Discovery and Development of Cyclic Peptide Proteasome Stimulators.

The proteasome degrades proteins, which is essential for cellular homeostasis. Ubiquitin independent proteolysis degrades highly disordered and misfolded proteins. A decline of proteasomal activity has been associated with multiple neurodegenerative diseases due to the accumulation of misfolded proteins. In this work, cyclic peptide proteasome stimulators (CyPPSs) that enhance the clearance of misfolded proteins were discovered. In the initial screen of predicted natural products (pNPs), several cyclic peptides were found to stimulate the 20S core particle (20S CP). Development of a robust structural activity relationship led to the identification of potent, cell permeable CyPPSs. In vitro assays revealed that CyPPSs stimulate degradation of highly disordered and misfolded proteins without affecting ordered proteins. Furthermore, using a novel flow-based assay for proteasome activity, several CyPPSs were found to stimulate the 20S CP in cellulo. Overall, this work describes the development of CyPPSs as chemical tools capable of stimulating the proteasome and provides strong support for proteasome stimulation as a therapeutic strategy for neurodegenerative diseases.

Antiferromagnetic Bosonic t-J Models and Their Quantum Simulation in Tweezer Arrays.

The combination of optical tweezer arrays with strong interactions-via dipole exchange of molecules and Van der Waals interactions of Rydberg atoms-has opened the door for the exploration of a wide variety of quantum spin models. A next significant step will be the combination of such settings with mobile dopants. This will enable one to simulate the physics believed to underlie many strongly correlated quantum materials. Here, we propose an experimental scheme to realize bosonic t-J models via encoding the local Hilbert space in a set of three internal atomic or molecular states. By engineering antiferromagnetic (AFM) couplings between spins, competition between charge motion and magnetic order similar to that in high-T_{c} cuprates can be realized. Since the ground states of the 2D bosonic AFM t-J model we propose to realize have not been studied extensively before, we start by analyzing the case of two dopants-the simplest instance in which their bosonic statistics plays a role-and compare our results to the fermionic case. We perform large-scale density matrix renormalization group calculations on six-legged cylinders, and find a strong tendency for bosonic holes to form stripes. This demonstrates that bosonic, AFM t-J models may contain similar physics as the collective phases in strongly correlated electrons.

Treatment of Delbet II/III Pediatric Femoral Neck Fractures With Proximal Femoral Locking Plate Versus Cannulated Screws.

INTRODUCTION: Complications following operative treatment of pediatric femoral neck fractures include nonunion, coxa vara, and avascular necrosis (AVN). Proximal femoral locking plates (PFLPs) provide a fixed-angle construct that may reduce the rates of coxa vara, but their use in pediatric femoral neck fractures has not been studied. The purpose of this study was to evaluate rates of union, coxa vara, and AVN in traumatic pediatric femoral neck fractures treated with PFLP or cannulated screws (CS). METHODS: We retrospectively reviewed all traumatic, nonpathologic Delbet II/III femoral neck fractures in patients below 18 years of age treated with PFLP or CS. All cases had ≥6 months of radiographic follow-up to evaluate for osseous union and AVN. Changes in proximal femoral alignment were determined by measuring injured and contralateral femoral neck-shaft angle and articulotrochanteric distance (ATD) between 6 and 12 months postoperatively. RESULTS: Forty-two patients were identified with mean age at surgery of 10.7±2.9 years (range 3.3 to 16.3 years) and mean follow-up of 36±27 months. Sixteen patients (38%) underwent PFLP fixation, whereas 26 patients (62%) underwent CS fixation. When compared with the CS cohort, the PFLP cohort had a greater proportion of males (87.5% vs. 50%, P =0.02) and Delbet III fractures (68.8% vs. 15.4%, P <0.001). There was no difference between PFLP and CS cohorts with respect to rates of union (81% vs. 88%, respectively, P =0.66), AVN (25% vs. 35%, respectively, P =0.73), or secondary surgery (62% vs 62%, P =0.95). There was no significant difference in neck-shaft angle between injured and contralateral hips in those patients treated with PFLP ( P =0.93) or CS ( P =0.16). However, the ATD was significantly decreased in hips treated with CS compared with the contralateral hip (18.4±4.6 vs. 23.3±4.2 mm, P =0.001), with no significant difference in the PFLP group ( P =0.57). CONCLUSIONS: This study suggests that the use of a PFLP in Delbet II/III femoral neck fractures does not appear to significantly increase nonunion rates or AVN and maintains anatomic ATD when compared with screw fixation. LEVEL OF EVIDENCE: Level III-therapeutic study.

Sequencing CTLA-4 blockade with cell-based immunotherapy for prostate cancer.

BACKGROUND: The FDA recently approved an anti-CTLA-4 antibody (Iplimumab) for the treatment of metastatic melanoma. This decision was based on Phase III results, which demonstrate that blocking this immune checkpoint provides a survival advantage in patients with advanced disease. As a single agent, ipilimumab is also being clinically evaluated in advanced (metastatic, castrate-resistant) prostate cancer and two randomized, placebo-controlled Phase III studies have recently completed accrual. METHODS: We used a well-described genetically engineered mouse (GEM), autochronous prostate cancer model (Pro-TRAMP) to explore the relative sequencing and dosing of anti-CTLA-4 antibody when combined with a cell-based, GM-CSF-secreting vaccine (GVAX). RESULTS: Our results show that combined treatment results in a dramatic increase in effector CD8 T cells in the prostate gland, and enhanced tumor-antigen directed lytic function. These effects are maximized when CTLA-4 blockade is applied after, but not before, vaccination. Additional experiments, using models of metastatic disease, show that incorporation of low-dose cyclophosphamide into this combined treatment regimen results in an additional pre-clinical benefit. CONCLUSIONS: Together these studies define a combination regimen using anti-CTLA-4/GVAX immunotherapy and low-dose chemotherapy for potential translation to a clinical trial setting.

Long-range enhancers on 8q24 regulate c-Myc.

Recent genomewide association studies have found multiple genetic variants on chromosome 8q24 that are significantly associated with an increased susceptibility to prostate, colorectal, and breast cancer. These risk loci are located in a "gene desert," a few hundred kilobases telomeric to the Myc gene. To date, the biological mechanism(s) underlying these associations remain unclear. It has been speculated that these 8q24 genetic variant(s) might affect Myc expression by altering its regulation or amplification status. Here, we show that multiple enhancer elements are present within this region and that they can regulate transcription of Myc. We also demonstrate that one such enhancer element physically interacts with the Myc promoter via transcription factor Tcf-4 binding and acts in an allele specific manner to regulate Myc expression.

Low-Dose Whole Brain Radiation Therapy for Alzheimer's Dementia: Results From a Pilot Trial in Humans.

PURPOSE: We report neurocognitive, imaging, ophthalmologic, and safety outcomes following low-dose whole brain radiation therapy (LD-WBRT) for patients with early Alzheimer dementia (eAD) treated in a pilot trial. METHODS AND MATERIALS: Trial-enrolled patients were at least 55 years of age, had eAD meeting NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association) Alzheimer's Criteria with confirmatory fluorodeoxyglucose and florbetapir positron emission tomography findings; had the capacity to complete neurocognitive function, psychological function, and quality-of-life assessments; had a Rosen modified Hachinski score ≤4; and had estimated survival >12 months. RESULTS: Five patients were treated with LD-WBRT (2 Gy × 5 over 1 week; 3 female; mean age, 73.2 years [range, 69-77]). Four of 5 patients had improved (n = 3) or stable (n = 1) Mini-Mental State Examination (second edition) T-scores at 1 year. The posttreatment scores of all 3 patients who improved increased to the average range. There were additional findings of stability of naming and other cognitive skills as well as stability to possible improvement in imaging findings. No safety issues were encountered. The only side effect was temporary epilation with satisfactory hair regrowth. CONCLUSIONS: Our results from 5 patients with eAD treated with LD-WBRT (10 Gy in 5 fractions) demonstrate a positive safety profile and provide preliminary, hypothesis-generating data to suggest that this treatment stabilizes or improves cognition. These findings will require further evaluation in larger, definitive, randomized trials.

Radiotherapy and Radiosurgery in the Management of Optic Nerve Sheath Meningiomas: An International Systematic Review and Meta-Analysis of Twenty Studies.

BACKGROUND: Optic nerve sheath meningiomas (ONMs) are often managed with radiotherapy (RT) with the goal of achieving radiographic local control (LC) and preventing deterioration of visual acuity (VA). We aimed to perform a systematic review and meta-analysis of outcomes for patients with ONM treated with RT. METHODS: The PICOS/PRISMA/MOOSE selection criteria were used to identify studies. Primary outcomes were stable or improved VA and radiographic LC at last follow-up. The secondary outcomes were incidences of radiation-induced retinopathy and xerophthalmia and stable or improved visual fields (VFs). Weighted random-effects meta-analyses using the DerSimonian and Laird methods were conducted to characterize effect sizes. Mixed-effects regression models were used to examine potential correlations between gross tumor volume (GTV) and outcomes. RESULTS: In total, 444 patients with ONM across 20 published studies were included. The estimated LC rate was 99.8% (95% confidence interval [CI], 98.3%-100%), and the estimated proportion of patients with stable or improved VA or VF was 89.7% (95% CI, 86.2%-92.4%) and 93.3% (95% CI, 89.5%-95.8%), respectively. Estimated incidences of radiation-induced retinopathy and xerophthalmia were 7.2% and 10.1%, respectively. GTV was significantly associated with VA (P = 0.014) with estimated VA rates of 96.4%, 91.4%, and 80.5% for GTVs of 2.0, 3.0, and 4.0 cm3, respectively. CONCLUSIONS: RT was well tolerated, with excellent LC achieved. Nearly 90% of patients noted either stability or improvement in VA and VF. Larger ONMs were associated with poorer VA.

Tumor recognition and self-recognition induce distinct transcriptional profiles in antigen-specific CD4 T cells.

Tumors express a wide variety of both mutated and nonmutated Ags. Whether these tumor Ags are broadly recognized as self or foreign by the immune system is currently unclear. Using an autochthonous prostate cancer model in which hemagglutinin (HA) is specifically expressed in the tumor (ProHA x TRAMP mice), as well as an analogous model wherein HA is expressed in normal tissues as a model self-Ag (C3HA(high)), we examined the transcriptional profile of CD4 T cells undergoing Ag-specific division. Consistent with our previous data, transfer of Ag-specific CD4 T cells into C3HA(high) resulted in a functionally inactivated CD4 T cell profile. Conversely, adoptive transfer of an identical CD4 T cell population into ProHA x TRAMP mice resulted in the induction of a regulatory phenotype of the T cell (Treg) both at the transcriptional and functional level. Interestingly, this Treg skewing was a property of even early-stage tumors, suggesting Treg induction as an important tolerance mechanism during tumor development.

Tc17 CD8 T cells: functional plasticity and subset diversity.

IL-17-secreting CD8 T cells (Tc17) have been described in several settings, but little is known regarding their functional characteristics. While Tc1 cells produced IFN-gamma and efficiently killed targets, Tc17 cells lacked lytic function in vitro. Interestingly, the small numbers of IFN-gamma-positive or IL-17/IFN-gamma-double-positive cells generated under Tc17 conditions also lacked lytic activity and expressed a similar pattern of cell surface proteins to IL-17-producing cells. As is the case for Th17 (CD4) cells, STAT3 is important for Tc17 polarization, both in vitro and in vivo. Adoptive transfer of highly purified, Ag-specific IL-17-secreting Tc17 cells into Ag-bearing hosts resulted in near complete conversion to an IFN-gamma-secreting phenotype and substantial pulmonary pathology, demonstrating functional plasticity. Tc17 also accumulated to a greater extent than did Tc1 cells, suggesting that adoptive transfer of CD8 T cells cultured in Tc17 conditions may have therapeutic potential for diseases in which IFN-gamma-producing cells are desired.

The Effect of Radiation on Meningioma Volume Change.

BACKGROUND: Radiation therapy is a common treatment for meningiomas. Volume changes of meningiomas in response to radiation are not well characterized. This study seeks to quantify the volume change of meningiomas following radiation. METHODS: Data were collected from a retrospective single-institution database of cases from 2005-2015. Tumors were measured using T1-weighted post-contrast magnetic resonance imaging. Volumes were calculated using the ABC/2 ellipsoidal approximation. RESULTS: A total of 63 patients fit the inclusion criteria; 37 patients (59%) received radiation following resection, 19 (30%) received radiation alone, 4 (6%) received radiation following a biopsy, and 3 (5%) had unknown surgical status. A total of 39 patients (62%) had skull base meningiomas; 43 tumors were World Health Organization (WHO) grade I, and 12 tumors were WHO grade II. Thirteen patients received radiosurgery, 43 received radiotherapy, and 7 received an unknown number of treatments. Eight patients did not attain local control and were excluded from volume analyses. WHO grade I meningiomas saw an average of 33% ± 19% decrease in tumor volume; WHO grade II tumor volumes decreased by an average 30% ± 23%. Radiosurgery saw an average volume decrease of 34% ± 13%, while radiotherapy resulted in volume decrease of 31% ± 21%. For those who achieved local control, there was an average decrease in tumor size of 30% ± 19%, 30% ± 22%, and 41% ± 19% over 0.5-1.5, 2.5-3.5, and >5 years, respectively. CONCLUSIONS: Meningiomas treated with radiation exhibit nonlinear decrease in size over time. The greatest decrease in tumor volume occurs within the first year and begins to plateau 5 years post-radiation treatment.

Hypofractionated Postprostatectomy Radiation Therapy for Prostate Cancer to Reduce Toxicity and Improve Patient Convenience: A Phase 1/2 Trial.

PURPOSE: The phase 1 portion of this multicenter, phase 1/2 study of hypofractionated (HypoFx) prostate bed radiation therapy (RT) as salvage or adjuvant therapy aimed to identify the shortest dose-fractionation schedule with acceptable toxicity. The phase 2 portion aimed to assess the health-related quality of life (QoL) of using this HypoFx regimen. METHODS AND MATERIALS: Eligibility included standard adjuvant or salvage prostate bed RT indications. Patients were assigned to receive 1 of 3 daily RT schedules: 56.6 Gy in 20 Fx, 50.4 Gy in 15 Fx, or 42.6 Gy in 10 Fx. Regional nodal irradiation and androgen deprivation therapy were not allowed. Participants were followed for 2 years after treatment with outcome measures based on prostate-specific antigen levels, toxicity assessments (Common Terminology Criteria for Adverse Events, v4.0), QoL measures (the Expanded Prostate Cancer Index Composite [EPIC] and EuroQol EQ-5D instruments), and out-of-pocket costs. RESULTS: There were 32 evaluable participants, and median follow-up was 3.53 years. The shortest dose-fractionation schedule with acceptable toxicity was determined to be 42.6 Gy in 10 Fx, with most patients (23) treated with this schedule. Grade 3 genitourinary (GU) and gastrointestinal (GI) toxicities occurred in 3 patients and 1 patient, respectively. There was 1 grade 4 sepsis event. Higher dose to the hottest 25% of the rectum was associated with increased risk of grade 2+ GI toxicity; no dosimetric factors were found to predict for GU toxicity. There was a significant decrease in the mean bowel, but not bladder, QoL score at 1 year compared with baseline. Prostate-specific antigen failure occurred in 34.3% of participants, using a definition of nadir plus 2 ng/mL. Metastases were more likely to occur in regional lymph nodes (5 of 7) than in bones (2 of 7). The mean out-of-pocket cost for patients during treatment was $223.90. CONCLUSIONS: We identified 42.6 Gy in 10 fractions as the shortest dose-fractionation schedule with acceptable toxicity in this phase 1/2 study. There was a higher than expected rate of grade 2 to 3 GU and GI toxicity and a decreased EPIC bowel QoL domain with this regimen. Future studies are needed to explore alternative adjuvant/salvage HypoFx RT schedules after radical prostatectomy.

LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems.

Lymphocyte activation gene-3 (LAG-3) is a cell-surface molecule with diverse biologic effects on T cell function. We recently showed that LAG-3 signaling is important in CD4+ regulatory T cell suppression of autoimmune responses. Here, we demonstrate that LAG-3 maintains tolerance to self and tumor antigens via direct effects on CD8+ T cells using 2 murine systems. Naive CD8+ T cells express low levels of LAG-3, and expression increases upon antigen stimulation. Our data show increased levels of LAG-3 protein on antigen-specific CD8+ T cells within antigen-expressing organs or tumors. In vivo antibody blockade of LAG-3 or genetic ablation of the Lag-3 gene resulted in increased accumulation and effector function of antigen-specific CD8+ T cells within organs and tumors that express their cognate antigen. Most notably, combining LAG-3 blockade with specific antitumor vaccination resulted in a significant increase in activated CD8+ T cells in the tumor and disruption of the tumor parenchyma. A major component of this effect was CD4 independent and required LAG-3 expression by CD8+ T cells. Taken together, these data demonstrate a direct role for LAG-3 on CD8+ T cells and suggest that LAG-3 blockade may be a potential cancer treatment.

Radiotherapy augments the immune response to prostate cancer in a time-dependent manner.

BACKGROUND: Cancer immunotherapy refers to an array of strategies intended to treat progressive tumors by augmenting a patient's anti-tumor immune response. As immunotherapy is eventually incorporated into oncology treatment paradigms, it is important to understand how these therapies interact with established cancer treatments such as chemotherapy or Radiotherapy (RT). To address this, we utilized a well-established, autochthonous murine model of prostate cancer to test whether RT could augment (or diminish) the CD4 T cell response to a tumor vaccine. METHODS: Transgenic mice that develop spontaneous prostate cancer (TRAMP) which also express a unique tumor associated antigen (Influenza hemagglutinin) under the control of a prostate-specific promoter were given local RT in combination with immunotherapy. The immunological outcome of this combinatorial strategy was assayed by monitoring the effector response of adoptively transferred, prostate-specific CD4 T cells. RESULTS: Neither RT nor immunotherapy alone was capable of priming an anti-tumor immune response in animals with evolving tumors. The combination of immunotherapy with RT resulted in anti-tumor T cell activation--this effect was profoundly dependent on the relative timing of RT and immunotherapy. Anti-tumor immune responses occurred when immunotherapy was administered 3-5 weeks post-RT, but such responses were undetectable when immunotherapy was administered either earlier (peri-radiotherapy) or later. CONCLUSIONS: The therapeutic temporal window of immunotherapy post-RT suggests that highly aggressive, immuno-suppressive tumors might be most sensitive to immunotherapy in a fairly narrow time window; these results should help to guide future development of clinical combinatorial strategies.

National Landscape of General Surgery Mock Oral Examination Practices: Survey of Residency Program Directors.

INTRODUCTION: Mock oral examinations (MOEs) are used within surgery residency programs to prepare trainees for the American Board of Surgery (ABS) Certifying Exam (CE), but little work exists to guide programs in terms of best practices for implementing a general surgery MOE program. This study, endorsed by the Association for Program Directors in Surgery (APDS) Research Committee, aimed to better understand the national scope of current practices for general surgery MOEs. METHODS: General surgery residency program directors (PDs) were invited via the APDS listserv to complete a 27-item survey about their perceptions of the importance and correlates of MOEs, how their exams are structured, implementation barriers, and recent revisions to their MOE program. RESULTS: Of 98 PDs responding to the survey, 94% (n = 92) responded about the characteristics of their formal MOE programs. The majority required upper level resident participation and held the exams 2 to 3 times annually; far fewer involved lower level residents. Most programs structure their MOEs to mimic the CE format with 3 exam rooms (76%), using premade questions (66%), presenting 4 scenarios per room (59%), and using two examiners per room (85%). Most PDs (88%) believed MOEs were very important or essential for surgery trainees, which correlated with their ratings of how important MOEs are to their Clinical Competency Committee for determining resident advancement (r = 0.32, p < 0.002). Common barriers for implementing MOEs were availability of examiners and scenarios. About half indicated making recent or ongoing revisions to improve their MOEs. Many PDs indicated interest in collaborating regionally or nationally on MOE initiatives. CONCLUSIONS: MOEs were largely regarded as a highly valuable tool by PDs to prepare trainees for the general surgery CE. The majority of programs in this study provide a testing experience as similar to the CE as possible, although some variability in the structure of MOEs was identified. PDs also reported significant implementation barriers and a desire for more MOE collaboration.

Severe acute gallstone pancreatitis with diffuse hemorrhagic gastritis.

A 67-year-old male presented with acute pancreatitis secondary to gallstones, also known as acute biliary pancreatitis, and subsequently developed gastric outlet obstruction and was transferred to our hospital. A gastro-jejunal feeding tube was placed and an open cholecystectomy was performed. The patient had a pancreatic drain placed for interval increase in pancreatic necrosis and then nearly exsanguinated from gastroduodenal artery pseudoaneurysm bleed. This was managed by coiling the gastroduodenal artery. The patient underwent a pancreatic necrosectomy with malencot drain placement and developed a post-operative upper gastrointestinal bleeding. An EGD showed diffuse gastritis, but no varices. And 18 days later the patient rebled, with the same diffuse gastritis. After further complications the patient elected to receive palliative care at a hospice facility. We are presenting this unusual case of diffuse, hemorrhagic gastritis after acute necrotizing pancreatitis.

On-demand pulsatile intracerebral delivery of carisbamate with closed-loop direct neurostimulation therapy in an electrically induced self-sustained focal-onset epilepsy rat model.

OBJECT: The authors evaluated the preclinical feasibility of acutely stabilizing an active bihemispheric limbic epileptic circuit using closed-loop direct neurostimulation therapy in tandem with "on-demand'" convection-enhanced intracerebral delivery of the antiepileptic drug (AED) carisbamate. A rat model of electrically induced self-sustained focal-onset epilepsy was employed. METHODS: A 16-contact depth-recording microelectrode was implanted bilaterally in the dentate gyrus (DG) of the hippocampus of Fischer 344 rats. The right microelectrode array included an integrated microcatheter for drug delivery at the distal tip. Bihemispheric spontaneous self-sustained limbic status epilepticus (SSLSE) was induced in freely moving rats using a 90-minute stimulation paradigm delivered to the right medial perforant white matter pathway. Immediately following SSLSE induction, closed-loop right PP stimulation therapy concurrent with on-demand nanoboluses of the AED [(14)C]-carisbamate (n = 4), or on-demand [(14)C]-carisbamate alone (n = 4), was introduced for a mean of 10 hours. In addition, 2 reference groups received either closed-loop stimulation therapy alone (n = 4) or stimulation therapy with saline vehicle only (n = 4). All animals were sacrificed after completing the specified therapy regimen. In situ [(14)C]-autoradiography was used to determine AED distribution. RESULTS: Closed-loop direct stimulation therapy delivered unilaterally in the right PP aborted ictal runs detected in either ipsi- or contralateral hippocampi. Freely moving rats receiving closed-loop direct stimulation therapy with ondemand intracerebral carisbamate delivery experienced a significant reduction in seizure frequency (p < 0.001) and minimized seizure frequency variability during the final 50% of the therapy/recording session compared with closed-loop stimulation therapy alone. CONCLUSIONS: Unilateral closed-loop direct stimulation therapy delivered to afferent hippocampal white matter pathways concurrent with on-demand ipsilateral intracerebral delivery of nano-bolused carisbamate can rapidly decrease the frequency of electrographic seizures in an active bihemispheric epileptic network. Additionally, direct pulsatile delivery of carisbamate can stabilize seizure frequency variability compared with direct stimulation therapy alone.

Primer on tumor immunology and cancer immunotherapy.

Individualized cancer therapy is a central goal of cancer biologists. Immunotherapy is a rational means to this end-because the immune system can recognize a virtually limitless number of antigens secondary to the biology of genetic recombination in B and T lymphocytes. The immune system is exquisitely structured to distinguish self from non-self, as demonstrated by anti-microbial immune responses. Moreover the immune system has the potential to recognize self from "altered-self", which is the case for cancer. However, the immune system has mechanisms in place to inhibit self-reactive responses, many of which are usurped by evolving tumors. Understanding the interaction of cancer with the immune system provides insights into mechanisms that can be exploited to disinhibit anti-tumor immune responses. Here, we summarize the 2012 SITC Primer, reviewing past, present, and emerging immunotherapeutic approaches for the treatment of cancer-including targeting innate versus adaptive immune components; targeting and/or utilizing dendritic cells and T cells; the role of the tumor microenvironment; and immune checkpoint blockade.

Immune modulation and stereotactic radiation: improving local and abscopal responses.

New and innovative treatment strategies for cancer patients in the fields of immunotherapy and radiotherapy are rapidly developing in parallel. Among the most promising preclinical treatment approaches is combining immunotherapy with radiotherapy where early data suggest synergistic effects in several tumor model systems. These studies demonstrate that radiation combined with immunotherapy can result in superior efficacy for local tumor control. More alluring is the emergence of data suggesting an equally profound systemic response also known as "abscopal" effects with the combination of radiation and certain immunotherapies. Studies addressing optimal radiation dose, fractionation, and modality to be used in combination with immunotherapy still require further exploration. However, recent anecdotal clinical reports combining stereotactic or hypofractionated radiation regimens with immunotherapy have resulted in dramatic sustained clinical responses, both local and abscopal. Technologic advances in clinical radiation therapy has made it possible to deliver hypofractionated regimens anywhere in the body using stereotactic radiation techniques, facilitating further clinical investigations. Thus, stereotactic radiation in combination with immunotherapy agents represents an exciting and potentially fruitful new space for improving cancer therapeutic responses.

Combined treatment effects of radiation and immunotherapy: studies in an autochthonous prostate cancer model.

PURPOSE: To optimize the combination of ionizing radiation and cellular immunotherapy using a preclinical autochthonous model of prostate cancer. METHODS AND MATERIALS: Transgenic mice expressing a model antigen under a prostate-specific promoter were treated using a platform that integrates cone-beam CT imaging with 3-dimensional conformal therapy. Using this technology we investigated the immunologic and therapeutic effects of combining ionizing radiation with granulocyte/macrophage colony-stimulating factor-secreting cellular immunotherapy for prostate cancer in mice bearing autochthonous prostate tumors. RESULTS: The combination of ionizing radiation and immunotherapy resulted in a significant decrease in pathologic tumor grade and gross tumor bulk that was not evident with either single-modality therapy. Furthermore, combinatorial therapy resulted in improved overall survival in a preventive metastasis model and in the setting of established micrometastases. Mechanistically, combined therapy resulted in an increase of the ratio of effector-to-regulatory T cells for both CD4 and CD8 tumor-infiltrating lymphocytes. CONCLUSIONS: Our preclinical model establishes a potential role for the use of combined radiation-immunotherapy in locally advanced prostate cancer, which warrants further exploration in a clinical setting.