, human pancreatic cell lines were cultured with interferon-γ (10 ng/mL) and murine models of pancreatic cancer were treated with irreversible electroporation and programmed death ligand-1 (PD-L1) expression was measured. In this phase 1b clinical trial (NCT03080974), surgical ablative irreversible electroporation was performed followed by nivolumab. The primary end point was dose-limiting toxicity. RESULTS: Human pancreatic cells express PD-L1 when cultured with interferon-γ: quantitative polymerase chain reaction MiaPaca (15.2 rel. fold ± 0.5; P < .01) and S20-13 (31.0 rel. fold ± 4.4; P < .01). Murine orthotopic tumors treated by irreversible electroporation had an increase in signal intensity score for the expression of PD-L1 in residual tumor (P < .01). Ten patients were included in the safety analysis with a 12-month median follow-up (interquartile range 6.0, 15.8). No dose-limiting toxicities occurred. Seven patients developed grade 3/4 treatment-related adverse events; none required a dose modification of nivolumab; nivolumab-related adverse events occurred in 1 patient. Mean time to progression was 6.3 months (confidence interval 3.5-10.0) with current median overall survival of 18.0 months (confidence interval 9.2-26.8). CONCLUSION: Irreversible electroporation induces expression of PD-L1 in vitro. Combination therapy with concurrent nivolumab is well tolerated. A multicenter, phase 2 adjuvant trial is underway using irreversible electroporation and nivolumab in patients with locally advanced pancreatic cancer.