Making Vaccines On Demand

The integrated US Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) has made great strides in strategic preparedness and response capabilities. There have been numerous advances in planning, biothreat countermeasure development, licensure, manufacturing, stockpiling and deployment. Increased biodefense surveillance capability has dramatically improved, while new tools and increased awareness have fostered rapid identification of new potential public health pathogens. Unfortunately, structural delays in vaccine design, development, manufacture, clinical testing and licensure processes remain significant obstacles to an effective national biodefense rapid response capability. This is particularly true for the very real threat of “novel pathogens” such as the avian-origin influenzas H7N9 and H5N1, and new coronaviruses such as hCoV-EMC. Conventional approaches to vaccine development, production, clinical testing and licensure are incompatible with the prompt deployment needed for an effective public health response. An alternative approach, proposed here, is to apply computational vaccine design tools and rapid production technologies that now make it possible to engineer vaccines for novel emerging pathogen and WMD biowarfare agent countermeasures in record time. These new tools have the potential to significantly reduce the time needed to design string-of-epitope vaccines for previously unknown pathogens. The design process—from genome to gene sequence, ready to insert in a DNA plasmid—can now be accomplished in less than 24 h. While these vaccines are by no means “standard,” the need for innovation in the vaccine design and production process is great. Should such vaccines be developed, their 60-d start-to-finish timeline would represent a 2-fold faster response than the current standard

Radiation Therapy Combined With Checkpoint Blockade Immunotherapy for Metastatic Undifferentiated Pleomorphic Sarcoma of the Maxillary Sinus With a Complete Response

Background: Undifferentiated pleomorphic sarcoma (UPS) of the maxillary sinus is an extremely rare malignancy of the head and neck. Surgery is the mainstay of treatment for UPS; however, proximity to vital structures makes it challenging to achieve negative surgical margins. Adjuvant therapy including radiation therapy with or without chemotherapy is generally indicated. Despite advances in multimodality treatment, objective response rates to available therapies and prognosis of metastatic UPS remain dismal. Immunotherapy has become a fourth cornerstone of cancer therapy and checkpoint blockade immunotherapy is a standard of care for recurrent or metastatic cisplatin-refractory head and neck squamous cell carcinoma. Checkpoint blockade immunotherapy is being studied in metastatic sarcoma, including UPS, and while initial results are promising, objective response rates remain below 20%. However, adding radiation therapy to checkpoint blockade immunotherapy has been shown, in both preclinical and retrospective clinical studies, to have combinatorial effects on both local and metastatic disease. Thus, further investigation into the effects of radiation therapy combined with immunotherapy in head and neck sarcomas is warranted.Case Presentation: We present a case of metastatic, chemotherapy-refractory, UPS of the maxillary sinus in a 55-year-old male treated with checkpoint blockade immunotherapy combined with radiation, which resulted in a complete response.Conclusions: This is the first report to our knowledge of metastatic UPS treated with a combination of radiation and dual agent checkpoint blockade immunotherapy. Further investigation is warranted to study the effects of this combination in patients with metastatic UPS that fail to respond to currently available therapies

Clinical Outcomes of Computed Tomography-Based Volumetric Brachytherapy Planning for Cervical Cancer

Purpose/objectivesA report of clinical outcomes of a computed tomography (CT)-based image guided brachytherapy (IGBT) technique for treatment of cervical cancer.Methods and materialsSeventy-six women with International Federation of Gynecology and Obstetrics stage IB to IVA cervical carcinoma diagnosed between 2007 and 2014 were treated with definitive external beam radiation therapy (EBRT) with or without concurrent chemotherapy followed by high-dose-rate (HDR) IGBT. All patients underwent planning CT simulation at each implantation. A high-risk clinical target volume (HRCTV) encompassing any visible tumor and the entire cervix was contoured on the simulation CT. When available, magnetic resonance imaging (MRI) was performed at implantation to assist with tumor delineation. The prescription dose was prescribed to the HRCTV.ResultsThe median follow-up time was 17 months. Thirteen patients (17%) had an MRI done before brachytherapy, and 16 patients (21%) were treated without MRI guidance. The mean EBRT/IGBT sum 2-Gy equivalent dose (EQD2) delivered to the 90% volume of the HRCTV was 86.3 Gy. The mean maximum EQD2s delivered to 2 cm(3) of the rectum, sigmoid, and bladder were 67.5 Gy, 66.2 Gy, and 75.3 Gy, respectively. The 2-year cumulative incidences of local, locoregional, and distant failure were 5.8% (95% confidence interval [CI]: 1.4%-14.8%), 15.1% (95% CI: 5.4%-29.4%), and 24.3% (95% CI: 12.1%-38.9%), respectively. The 2-year overall and disease-free survival rates were 75% (95% CI, 61%-91%) and 73% (95% CI, 60%-90%), respectively. Twenty-nine patients (38%) experienced grade ≥ 2 acute toxicity, with 5 cases of acute grade 3 toxicity and no grade ≥ 4 toxicities. One patient experienced grade 3 gastrointestinal toxicity. No other late grade ≥ 3 events were observed.ConclusionsThis is the largest report to date of CT/MRI-based IGBT for the treatment of cervical cancer. The results are promising, with excellent local control and acceptable toxicity. Further investigation is needed to assess the long-term safety and efficacy of this treatment

(P43) Radiatinghope: Advancing Cancer Care by Increasing Global Access to Radiation Therapy

Introduction: Cancer is the expected leading cause of death in Low and Middle Income Countries (LMIC), with higher mortality than that from malaria, tuberculosis and HIV/AIDS combined; more than 9 million cancer-related deaths are estimated in LMIC annually by 2030. Presenting at more advanced stages, 70% of LMIC cancer patients would benefit from radiation therapy (RT); less than 25% will receive RT. 358 million people in 55 LMIC have no access to RT. With a projected need of over 9000 teletherapy units by 2020 the cancer care gap for RT availability is enormous; 60% of the world\u27s cancer patients having access to 30% of the global RT units. Materials/Methods: RadiatingHope (RH) is a non-profit organization founded by radiation oncologists committed to increasing global access to radiation therapy. Through many advocacy and fundraising efforts, including mountain climbing, RH has increased awareness of this dearth of radiation oncology resources in the developing world. RH also facilitates radiation equipment donation (linear accelerators, HDR afterloaders), provides training needed for self-sustaining treatment delivery infrastructure and hosts meetings that encourage collaboration between developing, developed nations and industry to advance cancer care. Results: Since 2010, RH has facilitated the donation of over ten teletherapy units, including five linear accelerators sent to Peru, Ukraine, Tanzania and Honduras; ten HDR afterloaders have been donated, including Senegal\u27s first brachytherapy unit which provided a cure for cervical cancer. Training projects include visits to Panama and Senegal, weekly technical support, as well as financing attendance of international meetings to train physicists. RH volunteers have assisted in calibrating donated physics equipment and plan to do the same for two HDR after loaders en route to Ghana, where on site training will ensure safe use of the new equipment. In addition, RH has held over five mountain climbs (Everest Base Camp, Kilimanjaro) and three international symposia (Greater Horn Oncology Symposium, Cuban Radiation Oncology Symposium) to continue advocacy and provide platforms to discuss the global advancement of cancer care. Conclusions: RH will sustain its mission to advance global cancer care access, however, the universal need for radiation therapy equipment, human resources and infrastructure is staggering. Additional efforts in advocacy, education, fundraising, equipment donation and international collaborations are needed to overcome this global void in cancer care

The Unique Issues With Brachytherapy in Low- and Middle-Income Countries

Gynecologic carcinomas, including cervical cancer, present a significant burden on low- and middle-income countries (LMICs). Brachytherapy plays an integral role in the treatment of gynecologic carcinomas, as it is essential for both curative and palliative treatment. However, there are numerous geographic and economic barriers to providing brachytherapy to cancer patients in LMICs. This article examines the role and delivery of brachytherapy in gynecological cancer treatment; brachytherapy capacity in LMICs, including infrastructure, equipment, and human resources considerations; commissioning, training, and clinical implementation of brachytherapy in LMICs; other challenges, and strategies for improvement in brachytherapy delivery in LMICs, including innovation and current and upcoming international initiatives

PREVIS: Predictive visual analytics of anatomical variability for radiotherapy decision support

Radiotherapy (RT) requires meticulous planning prior to treatment, where the RT plan is optimized with organ delineations on a pre-treatment Computed Tomography (CT) scan of the patient. The conventionally fractionated treatment usually lasts several weeks. Random changes (e.g., rectal and bladder filling in prostate cancer patients) and systematic changes (e.g., weight loss) occur while the patient is being treated. Therefore, the delivered dose distribution may deviate from the planned. Modern technology, in particular image guidance, allows to minimize these deviations, but risks for the patient remain. We present PREVIS: a visual analytics tool for (i) the exploration and prediction of changes in patient anatomy during the upcoming treatment, and (ii) the assessment of treatment strategies, with respect to the anticipated changes. Records of during-treatment changes from a retrospective imaging cohort with complete data are employed in PREVIS, to infer expected anatomical changes of new incoming patients with incomplete data, using a generative model. Abstracted representations of the retrospective cohort partitioning provide insight into an underlying automated clustering, showing main modes of variation for past patients. Interactive similarity representations support an informed selection of matching between new incoming patients and past patients. A Principal Component Analysis (PCA)-based generative model describes the predicted spatial probability distributions of the incoming patient's organs in the upcoming weeks of treatment, based on observations of past patients. The generative model is interactively linked to treatment plan evaluation, supporting the selection of the optimal treatment strategy. We present a usage scenario, demonstrating the applicability of PREVIS in a clinical research setting, and we evaluate our visual analytics tool with eight clinical researchers

A framework for the implementation of new radiation therapy technologies and treatment techniques in low-income countries.

We present a practical, generic, easy-to-use framework for the implementation of new radiation therapy technologies and treatment techniques in low-income countries. The framework is intended to standardize the implementation process, reduce the effort involved in generating an implementation strategy, and provide improved patient safety by reducing the likelihood that steps are missed during the implementation process. The 10 steps in the framework provide a practical approach to implementation. The steps are, 1) Site and resource assessment, 2) Evaluation of equipment and funding, 3) Establishing timelines, 4) Defining the treatment process, 5) Equipment commissioning, 6) Training and competency assessment, 7) Prospective risk analysis, 8) System testing, 9) External dosimetric audit and incident learning, and 10) Support and follow-up. For each step, practical advice for completing the step is provided, as well as links to helpful supplementary material. An associated checklist is provided that can be used to track progress through the steps in the framework. While the emphasis of this paper is on addressing the needs of low-income countries, the concepts also apply in high-income countries

Salvage image guided radiation therapy to the prostate after cryotherapy failure

Purpose: Cryotherapy is an option for the primary treatment of localized prostate cancer, along with radical prostatectomy, external beam radiation therapy, and brachytherapy. Although it is known that local recurrence can occur in >20% of patients treated with primary cryotherapy, unfortunately there is a paucity of data on later salvage treatments. The use of external beam radiation therapy is an attractive option after cryotherapy failure, but there is little data on its efficacy and toxicity. We evaluated the biochemical control and complication rates of salvage dose-escalated image guided intensity modulated radiation therapy (IG-IMRT) after cryotherapy failure. Methods and materials: Patients who were treated at our institution from 2005 to 2016 were reviewed for those who underwent cryotherapy as initial treatment followed by salvage IGRT. Patients were treated with dose-escalated IG-IMRT using standard treatment margins of 3 mm posterior and 7 mm in all other directions and daily cone beam computed tomography or kv imaging to implanted fiducial markers. Biochemical progression was defined in accordance with the Phoenix consensus conference definition. Results: Eight patients were identified as having received post-cryotherapy salvage radiation within the study period. The median total dose was 77.7 Gy (range, 75.6-81.0 Gy). Median follow-up was 55 months (range, 6-88 months). Six patients remained biochemically controlled at the latest follow-up. One patient developed distant metastases after 22 months and one experienced biochemical failure at 30 months with no evidence of distant metastases. No patients experienced acute gastrointestinal toxicities of grade 2 or higher. There were no cases of late gastrointestinal or genitourinary toxicity. Conclusions: High-dose IG-IMRT results in high rates of salvage and extremely low rates of serious late toxicity for patients with locally recurrent prostate cancer after cryotherapy. Although the results are encouraging, given the small number of patients in this and other series, we remain cautious with regard to this treatment and believe the use of salvage radiation therapy after cryotherapy warrants further study