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Neoantigen-based adoptive T cell therapies (ACTs) represent a promising avenue in cancer immunotherapy due to their exquisite tumor specificity. The first cell-based immunotherapy for a solid tumor, comprising tumor-infiltrating lymphocytes, recently received FDA approval. Building on this, we designed a distinct ACT approach, where T cell responses against personalized neoantigens are systematically generated from autologous peripheral blood. Here we report the establishment of NEO-STIM, an ex vivo induction process to prime and expand pre-existing memory and de novo CD8 + and CD4 + T cell responses, thereby highlighting critical parameters for generating potent neoantigen-specific T cell responses. The drug products comprise mutant-reactive, polyfunctional, and cytotoxic CD8 + and CD4 + T cells, able to recognize autologous tumor material. Following infusion, T cell responses are detected in tumor and blood of a patient, and display activated/exhausted and cytotoxic phenotypes. A first-in-human clinical trial (NCT04625205) recently further validated proof-of-concept, supporting continued development of this ACT approach. Neoantigen-based adoptive T cell therapies represent a personalized approach for cancer immunotherapy. Here the authors describe NEO-STIM, an ex vivo T cell induction platform to STIMulate peripheral blood T cells to generate responses against tumor NEOantigens.

BackgroundChimeric Antigen Receptor (CAR) therapy has had a transformative impact on the treatment of hematologic malignancies1–6 but success in solid tumors remains elusive. We hypothesized solid tumors have cell-intrinsic resistance mechanisms to CAR T-cell cytotoxicity.MethodsTo systematically identify resistance pathways, we conducted a genome-wide CRISPR knockout screen in glioblastoma cells, a disease where CAR T-cells have had limited efficacy.7 8 We utilized the glioblastoma cell line U87 and targeted endogenously expressed EGFR with CAR T-cells generated from 6 normal donors for the screen. We validated findings in vitro and in vivo across a variety of human tumors and CAR T-cell antigens.ResultsLoss of genes in the interferon gamma receptor (IFNγR) signaling pathway (IFNγR1, JAK1, JAK2) rendered U87 cells resistant to CAR T-cell killing in vitro. IFNγR1 knockout tumors also showed resistance to CAR T cell treatment in vivo in a second glioblastoma line U251 in an orthotopic model. This phenomenon was irrespective of CAR target as we also observed resistance with IL13Ralpha2 CAR T-cells. In addition, resistance to CAR T-cell cytotoxicity through loss of IFNγR1 applied more broadly to solid tumors as pancreatic cell lines targeted with either Mesothelin or EGFR CAR T-cells also showed resistance. However, loss of IFNγR signaling did not impact sensitivity of liquid tumor lines (leukemia, lymphoma or multiple myeloma) to CAR T-cells in vitro or in an orthotopic model of leukemia treated with CD19 CAR. We isolated the effects of decreased cytotoxicity of IFNγR1 knockout glioblastoma tumors to be cancer-cell intrinsic because CAR T-cells had no observable differences in proliferation, activation (CD69 and LFA-1), or degranulation (CD107a) when exposed to wildtype versus knockout tumors. Using transcriptional profiling, we determined that glioblastoma cells lacking IFNγR1 had lower upregulation of cell adhesion pathways compared to wildtype glioblastoma cells after exposure to CAR T-cells. We found that loss of IFNγR1 reduced CAR T-cell binding avidity to glioblastoma.ConclusionsThe critical role of IFNγR signaling for susceptibility of solid tumors to CAR T-cells is surprising given that CAR T-cells do not require traditional antigen-presentation pathways. Instead, in glioblastoma tumors, IFNγR signaling was required for sufficient adhesion of CAR T-cells to mediate productive cytotoxicity. Our work demonstrates that liquid and solid tumors differ in their interactions with CAR T-cells and suggests that enhancing T-cell/tumor interactions may yield improved responses in solid tumors.AcknowledgementsRCL was supported by T32 GM007306, T32 AI007529, and the Richard N. Cross Fund. ML was supported by T32 2T32CA071345-21A1. SRB was supported by T32CA009216-38. NJH was supported by the Landry Cancer Biology Fellowship. JJ is supported by a NIH F31 fellowship (1F31-MH117886). GG was partially funded by the Paul C. Zamecnik Chair in Oncology at the Massachusetts General Hospital Cancer Center and NIH R01CA 252940. MVM and this work is supported by the Damon Runyon Cancer Research Foundation, Stand Up to Cancer, NIH R01CA 252940, R01CA238268, and R01CA249062.ReferencesMaude SL, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 2018;378:439–448.Neelapu SS, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 2017;377:2531–2544.Locke FL, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. The Lancet Oncology 2019;20:31–42.Schuster SJ, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med 2017;377:2545–2554.Wang M, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2020;382:1331–1342.Cohen AD, et al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J Clin Invest 2019;129:2210–2221.Bagley SJ, et al. CAR T-cell therapy for glioblastoma: recent clinical advances and future challenges. Neuro-oncology 2018;20:1429–1438.Choi BD, et al. Engineering chimeric antigen receptor T cells to treat glioblastoma. J Target Ther Cancer 2017;6:22–25.Ethics ApprovalAll human samples were obtained with informed consent and following institutional guidelines under protocols approved by the Institutional Review Boards (IRBs) at the Massachusetts General Hospital (2016P001219). Animal work was performed according to protocols approved by the Institutional Animal Care and Use Committee (IACUC) (2015N000218 and 2020N000114).

Chimeric antigen receptor (CAR) therapy has had a transformative effect on the treatment of haematologic malignancies 1 – 6 , but it has shown limited efficacy against solid tumours. Solid tumours may have cell-intrinsic resistance mechanisms to CAR T cell cytotoxicity. Here, to systematically identify potential resistance pathways in an unbiased manner, we conducted a genome-wide CRISPR knockout screen in glioblastoma, a disease in which CAR T cells have had limited efficacy 7 , 8 . We found that the loss of genes in the interferon-γ receptor (IFNγR) signalling pathway ( IFNGR1 , JAK1 or JAK2 ) rendered glioblastoma and other solid tumours more resistant to killing by CAR T cells both in vitro and in vivo. However, loss of this pathway did not render leukaemia or lymphoma cell lines insensitive to CAR T cells. Using transcriptional profiling, we determined that glioblastoma cells lacking IFNγR1 had lower upregulation of cell-adhesion pathways after exposure to CAR T cells. We found that loss of IFNγR1 in glioblastoma cells reduced overall CAR T cell binding duration and avidity. The critical role of IFNγR signalling in susceptibility of solid tumours to CAR T cells is surprising, given that CAR T cells do not require traditional antigen-presentation pathways. Instead, in glioblastoma tumours, IFNγR signalling was required for sufficient adhesion of CAR T cells to mediate productive cytotoxicity. Our work demonstrates that liquid and solid tumours differ in their interactions with CAR T cells and suggests that enhancing binding interactions between T cells and tumour cells may yield improved responses in solid tumours. A genome-wide CRISPR knockout screen in a model of glioblastoma shows that killing by chimeric antigen receptor T cells requires interferon-γ receptor-dependent adhesion to tumour cells, but cytotoxicity of liquid tumours does not rely on this pathway.

In 2014, the Centers for Disease Control and Prevention (CDC) launched “A Comprehensive Approach to Good Health and Wellness in Indian County” (GHWIC) to promote health and chronic disease prevention in tribal communities while facilitating cross-cultural learning and relationship-building. Through GHWIC, CDC aimed to work with American Indian and Alaska Native communities to identify effective health promotion strategies to address chronic disease disparities. Tribal sovereignty, community context, and consideration of tribal histories (e.g., oppression, genocide, and cultural erasure) are key to health improvement efforts and work with tribes. These elements center experience, knowledge, and self-determination to reclaim good health and wellness as Indigenous peoples see it. The Implementation Reflection Project was a qualitative inquiry composed of one-on-one discussions and small group sessions conducted to explore experiences of CDC staff, national partners, and tribal recipients as they implemented GHWIC program activities. The Project documented observations and recommendations for future tribal health funding efforts and identified best practices for effective partnerships with tribes and tribal organizations. Findings centered around tribal experiences with GHWIC, improved program processes, the importance of relationships, and the effects of internal capacity on implementation. Key suggestions for future work with tribal entities included simplifying and clarifying roles, expectations, and administration requirements, and establishing clear and consistent communication between program partners. The approach CDC used with GHWIC recipients was effective and respectful, but room for growth remains. Potential future collaborators in Indian Country should consider these findings when planning health promotion initiatives.

Approximately, 80,000 Americans are affected by sickle cell disease (SCD) and it is the most common inherited blood disorder in the United States. SCD is most prevalent among individuals of African, Mediterranean, Middle Eastern, and Asian Indian ancestry; however, statistics suggest that in the United States, African Americans are disproportionately affected by SCD (Sickle Cell Disease Association of America (SCDAA), 2007). Nearly, 1 in 400 African Americans is born with SCD; in addition, 1 in 12 African Americans is born with sickle cell trait (SCT) (National Human Genome Research Institute (NHGRI), 2007). Two carriers of the trait have a 25% chance of having an unaffected child, a 50% chance of having a child who is also a carrier, and a 25% chance of having a child with SCD. However, many African Americans lack knowledge about SCD and SCT and are unaware of their carrier status. The purpose of this two-phased sequential mixed methods study was to explore African American college students’ beliefs, attitudes, and knowledge of sickle cell disease (SCD) genetics, and of sickle cell trait (SCT) and SCD carrier testing. This purpose was accomplished by surveying 191 African American men and women between the ages of 19 and 30 years and then exploring those results in more depth through follow-up interviews with 8 purposefully selected individuals from the first phase. In the 1st phase, quantitative research questions addressed the relationship of African American college students’ current level of knowledge and attitude about SCD and SCT, attitude toward SCD carrier testing, and their intention to participate in carrier testing at various sites. A stepwise multiple regression analysis was used to determine which of these variables contributed most significantly to the participants’ decision to participate in carrier testing. In the 2nd phase, qualitative interviews with purposefully sampled individuals who participated in testing were used to explore the significance of participants’ attitude toward carrier testing. There have been few studies published that examined the knowledge and beliefs of young adults regarding SCD and SCD carrier testing. It was determined that the major factors that contributed to the students’ intention to participate in SCD carrier testing were attitude toward carrier testing, lack of knowledge regarding SCD and SCD carrier status, family history, cost, time and opportunity. It was revealed that the participants supported carrier testing and viewed SCD carrier testing for young adults as valuable. However, greater community health education about SCD and SCD carrier testing was desired. The implications for health education and promotion research are to (a) increase the SCD genetic knowledge of young adults in the African American community and (b) increase opportunities for minority populations to be informed of SCD carrier testing.

How well do serum samples from persons vaccinated with the mRNA-1273 vaccine neutralize the P.1 lineage, the B.1.1.7 lineage, the B.1.1.7 lineage plus the E484K mutation, the B.1.351 lineage, and the B.1.427/B.1.429 lineage of SARS-CoV-2? This study provides an answer.

Abstract For nearly 450 million years, mycorrhizal fungi have constructed networks to collect and trade nutrient resources with plant roots 1,2 . Owing to their dependence on host-derived carbon, these fungi face conflicting trade-offs in building networks that balance construction costs against geographical coverage and long-distance resource transport to and from roots 3 . How they navigate these design challenges is unclear 4 . Here, to monitor the construction of living trade networks, we built a custom-designed robot for high-throughput time-lapse imaging that could track over 500,000 fungal nodes simultaneously. We then measured around 100,000 cytoplasmic flow trajectories inside the networks. We found that mycorrhizal fungi build networks as self-regulating travelling waves—pulses of growing tips pull an expanding wave of nutrient-absorbing mycelium, the density of which is self-regulated by fusion. This design offers a solution to conflicting trade demands because relatively small carbon investments fuel fungal range expansions beyond nutrient-depletion zones, fostering exploration for plant partners and nutrients. Over time, networks maintained highly constant transport efficiencies back to roots, while simultaneously adding loops that shorten paths to potential new trade partners. Fungi further enhance transport flux by both widening hyphal tubes and driving faster flows along ‘trunk routes’ of the network 5 . Our findings provide evidence that symbiotic fungi control network-level structure and flows to meet trade demands, and illuminate the design principles of a symbiotic supply-chain network shaped by millions of years of natural selection.

A 3D vertical seismic profiling (VSP) survey was acquired using a distributed acoustic sensing (DAS) system in the Permian Basin, West Texas. In total, 682 shot points from a pair of vibroseis units were recorded using optical fibers installed in a 9000 ft (2743 m) vertical part and 5000 ft (1524 m) horizontal reach of a well. Transmitted and reflected P, S, and converted waves were evident in the DAS data. From first-break P and S arrivals, we found average P-wave velocities of approximately 14,000 ft/s (4570 m/s) and S-wave velocities of 8800 ft/s (3000 m/s) in the deep section. We modified the conventional geophone VSP processing workflow and produced P–P reflection and P–S volumes derived from the well’s vertical section. The Wolfcamp formation can be seen in two 3D volumes (P–P and P–S) from the vertical section of the well. They cover an area of 3000 ft (914 m) in the north–south direction and 1500 ft (460 m) in the west–east direction. Time slices showed coherent reflections, especially at 1.7 s (~11,000 ft), which was interpreted as the bottom of the Wolfcamp formation. Vp/Vs values from 2300 ft (701 m) –8800 ft (2682 m) interval range were between 1.7 and 2.0. These first data provide baseline images to compare to follow-up surveys after hydraulic fracturing as well as potential usefulness in extracting elastic properties and providing further indications of fractured volumes.

Tomato spotted wilt tospovirus (TSWV), one of the most important plant viruses, causes yield losses to many crops including tomato. The current disease management for TSWV is based mainly on breeding tomato cultivars containing the Sw- 5 locus. Unfortunately, several Sw-5 resistance-breaking strains of TSWV have been identified. Sw-7 is an alternative locus conferring resistance to a broad range of TSWV strains. In an effort to uncover gene networks that are associated with the Sw-7 resistance, we performed a comparative transcriptome profiling and gene expression analysis between a nearly-isogenic Sw-7 line and its susceptible recurrent parent (Fla. 8059) upon infection by TSWV. A total of 1,244 differentially expressed genes were identified throughout a disease progression process involving networks of host resistance genes, RNA silencing/antiviral defense genes, and crucial transcriptional and translational regulators. Notable induced genes in Sw-7 include those involved in callose accumulation, lignin deposition, proteolysis process, transcriptional activation/repression, and phosphorylation. Finally, we investigated potential involvement of PR-5 in the Sw-7 resistance. Interestingly, PR-5 overexpressed plants conferred enhanced resistance, resulting in delay in virus accumulation and symptom expression. These findings will facilitate breeding and genetic engineering efforts to incorporate this new source of resistance in tomato for protection against TSWV.

A 2D walkway vertical seismic profile (VSP) survey was conducted using a distributed acoustic sensing (DAS) system in southwest Utah, which is part of an enhanced geothermal system (EGS) project. The VSP was undertaken to obtain detailed structural information for a better understanding of the area’s subsurface geology and associated fracture development. By combining a 3D composite velocity model from previous studies and considering the complex geological structure beneath this region, we processed the data to create P-P depth image. We also modified the interval Q calculation using a moving window over the gauge-length corrected DAS record to generate the velocity profile and the comparable interval attenuation curve. The correlated P-P images from two DAS records successfully indicate not only the main contact between shallow unconsolidated sediments and the metamorphic basement rocks at 2650 ft (807.72 m) but also several distinct reflections related to the geological contacts. The refined velocity profiles and the depth images can provide baseline results for further seismic modeling and time-lapse imaging.