31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Preventive Service Use Among People With Serious Mental Illnesses: Results From the PRIME Study

Background/Aims: People with serious mental illnesses (SMI) experience excess morbidity and premature mortality resulting from preventable conditions. In response, concerns have been raised that people with SMI may not receive adequate preventive services. Understanding preventive service use patterns may help improve care delivery and reduce health disparities in this population. Methods: Participants included all adults ≥ 18 years with at least one prior 12-month health care visit in a large integrated service system (Kaiser Permanente Northwest [KPNW], n = 366,194) or in participating federally qualified health centers and safety-net clinics in 18 states (OCHIN, n = 437,082). We used electronic medical record data to examine receipt of needed preventive care, measured by 12 services (e.g. flu shots, mammogram screening). We computed proportion of needed care by dividing the number of out-of-date services by the number of eligible services and multiplying by 100. Mean rates for four diagnostic groups –– schizophrenia spectrum disorders, bipolar disorders/affective psychoses, major depressive disorders, anxiety disorders –– were compared to patients without SMI diagnoses. All models were adjusted for patient characteristics (e.g. age, gender, Medicaid/Medicare status) and service use. Results: At OCHIN, all SMI groups had lower rates of needed preventive services (schizophrenia: 34.12, bipolar disorders/affective psychoses: 35.68, major depressive disorders: 36.30, anxiety: 38.53) than non-SMI patients (39.97). Similarly, needed services did not differ or were lower among KPNW members with SMI, with bipolar disorders/affective psychoses (18.64) and major depressive disorders (18.63) showing significantly lower needed services than non-SMI members (20.64). Proportions of individuals with SMI completing cholesterol and diabetes screening were higher than individuals without SMI at both sites. At KPNW, individuals with SMI were more likely to have a recorded body mass index than those without SMI, but at OCHIN the reverse pattern was observed. Colorectal cancer screening did not differ by diagnosis but was more likely to occur at KPNW than at OCHIN. Blood pressure screening was common across diagnostic groups and sites. Flu vaccinations were uncommon, particularly at OCHIN. Conclusion: Contrary to hypotheses, individuals with serious mental illnesses received more preventive services than individuals without mental illnesses. Adjusting for number of health care visits reduced, but did not eliminate, these differences

Biospecific Recognition of Tethered Small Molecules Diluted in Self‐Assembled Monolayers

We describe the first in a series of studies designed to develop and to characterize self‐assembled monolayers containing isolated small‐molecule probes. We insert tether molecules into preformed oligo(ethylene glycol)‐terminated alkanethiolate monolayer matrices and covalently attach the neurotransmitter serotonin to the tethers. These monolayers selectively recognize serotonin antibodies and resist binding of nonspecific antibodies and proteins. We will use these capture materials for biosensor development and functionally‐directed proteomics

Inflammatory myofibroblastic tumors of the urinary tract: a clinicopathologic study of 46 cases, including a malignant example inflammatory fibrosarcoma and a subset associated with high-grade urothelial carcinoma

Inflammatory myofibroblastic tumor (IMT) of the urinary tract, also termed postoperative spindle cell nodule, inflammatory pseudotumor, and pseudosarcomatous fibromyxoid tumor, is rare and in the past was believed to reflect diverse entities. We reviewed a series of 46 IMTs arising in the ureter, bladder, and prostate, derived primarily from a large consultation practice. There were 30 male and 16 females aged 3 to 89 years (mean 53.6). Lesions were 1.2 to 12 cm (mean 4.2). There was a history of recent prior instrumentation in 8 cases. Morphology was similar to that previously described for IMT occurring in this region, with the exception of 1 case that focally appeared sarcomatous. Polypoid cystitis coexisted in 5 patients (11%). Mitoses were typically scant (0 to 20/10 hpf, mean 1). Necrosis was seen in 14 (30%) cases. Invasion of the muscularis propria was documented in 19 (41%). By immunohistochemistry (IHC), lesions at least focally expressed anaplastic lymphoma kinase (ALK) (20/35, 57%), AE1/3 (25/34, 73%), CAM5.2 (10/15, 67%), CK18 (6/6, 100%), actin (23/25, 92%), desmin (15/19, 79%), calponin (6/7, 86%), caldesmon (4/7, 57%, rare cells), p53 (10/13, 77%), and most lacked S100 (0/14), CD34 (0/13), CD117 (2/13, 15%), CD21 (0/5), and CD23 (0/3). ALK gene alterations were detected by fluorescence in situ hybridization (FISH) in 13/18 (72%) tested cases, including 2 with prior instrumentation; 13/18 (72%) showed agreement between FISH ALK results and ALK protein results by IHC. Most bladder IMTs were managed locally, but partial cystectomy was performed as the initial management in 7 cases and cystectomy in 1 (1 IMT was initially misinterpreted as carcinoma, 1 IMT was found incidentally as a separate lesion in a cystectomy specimen performed for urothelial carcinoma). Follow-up was available in 32 cases (range 3 to 120 mo; mean 33; median 24). There were 10 patients with recurrences (2 with 2 recurrences). Recurrences were unassociated with muscle invasion or with ALK alterations. In 2 cases, tumors of the urinary tract (TURs) showing IMT preceded (1 and 2 mo, respectively) TURs showing sarcomatoid carcinoma with high-grade invasive urothelial carcinoma accompanied with separate fragments of IMT. Even on re-review the IMT in these 2 cases were morphologically indistinguishable from other cases of IMT, with FISH demonstrating ALK alterations in the IMT areas in one of them. Both these patients died of their carcinomas. Lastly, there was 1 tumor with many morphological features of IMT and an ALK rearrangement, yet overtly sarcomatous. This case arose postirradiation for prostate cancer 4 years before the development of the lesion, with tumor recurrence at 4 months and death from intra-abdominal metastatic disease at 9 months. In summary, urinary tract IMTs are rare and share many features with counterparts in other sites, displaying similar morphology and immunogenotypic features whether de novo or postinstrumentation. Typical IMTs can be locally aggressive, sometimes requiring radical surgical resection, but none of our typical cases metastasized, although they can rarely arise contemporaneously with sarcomatoid urothelial carcinomas. For these reasons, close follow-up is warranted

Assessment of willingness to pay for expanded carrier screening among women and couples undergoing preconception carrier screening

<div><p>Background</p><p>Expanded carrier screening can provide risk information for numerous conditions. Understanding how individuals undergoing preconception expanded carrier screening value this information is important. The NextGen study evaluated the use of genome sequencing for expanded carrier screening and reporting secondary findings, and we measured participants’ willingness to pay for this approach to understand how it is valued by women and couples planning a pregnancy.</p><p>Methods</p><p>We assessed 277 participants’ willingness to pay for genome sequencing reporting carrier results for 728 gene/condition pairs and results for 121 secondary findings. We explored the association between attitudes and demographic factors and willingness to pay for expanded carrier screening using genome sequencing and conducted interviews with 58 of these participants to probe the reasoning behind their preferences.</p><p>Results</p><p>Most participants were willing to pay for expanded carrier screening using genome sequencing. Willingness to pay was associated with income level and religiosity, but not risk status for a condition in the carrier panel. Participants willing to pay nothing or a small amount cited issues around financial resources, whereas those willing to pay higher amounts were motivated by “peace of mind” from carrier results.</p><p>Conclusion</p><p>Women and couples planning a pregnancy value genome sequencing. The potentially high out-of-pocket cost of this service could result in healthcare disparities, since maximum amounts that participants were willing to pay were higher than a typical copay and related to income.</p></div

Characteristics of participants of preconception genomic carrier screening.

<p>Characteristics of participants of preconception genomic carrier screening.</p

Willingness to pay for expanded carrier screening using GS (females and male partners).

<p>Survey responses to WTP questions (n = 277). Data are expressed as percent of all respondents and of the total number of at risk or negative result with <25% risk participants.</p