Nicholas Petty

The modern stock market is a popular place to increase wealth and generate income, but the fundamental problem of when to buy or sell shares, or which stocks to buy has not been solved. With the availability of the Internet and its financial social networks, such as StockTwits and SeekingAlpha, investors around the world have new opportunities to gather and share their experiences. Individual experts can predict the movement of the stock market in financial social networks with reasonable accuracy, but how accurate is a large group of such experts in aggregate? One way to answer this question is by examining the sentiment of a massive group of these authors towards various stocks. By extracting the sentiment of the whole group, a collective prediction can be observed. Although sentiment extraction is a major technical challenge, the lexicon-based approach is an effective method of determining how positive or negative the content of a text document is. In this paper, we investigate if we can improve the performance of sentiment extraction from financial social media data by using lexicon-based approaches.

Current immunotherapeutic targets are often shared between neoplastic and normal hematopoietic stem and progenitor cells (HSPCs), leading to unwanted on-target, off-tumor toxicities. Deletion or modification of such targets to protect normal HSPCs is, therefore, of great interest. Although HSPC modifications commonly aim to mimic naturally occurring phenotypes, the long-term persistence and safety of gene-edited cells need to be evaluated. Here, we deleted the V-set domain of CD33, the immune-dominant domain targeted by most anti-CD33 antibodies used to treat CD33-positive malignancies, including acute myeloid leukemia, in the HSPCs of two rhesus macaques, performed autologous transplantation after myeloablative conditioning, and followed the animals for up to 3 years. CD33-edited HSPCs engrafted without any delay in recovery of neutrophils, the primary cell type expressing CD33. No impact on the blood composition, reconstitution of the bone marrow stem cell compartment, or myeloid differentiation potential was observed. Up to 20% long-term gene editing in HSPCs and blood cell lineages was seen with robust loss of CD33 detection on myeloid lineages. In conclusion, deletion of the V-set domain of CD33 on HSPCs, progenitors, and myeloid lineages did not show any adverse effects on their homing and engraftment potential or the differentiation and functionality of myeloid progenitors and lineages.

Abstract Despite recent advances in T cell immunotherapy for the treatment of human cancer, metastatic solid tumors remain an intractable challenge. Macrophages are usually the most abundant immune cell in the tumor microenvironment (TME) where, as immunosuppressive tumor-associated macrophages (TAMs), they participate in disease progression. The current goals of macrophage-based immunotherapies are to reduce TAM infiltration or enhance TAM phagocytosis. In contrast, we have developed a new paradigm based on the adoptive transfer of genetically engineered chimeric antigen receptor (CAR) macrophages (CAR-M) for the treatment of human cancer. CAR-M can only be produced using a unique adenoviral vector, since human macrophages are highly resistant to other methods of gene transfer. We have previously shown that the primary mechanism of action of CAR-M is phagocytosis, and that a single dose of primary human anti-HER2 CAR-M led to significantly improved overall survival in multiple xenograft models. We now establish that Ad5f35-transduced anti-HER2 CAR-M (CT-0508) adopt a unique proinflammatory and antitumor M1 phenotype. Functional evaluation and RNA sequencing revealed that CT-0508 maintain a proinflammatory M1 phenotype despite challenge with immunosuppressive environments in vitro, highlighting their resistance to subversion. By engrafting immunodeficient mice with human hematopoietic cells and human cancer cells, we established a novel xenografted human TME model. We demonstrate with single-cell resolution that CT-0508 maintain their phenotype within the human TME. Additionally, CT-0508 activated the human TME and generated an activated human dendritic cell signature. To further investigate the potential of CT-0508 for TME activation, we modeled the interaction of CT-0508 with immunosuppressive macrophages, dendritic cells, and T cells. CT-0508 shifted bystander macrophages toward a proinflammatory phenotype, induced activation and maturation markers on DCs, and recruited resting as well as activated T cells in chemotaxis assays. Lastly, CT-0508 demonstrated enhanced antigen presentation when compared to control human macrophages. These results show that in addition to direct antitumor activity, the anti-HER2 CAR macrophage cell product CT-0508 is capable of activating the solid cancer TME and promoting a proinflammatory phenotype. The safety of CT-0508 will be evaluated in an upcoming first-in-human phase I clinical trial. Citation Format: Konrad Gabrusiewicz, Nicholas Anderson, Xueqing Lu, Xinhe Shan, Olga Shestova, Nicholas Petty, Feng Shen, Maggie Schmierer, Andrew Best, Martha Zeeman, Yumi Ohtani, Katherine Cummins, Saar Gill, Michael Klichinsky. CT-0508, a novel CAR macrophage product directed against HER2, promotes a proinflammatory tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B65.

Background: Ex vivo gene-modified autologous cell products are increasingly explored to cure monogenic disorders (e.g. sickle cell disease, thalassemia). Efficient removal of bone marrow (BM)-resident hematopoietic stem/progenitor cells (HSPCs) is a requirement for successful engraftment of such cell products. To accomplish this, various conditioning regimens have been utilized, each with their own unique profile of target specificity and on- and off-target toxicities. Currently most widely used is busulfan but unwanted non-hematologic toxicities have provided the impetus to develop more specific approaches that spare normal tissues better. Monoclonal antibodies (mAbs) conjugated with either small molecule toxins or radionuclides to selectively target phenotypically distinct cells have gained attention for this purpose. Of particular interest as target is CD45, a glycoprotein expressed at very high copy number exclusively on almost all blood cells. CD45-targeted radioimmunotherapy (RIT) with the beta-emitter, iodine-131, has proven effective to augment conditioning before allogeneic hematopoietic cell transplantation (HCT). Here, we evaluated CD45-directed RIT using a the highly potent alpha emitter, astatine-211 (211At) as payload as sole conditioning agent before autologous HCT of ex vivo gene-edited HSPCs in a nonhuman primate (NHP) HCT and gene therapy model. Methods: A humanized version of the human/NHP cross-reactive CD45 mAb, BC8 (HuBC8), was conjugated with isothiocyanatophenethyl-ureido-closo-decaborate(2-) (HuBC8-B10), a boron cage molecule to enable subsequent labeling with 211At as done in our early phase clinical trials. Simultaneously, NHP CD34+ cells were mobilized with G-CSF/AMD3100, collected via leukapheresis, and cryopreserved after being gene modified ex vivo using adenine base editors to reactivate fetal hemoglobin (HBG) production as well as to delete CD33. 72 hours after administration of a single dose of 211At-labeled HuBC8-B10, gene-edited CD34+ cells were thawed and infused. Animals received 300 µCi/kg (n=2) or 400 µCi/kg (n=1) of 211At with 0.5 mg/kg of HuBC8-B10. All animals were monitored for toxicities, and blood count recovery as well as engraftment of gene-modified HSPCs and blood lineages which were assessed serially using flow cytometry and next generation sequencing. Results: The editing efficiency of CD33 and HBG in the infusion product ranged from 50-77% and 15-38%, respectively, with no measurable impact on cell viability or erythro-myeloid differentiation potential of edited cells in colony-forming cell assays. A total of 2-4x106 CD34+ cells/kg were infused into the animals and rapid recovery of neutrophils and platelets seen in between 6-8 and 10-13 days, respectively. Transient weight loss over the first 20-30 days was seen (n=3) and gastric ulcer treatment needed (n=1). An 211At dose of 300 µCi/kg led to incomplete myeloablation with neutrophils remaining above 400/µl, whereas full myeloablation was seen at a dose of 400 µCi/kg. Ablation of monocytes, lymphocytes, and platelets was seen in all animals, whereas CD45-negative erythrocytes were spared and the hemoglobin remaining stable throughout the study. Two animals were entirely transfusion-independent and the third animal receive a single platelet transfusion. Dose-dependent engraftment of gene-editing in the peripheral blood was seen with 20-40% CD33-negative cells and 5-10% HBF reactivation in the two animals receiving 211At at 300 µCi/kg as compared to 80% of CD33-negative cells and 20% HBF reactivation in the single animal receiving 211At at 400 µCi/kg. Full recovery of the BM stem cell compartment was confirmed at 3-month post-transplant by flow cytometry. Conclusion: CD45-targeted alpha emitter-based RIT with 211At enables stable engraftment of ex vivo gene-edited autologous stem cell products. Our studies identify 211At-CD45 RIT as a targeted alternative for myeloablative conditioning followed by autologous transplantation of gene-modified HSPCs. 211At-HuBC8-B10 is well tolerated with only minimal adverse reactions observed in NHPs. While 211At-CD45 RIT demonstrates selective depletion of CD45-positive white blood cells as well as HSPCs in the BM, CD45-negative erythrocytes are spared, likely contributing to the minimal supportive care needs needed following autografting.