Long-term survival correlates with immunological responses in renal cell carcinoma patients treated with mRNA-based immunotherapy.

Renal cell carcinoma (RCC) is an immunogenic tumor for which immunotherapeutic approaches could be associated with clinically relevant responses. It was recently shown, that induction of T-cell responses against multiple tumor-associated antigen (TAA) epitopes results in prolonged overall survival in RCC patients. In 2003-2005, we performed a phase I/II trial testing an mRNA-based vaccine formulation consisting of a mixture of in vitro transcribed RNA coding for six different TAAs (MUC1, CEA, Her2/neu, telomerase, survivin, MAGE-A1) in 30 metastatic RCC (mRCC) patients. In the first 14 patients, vaccinations were applied i.d. on days 0, 14, 28, and 42. In the consecutive 16 patients, an intensified protocol consisting of i.d. injections (daily on days 0-3, 7-10, 28, and 42) was used. After the respective induction periods, patients in both cohorts were vaccinated monthly until tumor progression. At survival update performed in July 2015, one of the 30 patients was still alive. One patient was lost to follow-up. Median survival of 24.5 mo (all patients) and 89 mo (favorable risk patients) exceeded predicted survival according to Memorial Sloan Kettering Cancer Center (MSKCC) risk score. Impressively, long-term survivors displayed immunological responses to the applied antigens while vice versa no patient without detectable immune response had survived more than 33 mo. The current survival update shows a clear correlation between survival and immunological responses to TAAs encoded by the naked mRNA vaccine. This is one of the first vaccination studies and the only RNA trial that reports on safety and efficacy after a follow-up of more than 10 y.

Role of dynamic contrast-enhanced sonography for characterization and monitoring of extramedullary myeloma: comparison with serologic data.

OBJECTIVE: To measure blood perfusion in extramedullary myeloma by contrast-enhanced sonography, correlate it with specific hematologic parameters, and determine their utility for local and systemic response monitoring. METHODS: Twenty-five consecutive patients (14 male and 11 female; median age, 68 years) with extramedullary myeloma were included. After intravenous administration of 2.4 mL of sulfur hexafluoride, extramedullary myeloma masses were examined for 60 seconds. All patients underwent contrast-enhanced sonography at baseline, and 15 were monitored additionally (3 weeks during therapy). Average peak perfusion, regional blood flow (RBF), and regional blood volume (RBV) were calculated. Baseline perfusion parameters were compared with short-term follow-up sonographic data and serologic biomarkers (M gradient). For validation of extramedullary myeloma and systemic myeloma, patients underwent midterm (<3 months) imaging and serologic diagnosis. RESULTS: Patients with baseline ß2-microglobulin (B2M) greater than 3.5 mg/L (n = 17) showed higher perfusion parameters compared with baseline B2M less than 3.5 mg/L (n = 8). At short-term follow-up, patients were classified by serologic criteria as responders (n = 9) and nonresponders (n = 6) and by sonographic criteria as responders (n = 10) and nonresponders (n = 5). In sonographic responders, mean peak, RBV, and RBF dropped from 59.13, 1446.09, and 71.52 (artificial units) at baseline to 29.30, 364.19, and 34.64 at follow-up (P < .05), whereas in nonresponders, perfusion parameters increased from 33.18, 789.82, and 36.92 at baseline to 51.14, 1491.06, and 65.34 at follow-up (P > .05). Prediction of a midterm course of systemic myeloma using serologic data yielded sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 0.66, 0.77, 0.66, and 0.77, whereas sonographic results (judged by RBV) yielded values of 0.66, 0.55, 0.5, and 0.71. Separate prediction of a local (extramedullary myeloma) response by sonography yielded sensitivity, specificity, PPV, and NPV of 0.8, 1.0, 1.0, and 0.71. CONCLUSIONS: Contrast-enhanced sonography is a valuable tool for short-term monitoring of the treatment response in extramedullary myeloma.

Intradermal vaccinations with RNA coding for TAA generate CD8+ and CD4+ immune responses and induce clinical benefit in vaccinated patients.

The aim of this phase I/II nonrandomized trial was to assess feasibility, safety as well as immunological and clinical responses of a mRNA-based vaccination in patients with stage IV renal cell cancer using granulocyte-macrophage colony stimulating factor (GM-CSF) as adjuvant. Intradermal injections of in vitro transcribed naked mRNA, which was generated using plasmids coding for the tumor-associated antigens mucin 1(MUC1), carcinoembryonic (CEA), human epidermal growth factor receptor 2 (Her-2/neu), telomerase, survivin, and melanoma-associated antigen 1 (MAGE-A1) were performed in 30 enrolled patients. In the first 14 patients (cohort A) vaccinations were administered on days 0, 14, 28, and 42 (20 µg/antigen) while in the consecutive 16 patients (cohort B) an intensified protocol consisting of injections at days 0-3, 7-10, 28, and 42 (50 µg/antigen) was used. In both cohorts, after this induction period, vaccinations were repeated monthly until tumor progression analyzed by Response Evaluation Criteria In Solid Tumors criteria (RECIST). Vaccinations were well tolerated with no severe side effects and induced clinical responses [six stable diseases (SD) and one partial response in cohort A and nine SD in cohort B]. In cohort A, 35.7% survived 4 years (median survival 24 months) compared to 31.25% in cohort B (median survival 29 months). Induction of CD4(+) and CD8(+) T cell responses was shown for several tumor-associated antigens (TAA) using interferon-γ (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) and Cr-release assays.

Evaluation of response in malignant tumors treated with the multitargeted tyrosine kinase inhibitor sorafenib: a multitechnique imaging assessment.

OBJECTIVE: The purpose of this article is to illustrate the characteristic changes induced in different tumor types by the multitargeted tyrosine kinase inhibitor sorafenib. CONCLUSION: Sorafenib reduces tumor perfusion and thereby induces necrosis and often hemorrhage. Malignant tumors treated with sorafenib undergo both morphologic and functional changes; however, the morphologic changes are less frequent and inadequate for early evaluation of response. Therefore, imaging tools accurately assessing hemorrhage and decrease in tumor perfusion with subsequent necrosis should be the mainstay in monitoring targeted therapy agents.

Pathologic fractures in patients with multiple myeloma undergoing bisphosphonate therapy: incidence and correlation with course of disease.

OBJECTIVE: The purposes of this study were single-center analysis of the incidence of pathologic fractures in patients with multiple myeloma undergoing bisphosphonate therapy and correlation of the occurrence of pathologic fractures with the course of disease. MATERIALS AND METHODS: One hundred ninety-one patients with multiple myeloma consecutively underwent unenhanced whole-body low-dose MDCT in parallel with hematologic follow-up. Only patients undergoing at least two whole-body low-dose MDCT examinations were included in this retrospective study, resulting in 561 survey intervals. The median analysis period per patient was 23 months (range, 3-53 months). Fracture incidence and the relation between newly occurring fractures and course of the disease were assessed. RESULTS: Forty-nine pathologic fractures were detected in 49 of the 561 survey intervals (8.7%) and in 36 of the 191 patients (19%). Fractures were found on MDCT images irrespective of disease course. They were found in 25 of 202 intervals (12.4%) of progressive disease, in 14 of 171 intervals (8.2%) of disease remission, and in 10 of 188 intervals (5.3%) of stable disease. The overall calculated annual incidence of pathologic fractures in patients with multiple myeloma was 14%. Eleven patients had more than one fracture, all of which were vertebral compression fractures. Three patients had three episodes of bone fracture, and eight patients had two episodes. CONCLUSION: Pathologic fractures in patients with multiple myeloma undergoing bisphosphonate therapy occur independently of myeloma activity and therefore should not be considered a sign of disease progression.

Marginal zone B-cell non-Hodgkin's lymphoma of mucosa-associated lymphoid tissue type: imaging findings.

OBJECTIVE: The aim of this essay is to describe the imaging features of marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type throughout various organs. CONCLUSION: Awareness of the expected locations of MALT lymphoma combined with knowledge of the incidence and imaging findings leads to accurate diagnosis of lesions suspicious for this disorder and helps to differentiate this disease from other abnormalities.