Tumor-Specific Inhibition of In Situ Vaccination by Distant Untreated Tumor Sites.

In situ vaccination is an emerging cancer treatment strategy that uses local therapies to stimulate a systemic antitumor immune response. We previously reported an in situ vaccination effect when combining radiation (RT) with intratumor (IT) injection of tumor-specific immunocytokine (IC), a fusion of tumor-specific antibody and IL2 cytokine. In mice bearing two tumors, we initially hypothesized that delivering RT plus IT-IC to the "primary" tumor would induce a systemic antitumor response causing regression of the "secondary" tumor. To test this, mice bearing one or two syngeneic murine tumors of B78 melanoma and/or Panc02 pancreatic cancer were treated with combined external beam RT and IT-IC to the designated "primary" tumor only. Primary and secondary tumor response as well as animal survival were monitored. Immunohistochemistry and quantitative real-time PCR were used to quantify tumor infiltration with regulatory T cells (Treg). Transgenic "DEREG" mice or IgG2a anti-CTLA-4 were used to transiently deplete tumor Tregs. Contrary to our initial hypothesis, we observed that the presence of an untreated secondary tumor antagonized the therapeutic effect of RT + IT-IC delivered to the primary tumor. We observed reciprocal tumor specificity for this effect, which was circumvented if all tumors received RT or by transient depletion of Tregs. Primary tumor treatment with RT + IT-IC together with systemic administration of Treg-depleting anti-CTLA-4 resulted in a renewed in situ vaccination effect. Our findings show that untreated tumors can exert a tumor-specific, Treg-dependent, suppressive effect on the efficacy of in situ vaccination and demonstrate clinically viable approaches to overcome this effect. Untreated tumor sites antagonize the systemic and local antitumor immune response to an in situ vaccination regimen. This effect is radiation sensitive and may be mediated by tumor-specific regulatory T cells harbored in the untreated tumor sites. Cancer Immunol Res; 6(7); 825-34. ©2018 AACR.

VcR-CVAD Induction Chemotherapy Followed by Maintenance Rituximab Produces Durable Remissions in Mantle Cell Lymphoma: A Wisconsin Oncology Network Study.

INTRODUCTION: VcR-CVAD was developed as an intermediate-intensity induction regimen with maintenance rituximab (MR) to improve remission durations after first-line therapy for mantle cell lymphoma (MCL) in older and younger patients with MCL. PATIENTS AND METHODS: Patients with previously untreated MCL received VcR-CVAD induction chemotherapy for 6 cycles (21-day cycles). Patients achieving at least a partial response received rituximab consolidation (375 mg/m2 × 4 weekly doses) and MR (375 mg/m2 every 12 weeks × 20 doses). The primary endpoints were overall and complete response (CR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Thirty patients were enrolled, with a median age of 61 years. There was an even distribution of patients < 60 years and ≥ 60 years. Mantle cell lymphoma international prognostic index medium- or high-risk disease was present in 60%. The overall response rate observed was 90% (77% CR/unconfirmed CR). After a median follow-up of 7.8 years, the 6-year PFS and OS were 53% and 70%, respectively. There was no difference in 6-year PFS or OS between the younger (age < 60 years) and older (age ≥ 60 years) subgroups. In a univariate analysis, lactate dehydrogenase, when analyzed for interaction with age, had a significant effect on PFS outcomes at 6 years. There were no pretreatment variables determined to have a significant effect on OS outcomes at 6 years. CONCLUSIONS: Long-term outcomes with VcR-CVAD are comparable with more intensive inductions and consolidation approaches. MCL is biologically heterogeneous, and durable remission can be achieved with intermediate intensity therapy. MR appears to contribute to these excellent outcomes.

In Situ Tumor Vaccination by Combining Local Radiation and Tumor-Specific Antibody or Immunocytokine Treatments.

Interest in combining radiotherapy and immune checkpoint therapy is growing rapidly. In this study, we explored a novel combination of this type to augment antitumor immune responses in preclinical murine models of melanoma, neuroblastoma, and head and neck squamous cell carcinoma. Cooperative effects were observed with local radiotherapy and intratumoral injection of tumor-specific antibodies, arising in part from enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). We could improve this response by combining radiation with intratumoral injection of an IL2-linked tumor-specific antibody (termed here an immunocytokine), resulting in complete regression of established tumors in most animals associated with a tumor-specific memory T-cell response. Given the T-cell response elicited by combined local radiation and intratumoral immunocytokine, we tested the potential benefit of adding this treatment to immune checkpoint blockade. In mice bearing large primary tumors or disseminated metastases, the triple-combination of intratumoral immunocytokine, radiation, and systemic anti-CTLA-4 improved primary tumor response and animal survival compared with combinations of any two of these three interventions. Taken together, our results show how combining radiation and intratumoral immunocytokine in murine tumor models can eradicate large tumors and metastases, eliciting an in situ vaccination effect that can be leveraged further by T-cell checkpoint blockade, with immediate implications for clinical evaluation. Cancer Res; 76(13); 3929-41. ©2016 AACR.

Pharmacodynamic study of axitinib in patients with advanced malignancies assessed with (18)F-3'deoxy-3'fluoro-L-thymidine positron emission tomography/computed tomography.

PURPOSE: Rapid disease progression associated with increased tumor proliferation has been observed during withdrawal of anti-angiogenic therapy. We characterize the dynamics of withdrawal flare for axitinib. METHODS: Thirty patients with metastatic solid malignancies received axitinib for 2 weeks, followed by a 1-week drug holiday. Twenty patients suitable for PET imaging received scans with (18)F-3'deoxy-3'fluoro-L-thymidine (FLT), a marker of proliferation. Plasma VEGF and axitinib pharmacokinetic levels were also assessed at specified time points. RESULTS: During axitinib withdrawal, significant increases in both SUVmax (+22 %; p = 0.006) and SUVmean (+20 %; p = 0.001) were observed. Significant increases relative to peak axitinib concentration were observed at day 2 withdrawal for SUVmax and SUVmean, with no further significant increase from day 2 to day 7 of withdrawal. No significant change in SUVmax or SUVmean was observed during the treatment period, relative to baseline. VEGF concentration significantly increased when on drug (p < 0.001) and decreased back to a level indistinguishable from baseline by day 7 of drug washout (p = 0.448). No correlation between change in VEGF and change in imaging metrics was observed. CONCLUSIONS: A significant increase in tumor proliferation was observed during withdrawal of axitinib therapy, and this flare occurred within 2 days of axitinib withdrawal. An exploratory analysis indicated that this flare may be associated with poor clinical outcome.

Notched audiograms and noise exposure history in older adults.

OBJECTIVE: Using data from a population-based cohort study, we compared four published algorithms for identifying notched audiograms and compared their resulting classifications with noise exposure history. DESIGN: Four algorithms: (1) , (2) , (3) , and (4) were used to identify notched audiograms. Audiometric evaluations were collected as a part of the 10-yr follow-up examinations of the Epidemiology of Hearing Loss Study, in Beaver Dam, WI (2003-2005, N = 2395). Detailed noise exposure histories were collected by interview at the baseline examination (1993-1995) and updated at subsequent visits. An extensive history of occupational noise exposure, participation in noisy hobbies, and firearm usage was used to evaluate consistency of the notch classifications with the history of noise exposure. RESULTS: The prevalence of notched audiograms varied greatly by definition (31.7, 25.9, 47.2, and 11.7% for methods 1, 2, 3, and 4, respectively). In this cohort, a history of noise exposure was common (56.2% for occupational noise, 71.7% for noisy hobbies, 13.4% for firearms, and 81.2% for any of these three sources). Among participants with a notched audiogram, almost one-third did not have a history of occupational noise exposure (31.4, 33.0, 32.5, and 28.1% for methods 1, 2, 3, and 4, respectively), and approximately 11% did not have a history of exposure to any of the three sources of noise (11.5, 13.6, 10.3, and 7.6%). Discordance was greater in women than in men. CONCLUSIONS: These results suggest that there is a poor agreement across existing algorithms for audiometric notches. In addition, notches can occur in the absence of a positive noise history. In the absence of an objective consensus definition of a notched audiogram and in light of the degree of discordance in women between noise history and notches by each of these algorithms, researchers should be cautious about classifying noise-induced hearing loss by notched audiograms.

Olfaction and the 5-year incidence of cognitive impairment in an epidemiological study of older adults.

OBJECTIVES: To determine whether odor identification ability is associated with the 5-year incidence of cognitive impairment in a large population of older adults with normal cognition at baseline and whether olfactory impairment contributes to the prediction of cognitive decline. DESIGN: Population-based longitudinal study. SETTING: Beaver Dam, Wisconsin. PARTICIPANTS: One thousand nine hundred twenty participants in the Epidemiology of Hearing Loss Study (mean age 66.9). MEASUREMENTS: Olfaction was measured using the San Diego Odor Identification Test (SDOIT). Incident cognitive impairment was defined as a Mini-Mental State Examination (MMSE) score of less than 24 or reported diagnosis of dementia or Alzheimer's disease (AD) at follow-up in participants with a MMSE score of 24 or greater and no diagnosis of dementia or AD at baseline. RESULTS: There was a significant association between olfactory impairment at baseline and 5-year incidence of cognitive impairment (odds ratio (OR)=6.62, 95% confidence interval (CI)=4.36-10.05). The association remained significant after adjusting for possible confounders (OR=3.72, 95% CI=2.31-5.99). The positive predictive value of the SDOIT was 15.9%, the negative predictive value was 97.2%, the sensitivity was 55.1%, and the specificity was 84.4% for 5-year incidence of cognitive impairment. CONCLUSION: Olfactory impairment at baseline was strongly associated with 5-year incidence of cognitive impairment as measured using the MMSE. Odor identification testing may be useful in high-risk settings, but not in the general population, to identify patients at risk for cognitive decline.