Toward more accurate preclinical glioblastoma modeling: Reverse translation of clinical standard of care in a glioblastoma mouse model.

Glioblastoma (GBM) is the deadliest of all brain cancers. GBM patients receive an intensive treatment schedule consisting of surgery, radiotherapy and chemotherapy, which only modestly extends patient survival. Therefore, preclinical studies are testing novel experimental treatments. In such preclinical studies, these treatments are administered as monotherapy in the majority of cases; conversely, in patients the new treatments are always combined with the standard of care. Most likely, this difference contributes to the failure of clinical trials despite the successes of the preclinical studies. In this methodological study, we show in detail how to implement the full clinical standard of care in preclinical GBM research. Systematically testing new treatments, including cellular immunotherapies, in combination with the clinical standard of care can result in a better translation of preclinical results to the clinic and ultimately increase patient survival.

TIM3 Checkpoint Inhibition Fails to Prolong Survival in Ovarian Cancer-Bearing Mice.

Immune checkpoint inhibitor (ICI) therapy has proven revolutionary in the treatment of some cancers. However, ovarian cancer remains unresponsive to current leading ICIs, such as anti-PD1 or anti-PD-L1. In this article, we explored the potential of an upcoming checkpoint molecule, T-cell immunoglobulin and mucin domain 3 (TIM3), for the treatment of ovarian cancer using a syngeneic orthotopic mouse model (ID8-fLuc). Besides therapeutic efficacy, we focused on exploring immune changes in tumor tissue and peritoneal fluid. Our results showed no improvement in survival in ovarian cancer-bearing mice after anti-TIM3 treatment when used as monotherapy nor when combined with anti-PD1 or standard-of-care chemotherapy (carboplatin/paclitaxel). This was reflected in the unaltered immune infiltration in treated mice compared to control mice. Altering the order of drug administration within the combination treatment altered the survival results, but did not result in a survival benefit over chemotherapy alone. These findings highlight the need for further preclinical studies to find beneficial treatment schemes and combination therapies for ovarian cancer.

A Microfluidics Approach for Ovarian Cancer Immune Monitoring in an Outpatient Setting.

Among cancer diagnoses in women, ovarian cancer has the fifth-highest mortality rate. Current treatments are unsatisfactory, and new therapies are highly needed. Immunotherapies show great promise but have not reached their full potential in ovarian cancer patients. Implementation of an immune readout could offer better guidance and development of immunotherapies. However, immune profiling is often performed using a flow cytometer, which is bulky, complex, and expensive. This equipment is centralized and operated by highly trained personnel, making it cumbersome and time-consuming. We aim to develop a disposable microfluidic chip capable of performing an immune readout with the sensitivity needed to guide diagnostic decision making as close as possible to the patient. As a proof of concept of the fluidics module of this concept, acquisition of a limited immune panel based on CD45, CD8, programmed cell death protein 1 (PD1), and a live/dead marker was compared to a conventional flow cytometer (BD FACSymphony). Based on a dataset of peripheral blood mononuclear cells of 15 patients with ovarian cancer across different stages of treatment, we obtained a 99% correlation coefficient for the detection of CD8+PD1+ T cells relative to the total amount of CD45+ white blood cells. Upon further system development comprising further miniaturization of optics, this microfluidics chip could enable immune monitoring in an outpatient setting, facilitating rapid acquisition of data without the need for highly trained staff.

Type of chemotherapy has substantial effects on the immune system in ovarian cancer.

Chemotherapy induces a variety of immunological changes. Studying these effects can reveal opportunities for successful combining chemotherapy and immunotherapy. Immuno-chemotherapeutic combinations in ovarian cancer are currently not generating the anticipated positive effects. To date, only scattered and inconsistent information is available about the immune-induced changes by chemotherapy in ovarian cancer. In this study, we compared six common chemotherapeutics used in ovarian cancer patients (carboplatin, paclitaxel, pegylated liposomal doxorubicin, gemcitabine, carboplatin-paclitaxel and carboplatin-gemcitabine) and studied their effects on the immune system in an ovarian cancer mouse model. Mice received a single chemotherapy or vehicle injection 21 days after tumor inoculation with ID8-fluc cells. One week after therapy administration, we collected peritoneal washings for flow cytometry, serum for cytokine analysis with cytometric bead array and tumor biopsies for immunohistochemistry. Carboplatin-paclitaxel showed the most favorable profile with a decrease in immunosuppressive cells in the peritoneal cavity and an increase of interferon-gamma in serum. In contrast, carboplatin-gemcitabine seemed to promote a hostile immune environment with an increase in regulatory T-cells in tumor tissue and an increase of macrophage-inflammatory-protein-1-beta in the serum.