Durable response to BRAF inhibitor monotherapy in recurrent metastatic low grade serous ovarian cancer.

Low grade serous ovarian cancers (LGSOC) in an advanced setting have limited systemic treatment options. In this paper we report a case of metastatic LGSOC harboring a BRAF mutation, treated with dabrafenib. We discuss the clinical, pathologic and molecular characteristics as well as surgical considerations and ongoing investigations in LGSOC.

Association Between Patient-Level, Clinic-Level, and Geographical-Level Factors and 1-Year Surveillance Colonoscopy Adherence.

INTRODUCTION: Surveillance colonoscopy 1 year after surgical resection for patients with stages I-III colorectal cancer (CRC) is suboptimal, and data on factors associated with lack of adherence are limited. Using surveillance colonoscopy data from Washington state, we aimed to determine the patient, clinic, and geographical factors associated with adherence. METHODS: Using administrative insurance claims linked to Washington cancer registry data, we conducted a retrospective cohort study of adult patients diagnosed with stage I-III CRC between 2011 and 2018 with continuous insurance for at least 18 months after diagnosis. We determined the adherence rate to 1-year surveillance colonoscopy and conducted logistic regression analysis to identify factors associated with completion. RESULTS: Of 4,481 patients with stage I-III CRC identified, 55.8% completed a 1-year surveillance colonoscopy. The median time to colonoscopy completion was 370 days. On multivariate analysis, older age, higher-stage CRC, Medicare insurance or multiple insurance carriers, higher Charlson Comorbidity Index score, and living without a partner were significantly associated with decreased adherence to 1-year surveillance colonoscopy. Among 29 eligible clinics, 51% (n = 15) reported lower-than-expected surveillance colonoscopy rates based on patient mix. DISCUSSION: Surveillance colonoscopy 1 year after surgical resection is suboptimal in Washington state. Patient and clinic factors, but not geographic factors (Area Deprivation Index), were significantly associated with surveillance colonoscopy completion. These data will inform the development of patient-level and clinic-level interventions to address an important quality-of-care issue across Washington.

Postablation Modulation after Single High-Dose Radiation Therapy Improves Tumor Control via Enhanced Immunomodulation.

PURPOSE: Radiotherapy (RT) is frequently used for local control of solid tumors using equal dose per fraction. Recently, single high-dose radiation has been used for ablation of solid tumors. In this report, we provide a novel immunological basis for radiation dose fractionation consisting of a single high-dose radiotherapy, followed by postablation modulation (PAM) with four daily low-dose fractions (22 Gy + 0.5 Gy × 4) to reprogram the tumor microenvironment by diminishing immune suppression, enabling infiltration of effector cells and increasing efficacy of tumor control. EXPERIMENTAL DESIGN: Palpable 3LL and 4T1 tumors in C57Bl/6 and Balb/c mice were irradiated with the Small-Animal Radiation Research Platform irradiator, and tumor growth and survival were monitored. Immunomodulation of tumor and immune cells in vitro and in vivo characterization of tumor-infiltrating immune effector cells were performed by FACS. For systemic application of PAM-RT, whole-lung irradiation was administered in 4T1-bearing Balb/c mice. RESULTS: We report significant tumor growth delays and increased survival in 3LL tumor-bearing mice with PAM. Primary tumor PAM-RT increased infiltration of immune effector cells and decreased Treg in irradiated tumors and secondary lymphoid organs. In a model of murine metastatic breast cancer (4T1), we demonstrated that systemic PAM-RT to the whole lung, 12 days after primary tumor ablative radiotherapy, increased survival with suppression of pulmonary metastases. CONCLUSIONS: We provide a novel immunologic basis for radiation dose fractionation consisting of a single high dose of radiotherapy followed by daily low-dose PAM-RT fractionation to improve the immunogenic potential of ablative radiotherapy.

Mertk on tumor macrophages is a therapeutic target to prevent tumor recurrence following radiation therapy.

Radiation therapy provides a means to kill large numbers of cancer cells in a controlled location resulting in the release of tumor-specific antigens and endogenous adjuvants. However, by activating pathways involved in apoptotic cell recognition and phagocytosis, irradiated cancer cells engender suppressive phenotypes in macrophages. We demonstrate that the macrophage-specific phagocytic receptor, Mertk is upregulated in macrophages in the tumor following radiation therapy. Ligation of Mertk on macrophages results in anti-inflammatory cytokine responses via NF-kB p50 upregulation, which in turn limits tumor control following radiation therapy. We demonstrate that in immunogenic tumors, loss of Mertk is sufficient to permit tumor cure following radiation therapy. However, in poorly immunogenic tumors, TGFß inhibition is also required to result in tumor cure following radiation therapy. These data demonstrate that Mertk is a highly specific target whose absence permits tumor control in combination with radiation therapy.

Optimizing Timing of Immunotherapy Improves Control of Tumors by Hypofractionated Radiation Therapy.

The anecdotal reports of promising results seen with immunotherapy and radiation in advanced malignancies have prompted several trials combining immunotherapy and radiation. However, the ideal timing of immunotherapy with radiation has not been clarified. Tumor bearing mice were treated with 20Gy radiation delivered only to the tumor combined with either anti-CTLA4 antibody or anti-OX40 agonist antibody. Immunotherapy was delivered at a single timepoint around radiation. Surprisingly, the optimal timing of these therapies varied. Anti-CTLA4 was most effective when given prior to radiation therapy, in part due to regulatory T cell depletion. Administration of anti-OX40 agonist antibody was optimal when delivered one day following radiation during the post-radiation window of increased antigen presentation. Combination treatment of anti-CTLA4, radiation, and anti-OX40 using the ideal timing in a transplanted spontaneous mammary tumor model demonstrated tumor cures. These data demonstrate that the combination of immunotherapy and radiation results in improved therapeutic efficacy, and that the ideal timing of administration with radiation is dependent on the mechanism of action of the immunotherapy utilized.

TGFß inhibition prior to hypofractionated radiation enhances efficacy in preclinical models.

The immune infiltrate in colorectal cancer has been correlated with outcome, such that individuals with higher infiltrations of T cells have increased survival independent of the disease stage. For patients with lower immune infiltrates, overall survival is limited. Because the patients with colorectal cancer studied have received conventional cancer therapies, these data may indicate that the pretreatment tumor environment increases the efficacy of treatments such as chemotherapy, surgery, and radiotherapy. This study was designed to test the hypothesis that an improved immune environment in the tumor at the time of treatment will increase the efficacy of radiotherapy. We demonstrate that inhibition of TGFß using the orally available small-molecule inhibitor SM16 improved the immune environment of tumors in mice and significantly improved the efficacy of subsequent radiotherapy. This effect was not due to changes in radiosensitivity, epithelial-mesenchymal transition, or changes in vascular function in the tumor; rather, this effect was dependent on adaptive immunity and resulted in long-term protective immunity in cured mice. These data demonstrate that immunotherapy is an option to improve the immune status of patients with poor tumor infiltrates and that pretreatment improves the efficacy of radiotherapy.

Expression of arginase I in myeloid cells limits control of residual disease after radiation therapy of tumors in mice.

An accumulating body of evidence demonstrates that radiation therapy can generate adaptive immune responses that contribute to tumor control. However, in the absence of additional immune therapy, the adaptive immune response is insufficient to prevent tumor recurrence or affect distant disease. It has been shown in multiple models that tumor-infiltrating myeloid cells exhibit alternative activation phenotypes and are able to suppress adaptive immune responses, and recent data suggests that the myeloid response in tumors treated with cytotoxic therapy limits tumor control. We hypothesized that tumor myeloid cells inhibit the adaptive immune response after radiation therapy through expression of the enzyme arginase I. Using a myeloid cell-specific deletion of arginase I in mice, we demonstrate an improved tumor control after radiation therapy. However, tumors still recurred despite the conditional knockdown of arginase I. Since multiple alternative factors may combine to inhibit adaptive immunity, we propose that targeting macrophage differentiation may be a more effective strategy than targeting individual suppressive pathways.

The peripheral myeloid expansion driven by murine cancer progression is reversed by radiation therapy of the tumor.

Expansion of myeloid-lineage leukocytes in tumor-bearing mice has been proposed as a cause of systemic immunosuppression. We demonstrate that radiation therapy of tumors leads to a decline in myeloid cell numbers in the blood and a decrease in spleen size. The frequency of myeloid cells does not decline to the level seen in tumor-free mice: we demonstrate that metastatic disease can prevent myeloid cell numbers from returning to baseline, and that tumor recurrence from residual disease correlates with re-expansion of myeloid lineage cells. Radiation therapy results in increased proliferation of T cells in the spleen and while T cell responses to foreign antigens are not altered by tumor burden or myeloid cell expansion, responses to tumor-associated antigens are increased after radiation therapy. These data demonstrate that myeloid cell numbers are directly linked to primary tumor burden, that this population contracts following radiation therapy, and that radiation therapy may open a therapeutic window for immunotherapy of residual disease.

Circulating and intratumoral macrophages in patients with hepatocellular carcinoma: correlation with therapeutic approach.

BACKGROUND: Hepatocellular carcinoma arises in an environment of chronic injury, and wound-healing responses may vary by treatment. METHODS: Peripheral blood myeloid populations were quantified in 39 patients with hepatocellular carcinoma treated with surgical or endoluminal therapy. Macrophages were quantified in tissue when available. RESULTS: There was a similar expansion of myeloid populations after operative procedures compared with endoluminal treatments. Immunostaining for CD68 revealed no significant differences in the number of macrophages within benign versus malignant tumors and when tumors were compared with nontumor liver. Cytotoxic CD8+ T cells were rare within tumors compared with the surrounding liver (P < .0001). Progression-free survival was reduced in patients with preoperative peripheral blood monocyte expansion (P < .05). CONCLUSIONS: These data provide preliminary evidence of poor prognostic significance of elevated peripheral blood monocyte counts. We propose that the inflammatory environment of hepatocellular carcinoma may represent a consistent feature to both predict and alter the course of disease.

Expression of NF-κB p50 in tumor stroma limits the control of tumors by radiation therapy.

Radiation therapy aims to kill cancer cells with a minimum of normal tissue toxicity. Dying cancer cells have been proposed to be a source of tumor antigens and may release endogenous immune adjuvants into the tumor environment. For these reasons, radiation therapy may be an effective modality to initiate new anti-tumor adaptive immune responses that can target residual disease and distant metastases. However, tumors engender an environment dominated by M2 differentiated tumor macrophages that support tumor invasion, metastases and escape from immune control. In this study, we demonstrate that following radiation therapy of tumors in mice, there is an influx of tumor macrophages that ultimately polarize towards immune suppression. We demonstrate using in vitro models that this polarization is mediated by transcriptional regulation by NFκB p50, and that in mice lacking NFκB p50, radiation therapy is more effective. We propose that despite the opportunity for increased antigen-specific adaptive immune responses, the intrinsic processes of repair following radiation therapy may limit the ability to control residual disease.