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.

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.

Preclinical studies performed in appropriate models could help identify optimal timing of combined chemotherapy and immunotherapy.

Immune checkpoint inhibitors (ICI) have been revolutionary in the field of cancer therapy. However, their success is limited to specific indications and cancer types. Recently, the combination treatment of ICI and chemotherapy has gained more attention to overcome this limitation. Unfortunately, many clinical trials testing these combinations have provided limited success. This can partly be attributed to an inadequate choice of preclinical models and the lack of scientific rationale to select the most effective immune-oncological combination. In this review, we have analyzed the existing preclinical evidence on this topic, which is only limitedly available. Furthermore, this preclinical data indicates that besides the selection of a specific drug and dose, also the sequence or order of the combination treatment influences the study outcome. Therefore, we conclude that the success of clinical combination trials could be enhanced by improving the preclinical set up, in order to identify the optimal treatment combination and schedule to enhance the anti-tumor immunity.

Drug Repurposing for Targeting Myeloid-Derived Suppressor-Cell-Generated Immunosuppression in Ovarian Cancer: A Literature Review of Potential Candidates.

The lethality of patients with ovarian cancer (OC) remains high. Current treatment strategies often do not lead to the desired outcome due to the development of therapy resistance, resulting in high relapse rates. Additionally, clinical trials testing immunotherapy against OC have failed to reach significant results to date. The OC tumor microenvironment and specifically myeloid-derived suppressor cells (MDSC) are known to generate immunosuppression and inhibit the anti-tumor immune response following immunotherapy treatment. Our review aims to characterize potential candidate treatments to target MDSC in OC through drug-repurposing. A literature search identified repurposable compounds with evidence of their suppressing the effect of MDSC. A total of seventeen compounds were withheld, of which four were considered the most promising. Lurbinectedin, metformin, celecoxib, and 5-azacytidine have reported preclinical effects on MDSC and clinical evidence in OC. They have all been approved for a different indication, characterizing them as the most promising candidates for repurposing to treat patients with OC.

Intraperitoneal alpha therapy with 224Ra-labeled microparticles combined with chemotherapy in an ovarian cancer mouse model.

A novel alpha-therapy consisting of 224Ra-labeled calcium carbonate microparticles (224Ra-CaCO3-MP) has been designed to treat micrometastatic peritoneal disease via intraperitoneal (IP) administration. This preclinical study aimed to evaluate its efficacy and tolerability when given as a single treatment or in combination with standard of care chemotherapy regimens, in a syngeneic model of ovarian cancer in immune competent mice. Female C57BL/6 mice bearing ID8-fLuc ovarian cancer were treated with 224Ra-CaCO3-MP 1 day after IP tumor cell inoculation. The activity dosages of 224Ra ranged from 14 to 39 kBq/mouse. Additionally, 224Ra-CaCO3-MP treatment was followed by either carboplatin (80 mg/kg)-pegylated liposomal doxorubicin (PLD, 1.6 mg/kg) or carboplatin (60 mg/kg)-paclitaxel (10 mg/kg) on day 14 post tumor cell inoculation. All treatments were administered via IP injections. Readouts included survival, clinical signs, and body weight development over time. There was a slight therapeutic benefit after single treatment with 224Ra-CaCO3-MP compared to the vehicle control, with median survival ratios (MSRs) ranging between 1.1 and 1.3. The sequential administration of 224Ra-CaCO3-MP with either carboplatin-paclitaxel or carboplatin-PLD indicated a synergistic effect on overall survival at certain 224Ra activities. Moreover, the combinations tested appeared well tolerated in terms of weight assessment in the first 4 weeks after treatment. Overall, this research supports the further evaluation of 224Ra-CaCO3-MP in patients with ovarian cancer. However, the most optimal chemotherapy regimen to combine with 224Ra-CaCO3-MP should be identified to fully exploit its therapeutic potential.

Peripherally-driven myeloid NFkB and IFN/ISG responses predict malignancy risk, survival, and immunotherapy regime in ovarian cancer.

BACKGROUND: Tumors can influence peripheral immune macroenvironment, thereby creating opportunities for non-invasive serum/plasma immunobiomarkers for immunostratification and immunotherapy designing. However, current approaches for immunobiomarkers' detection are largely quantitative, which is unreliable for assessing functional peripheral immunodynamics of patients with cancer. Hence, we aimed to design a functional biomarker modality for capturing peripheral immune signaling in patients with cancer for reliable immunostratification. METHODS: We used a data-driven in silico framework, integrating existing tumor/blood bulk-RNAseq or single-cell (sc)RNAseq datasets of patients with cancer, to inform the design of an innovative serum-screening modality, that is, serum-functional immunodynamic status (sFIS) assay. Next, we pursued proof-of-concept analyses via multiparametric serum profiling of patients with ovarian cancer (OV) with sFIS assay combined with Luminex (cytokines/soluble immune checkpoints), CA125-antigen detection, and whole-blood immune cell counts. Here, sFIS assay's ability to determine survival benefit or malignancy risk was validated in a discovery (n=32) and/or validation (n=699) patient cohorts. Lastly, we used an orthotopic murine metastatic OV model, with anti-OV therapy selection via in silico drug-target screening and murine serum screening via sFIS assay, to assess suitable in vivo immunotherapy options. RESULTS: In silico data-driven framework predicted that peripheral immunodynamics of patients with cancer might be best captured via analyzing myeloid nuclear factor kappa-light-chain enhancer of activated B cells (NFκB) signaling and interferon-stimulated genes' (ISG) responses. This helped in conceptualization of an 'in sitro' (in vitro+in situ) sFIS assay, where human myeloid cells were exposed to patients' serum in vitro, to assess serum-induced (si)-NFκB or interferon (IFN)/ISG responses (as active signaling reporter activity) within them, thereby 'mimicking' patients' in situ immunodynamic status. Multiparametric serum profiling of patients with OV established that sFIS assay can: decode peripheral immunology (by indicating higher enrichment of si-NFκB over si-IFN/ISG responses), estimate survival trends (si-NFκB or si-IFN/ISG responses associating with negative or positive prognosis, respectively), and coestimate malignancy risk (relative to benign/borderline ovarian lesions). Biologically, we documented dominance of pro-tumorigenic, myeloid si-NFκB responseHIGHsi-IFN/ISG responseLOW inflammation in periphery of patients with OV. Finally, in an orthotopic murine metastatic OV model, sFIS assay predicted the higher capacity of chemo-immunotherapy (paclitaxel-carboplatin plus anti-TNF antibody combination) in achieving a pro-immunogenic peripheral milieu (si-IFN/ISG responseHIGHsi-NFκB responseLOW), which aligned with high antitumor efficacy. CONCLUSIONS: We established sFIS assay as a novel biomarker resource for serum screening in patients with OV to evaluate peripheral immunodynamics, patient survival trends and malignancy risk, and to design preclinical chemo-immunotherapy strategies.