Homologous recombination deficiency and molecular subtype are associated with immunogenicity in ovarian cancer.

Aim: There is an unmet need for predictive biomarkers for immune checkpoint blockade in ovarian cancer. Homologous recombination deficiency (HRD) and immunoreactive molecular subtype may be associated with determinants of immunogenicity. Materials & methods: Neoantigen load, tumor inflammation signature (TIS), immune cell infiltrates and individual immune checkpoints were assessed based on HRD status and molecular subtype. Results: Tumors with HRD demonstrated significantly higher expression of neoantigens and multiple immune check points, but not higher TIS scores or increased immune cell infiltrates. Immunoreactive tumors had significantly higher neoantigen expression, TIS scores, immune cell infiltrate and immune checkpoint expression compared with other subtypes. Conclusion: HRD and the immunoreactive molecular subtype signature were associated with multiple determinants of immunogenicity and deserve further exploration as predictive biomarkers.

Correction to: Immunotherapy Utilizing the Combination of Natural Killer- and Antibody Dependent Cellular Cytotoxicity (ADCC)-Mediating Agents with Poly (ADP-ribose) polymerase (PARP) Inhibition.

Following publication of the original article [1], an error was noted in the GAPDH in the western blot depicted in Figure 4b.

Immunotherapy utilizing the combination of natural killer- and antibody dependent cellular cytotoxicity (ADCC)-mediating agents with poly (ADP-ribose) polymerase (PARP) inhibition.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPi) prevent single-stranded DNA repair. Olaparib is a PARPi approved for the treatment of BRCA mutant ovarian and breast carcinoma. Emerging clinical data suggest a benefit of combining olaparib with immunotherapy in prostate cancer patients both with and without somatic BRCA mutations. METHODS: We examined if olaparib, when combined with IgG1 antibody-dependent cellular cytotoxicity (ADCC)-mediating monoclonal antibodies (mAbs) cetuximab (anti-EGFR), or avelumab (anti-PD-L1), would increase tumor cell sensitivity to killing by natural killer (NK) cells independently of BRCA status or mAb target upregulation. BRCA mutant and BRCA wildtype (WT) prostate carcinoma cell lines were pretreated with olaparib and then exposed to NK cells in the presence or absence of cetuximab or avelumab. RESULTS: NK-mediated killing was significantly increased in both cell lines and was further increased using the ADCC-mediating mAbs. Pre-exposure of NK cells to recombinant IL-15/IL-15Rα further increased the lysis of olaparib treated tumor cells. In addition, olaparib treated tumor cells were killed to a significantly greater degree by engineered high-affinity NK cells (haNK). We show here for the first time that (a) olaparib significantly increased tumor cell sensitivity to NK killing and ADCC in both BRCA WT and BRCA mutant prostate carcinoma cells, independent of PD-L1 or EGFR modulation; (b) mechanistically, treatment with olaparib upregulated death receptor TRAIL-R2; and (c) olaparib significantly enhanced NK killing of additional tumor types, including breast, non-small cell lung carcinoma, and chordoma. CONCLUSIONS: These studies support the combined use of NK- and ADCC-mediating agents with correctly timed PARP inhibition.

Predicting clinical outcomes in chordoma patients receiving immunotherapy: a comparison between volumetric segmentation and RECIST.

BACKGROUND: The Response Evaluation Criteria in Solid Tumors (RECIST) are the current standard for evaluating disease progression or therapy response in patients with solid tumors. RECIST 1.1 calls for axial, longest-diameter (or perpendicular short axis of lymph nodes) measurements of a maximum of five tumors, which limits clinicians' ability to adequately measure disease burden, especially in patients with irregularly shaped tumors. This is especially problematic in chordoma, a disease for which RECIST does not always adequately capture disease burden because chordoma tumors are typically irregularly shaped and slow-growing. Furthermore, primary chordoma tumors tend to be adjacent to vital structures in the skull or sacrum that, when compressed, lead to significant clinical consequences. METHODS: Volumetric segmentation is a newer technology that allows tumor burden to be measured in three dimensions on either MR or CT. Here, we compared the ability of RECIST measurements and tumor volumes to predict clinical outcomes in a cohort of 21 chordoma patients receiving immunotherapy. RESULTS: There was a significant difference in radiologic time to progression Kaplan-Meier curves between clinical outcome groups using volumetric segmentation (P = 0.012) but not RECIST (P = 0.38). In several cases, changes in volume were earlier and more sensitive reflections of clinical status. CONCLUSION: RECIST is a useful evaluation method when obvious changes are occurring in patients with chordoma. However, in many cases, RECIST does not detect small changes, and volumetric assessment was capable of detecting changes and predicting clinical outcome earlier than RECIST. Although this study was small and retrospective, we believe our results warrant further research in this area.

Resources Required for Semi-Automatic Volumetric Measurements in Metastatic Chordoma: Is Potentially Improved Tumor Burden Assessment Worth the Time Burden?

The Response Evaluation Criteria in Solid Tumors (RECIST) is the current standard for assessing therapy response in patients with malignant solid tumors; however, volumetric assessments are thought to be more representative of actual tumor size and hence superior in predicting patient outcomes. We segmented all primary and metastatic lesions in 21 chordoma patients for comparison to RECIST. Primary tumors were segmented on MR and validated by a neuroradiologist. Metastatic lesions were segmented on CT and validated by a general radiologist. We estimated times for a research assistant to segment all primary and metastatic chordoma lesions using semi-automated volumetric segmentation tools available within our PACS (v12.0, Carestream, Rochester, NY), as well as time required for radiologists to validate the segmentations. We also report success rates of semi-automatic segmentation in metastatic lesions on CT and time required to export data. Furthermore, we discuss the feasibility of volumetric segmentation workflow in research and clinical settings. The research assistant spent approximately 65 h segmenting 435 lesions in 21 patients. This resulted in 1349 total segmentations (average 2.89 min per lesion) and over 13,000 data points. Combined time for the neuroradiologist and general radiologist to validate segmentations was 45.7 min per patient. Exportation time for all patients totaled only 6 h, providing time-saving opportunities for data managers and oncologists. Perhaps cost-neutral resource reallocation can help acquire volumes paralleling our example workflow. Our results will provide researchers with benchmark resources required for volumetric assessments within PACS and help prepare institutions for future volumetric assessment criteria.