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Chimeric antigen receptor (CAR) T-cell therapy targeting solid tumors has stagnated as a result of tumor heterogeneity, immunosuppressive microenvironments, and inadequate intratumoral T cell trafficking and persistence. Early (≤3 days) intratumoral presentation of CAR T cells post-treatment is a superior predictor of survival than peripheral persistence. Therefore, we have co-opted IL-8 release from tumors to enhance intratumoral T-cell trafficking through a CAR design for maximal antitumor activity in solid tumors. Here, we demonstrate that IL-8 receptor, CXCR1 or CXCR2, modified CARs markedly enhance migration and persistence of T cells in the tumor, which induce complete tumor regression and long-lasting immunologic memory in pre-clinical models of aggressive tumors such as glioblastoma, ovarian and pancreatic cancer. CAR T-cell therapy efficacy in solid tumors is limited by inadequate T-cell migration and/or persistence in tumour microenvironment. Here, the authors show that the activity of tumour-antigen specific CAR T cells, in multiple preclinical mouse models, can be enhanced by co-expression of two IL-8 receptors that mediate their migration into the tumor microenvironment when IL-8 production in tumor is naturally expressed or enhanced by radiation.

While mechanical properties of the brain have been investigated thoroughly, the mechanical properties of human brain tumors rarely have been directly quantified due to the complexities of acquiring human tissue. Quantifying the mechanical properties of brain tumors is a necessary prerequisite, though, to identify appropriate materials for surgical tool testing and to define target parameters for cell biology and tissue engineering applications. Since characterization methods vary widely for soft biological and synthetic materials, here, we have developed a characterization method compatible with abnormally shaped human brain tumors, mouse tumors, animal tissue and common hydrogels, which enables direct comparison among samples. Samples were tested using a custom-built millimeter-scale indenter, and resulting force-displacement data is analyzed to quantify the steady-state modulus of each sample. We have directly quantified the quasi-static mechanical properties of human brain tumors with effective moduli ranging from 0.17-16.06 kPa for various pathologies. Of the readily available and inexpensive animal tissues tested, chicken liver (steady-state modulus 0.44 ± 0.13 kPa) has similar mechanical properties to normal human brain tissue while chicken crassus gizzard muscle (steady-state modulus 3.00 ± 0.65 kPa) has similar mechanical properties to human brain tumors. Other materials frequently used to mimic brain tissue in mechanical tests, like ballistic gel and chicken breast, were found to be significantly stiffer than both normal and diseased brain tissue. We have directly compared quasi-static properties of brain tissue, brain tumors, and common mechanical surrogates, though additional tests would be required to determine more complex constitutive models.

While promising, immunotherapy has yet to be fully unlocked for the preponderance of cancers where conventional chemoradiation reigns. This remains particularly evident in pediatric sarcomas where standard of care has not appreciably changed in decades. Importantly, pediatric bone sarcomas, like osteosarcoma and Ewing’s sarcoma, possess unique tumor microenvironments driven by distinct molecular features, as do rhabdomyosarcomas and soft tissue sarcomas. A better understanding of each malignancy’s biology, heterogeneity, and tumor microenvironment may lend new insights toward immunotherapeutic targets in novel platform technologies for cancer vaccines and adoptive cellular therapy. These advances may pave the way toward new treatments requisite for pediatric sarcomas and patients in need of new therapies.

Background Despite advancements in the successful use of immunotherapy in treating a variety of solid tumors, applications in treating brain tumors have lagged considerably. This is due, at least in part, to the lack of well-characterized antigens expressed within brain tumors that can mediate tumor rejection; the low mutational burden of these tumors that limits the abundance of targetable neoantigens; and the immunologically “cold” tumor microenvironment that hampers the generation of sustained and productive immunologic responses. The field of mRNA-based therapeutics has experienced a boon following the universal approval of COVID-19 mRNA vaccines. mRNA-based immunotherapeutics have also garnered widespread interest for their potential to revolutionize cancer treatment. In this study, we developed a novel and scalable approach for the production of personalized mRNA-based therapeutics that target multiple tumor rejection antigens in a single therapy for the treatment of refractory brain tumors. Methods Tumor-specific neoantigens and aberrantly overexpressed tumor-associated antigens were identified for glioblastoma and medulloblastoma tumors using our cancer immunogenomics pipeline called O pen R eading Frame A ntigen N etwork (O.R.A.N). Personalized tumor antigen-specific mRNA vaccine was developed for each individual tumor model using selective gene capture and enrichment strategy. The immunogenicity and efficacy of the personalized mRNA vaccines was evaluated in combination with anti-PD-1 immune checkpoint blockade therapy or adoptive cellular therapy with ex vivo expanded tumor antigen-specific lymphocytes in highly aggressive murine GBM models. Results Our results demonstrate the effectiveness of the antigen-specific mRNA vaccines in eliciting robust anti-tumor immune responses in GBM hosts. Our findings substantiate an increase in tumor-infiltrating lymphocytes characterized by enhanced effector function, both intratumorally and systemically, after antigen-specific mRNA-directed immunotherapy, resulting in a favorable shift in the tumor microenvironment from immunologically cold to hot. Capacity to generate personalized mRNA vaccines targeting human GBM antigens was also demonstrated. Conclusions We have established a personalized and customizable mRNA-therapeutic approach that effectively targets a plurality of tumor antigens and demonstrated potent anti-tumor response in preclinical brain tumor models. This platform mRNA technology uniquely addresses the challenge of tumor heterogeneity and low antigen burden, two key deficiencies in targeting the classically immunotherapy-resistant CNS malignancies, and possibly other cold tumor types.

Background The current standard of care treatments for medulloblastoma are insufficient as these do not take tumor heterogeneity into account. Newer, safer, patient-specific treatment approaches are required to treat high-risk medulloblastoma patients who are not cured by the standard therapies. Immunotherapy is a promising treatment modality that could be key to improving survival and avoiding morbidity. For an effective immune response, appropriate tumor antigens must be targeted. While medulloblastoma patients with subgroup-specific genetic substitutions have been previously reported, the immunogenicity of these genetic alterations remains unknown. The aim of this study is to identify potential tumor rejection antigens for the development of antigen-directed cellular therapies for medulloblastoma. Methods We developed a cancer immunogenomics pipeline and performed a comprehensive analysis of medulloblastoma subgroup-specific transcription profiles ( n  = 170, 18 WNT, 46 SHH, 41 Group 3, and 65 Group 4 patient tumors) available through International Cancer Genome Consortium (ICGC) and European Genome-Phenome Archive (EGA). We performed in silico antigen prediction across a broad array of antigen classes including neoantigens, tumor-associated antigens (TAAs), and fusion proteins. Furthermore, we evaluated the antigen processing and presentation pathway in tumor cells and the immune infiltrating cell landscape using the latest computational deconvolution methods. Results Medulloblastoma patients were found to express multiple private and shared immunogenic antigens. The proportion of predicted TAAs was higher than neoantigens and gene fusions for all molecular subgroups, except for sonic hedgehog (SHH), which had a higher neoantigen burden. Importantly, cancer-testis antigens, as well as previously unappreciated neurodevelopmental antigens, were found to be expressed by most patients across all medulloblastoma subgroups. Despite being immunologically cold, medulloblastoma subgroups were found to have distinct immune cell gene signatures. Conclusions Using a custom antigen prediction pipeline, we identified potential tumor rejection antigens with important implications for the development of immunotherapy for medulloblastoma.

•First trial on the impact of statins on pneumococcal polysaccharide vaccination.•Atorvastatin enhanced total pneumococcal-specific antibody response by 41.5%.•Atorvastatin enhanced primary humoral immunity to T cell-independent vaccination.•Statins may be a novel vaccine adjuvant. The immunomodulatory effects of statins on vaccine response remain uncertain. Therefore, the objective of this study was to determine if atorvastatin enhances pneumococcal-specific antibody titer following 23-valent pneumococcal polysaccharide vaccination. Double-blind, placebo-controlled, single-center randomized clinical trial entitled StatVax. Subjects were enrolled between June and July 2014 and followed up through September 2014. 33 healthy volunteers signed informed consent after volunteer sampling. 11 participants were excluded; 22 healthy volunteers without prior pneumococcal vaccination were enrolled and completed the study. Participants were randomized to receive a 28-day course of 40 mg atorvastatin (n = 12) or matching lactose placebo (n = 10). On day 7 of treatment, Pneumovax 23 was administered intramuscularly. The primary outcome was fold change in total pneumococcal-specific antibody titer determined by a ratio of post-vaccination titer over baseline titer. Secondary outcomes included serotype-specific pneumococcal antibody titer, seroconversion, complete blood counts (CBC), erythrocyte sedimentation rate (ESR), and serum cytokine analysis. Of the 22 randomized patients (mean age, 23.86; SD, 4.121; 11 women [50%]), 22 completed the trial. Total anti-pneumococcal antibody titer in the atorvastatin group went from a baseline mean of 32.58 (SD, 15.96) to 147.7 (SD, 71.52) μg/mL at 21 days post-vaccination while titer in the placebo group went from a mean of 30.81 (SD, 13.04) to 104.4 (SD, 45) μg/mL. When comparing fold change between treatment groups, there was a significant increase in fold change of total anti-pneumococcal antibody titer in the atorvastatin group compared to the placebo group (2-way ANOVA, p = .0177). Atorvastatin enhances antigen-specific primary humoral immune response to a T cell-independent pneumonia vaccination. Pending confirmation by larger cohort studies of target populations, peri-vaccination conventional doses of statins can become a novel adjuvant for poorly-immunogenic polysaccharide-based vaccines. Trial Registration: clinicaltrials.gov Identifier: NCT02097589

Chronic traumatic encephalopathy is a disease afflicting individuals exposed to repetitive neurotrauma. Unfortunately, diagnosis is made by postmortem pathologic analysis, and treatment options are primarily symptomatic. In this clinical update, we review clinical and pathologic diagnostic criteria and recommended symptomatic treatments. We also review animal models and recent discoveries from pre-clinical studies. Furthermore, we highlight the recent advances in diagnosis using diffusor tensor imaging, functional magnetic resonance imaging, positron emission tomography, and the fluid biomarkers t-tau, sTREM2, CCL11, NFL, and GFAP. We also provide an update on emerging pharmaceutical treatments, including immunotherapies and those that target tau acetylation, tau phosphorylation, and inflammation. Lastly, we highlight the current literature gaps and guide future directions to further improve clinical diagnosis and management of patients suffering from this condition.

Introduction Brain tumors remain especially challenging to treat due to the presence of the blood–brain barrier. The unique biophysical properties of nanomaterials enable access to the tumor environment with minimally invasive injection methods such as intranasal and systemic delivery. Methods In this review, we will discuss approaches taken in NP delivery to brain tumors in preclinical neuro-oncology studies and ongoing clinical studies. Results Despite recent development of many promising nanoparticle systems to modulate immunologic function in the preclinical realm, clinical work with nanoparticles in malignant brain tumors has largely focused on imaging, chemotherapy, thermotherapy and radiation. Conclusion Review of early preclinical studies and clinical trials provides foundational safety, feasibility and toxicology data that can usher a new wave of nanotherapeutics in application of immunotherapy and translational oncology for patients with brain tumors.

MD-PhD training programs train physician-scientists to pursue careers involving both clinical care and research, but decreasing numbers of physician-scientists stay engaged in clinical research. We sought to identify current clinical research training methods utilized by MD-PhD programs and to assess how effective they are in promoting self-efficacy for clinical research. The US MD-PhD students were surveyed in April-May 2018. Students identified the clinical research training methods they participated in, and self-efficacy in clinical research was determined using a modified 12-item Clinical Research Appraisal Inventory. Responses were received from 61 of 108 MD-PhD institutions. Responses were obtained from 647 MD-PhD students in all years of training. The primary methods of clinical research training included no clinical research training, and various combinations of didactics, mentored clinical research, and a clinical research practicum. Students with didactics plus mentored clinical research had similar self-efficacy as those with didactics plus clinical research practicum. Training activities that differentiated students who did and did not have the clinical research practicum experience and were associated with higher self-efficacy included exposure to Institutional Review Boards and participation in human subject recruitment. A clinical research practicum was found to be an effective option for MD-PhD students conducting basic science research to gain experience in clinical research skills. Clinical research self-efficacy was correlated with the amount of clinical research training and specific clinical research tasks, which may inform curriculum development for a variety of clinical and translational research training programs, for example, MD-PhD, TL1, and KL2.

OBJECTIVES/SPECIFIC AIMS: The study aims to determine the current clinical research training interventions of MD-PhD programs and how effective they are in promoting clinical research self-efficacy. METHODS/STUDY POPULATION: A national survey of MD-PhD trainees was conducted in 2018 to identify clinical research training methods and self-efficacy for clinical research skills. MD-PhD program directors and coordinators from 108 institutions were asked to distribute the survey to their students. Responses were received from 61 institutions (56.5%). Responses were obtained from 647 MD-PhD students in all years of training, representing 17.9% of the 3613 possible participants at the 61 medical schools represented. No compensation was provided for this study. RESULTS/ANTICIPATED RESULTS: The primary methods of clinical research training reported by students included didactics, mentored clinical research, didactics plus mentored clinical research, didactics plus clinical research practicum, and didactics plus mentored clinical research plus clinical research practicum. A quarter of all participants reported having no clinical research training. Clinical research self-efficacy was then correlated with the amount of clinical research training. Students exposed to no clinical research had the lowest self-efficacy in clinical research skills and students experiencing didactics plus mentored clinical research plus clinical research practicum had the highest perceived self-efficacy in clinical research domains. DISCUSSION/SIGNIFICANCE OF IMPACT: This is one of the first studies assessing clinical research training methods for MD-PhD students and assessing their efficacy. We found that of all students questioned, 25% mentioned had not received any type of clinical research training. The remaining students identified 5 research training methods that institutions currently use. This work highlights the importance of clinical research experience students need to improve their self-efficacy, a major influence on research career outcomes.