Diffuse Atomic and Molecular Gas in the Interstellar Medium of M82 toward SN 2014J

We present a comprehensive analysis of interstellar absorption lines seen in moderately-high resolution, high signal-to-noise ratio optical spectra of SN 2014J in M82. Our observations were acquired over the course of six nights, covering the period from ~6 days before to ~30 days after the supernova reached its maximum B-band brightness. We examine complex absorption from Na I, Ca II, K I, Ca I, CH+, CH, and CN, arising primarily from diffuse gas in the interstellar medium (ISM) of M82. We detect Li I absorption over a range in velocity consistent with that exhibited by the strongest Na I and K I components associated with M82; this is the first detection of interstellar Li in a galaxy outside of the Local Group. There are no significant temporal variations in the absorption-line profiles over the 37 days sampled by our observations. The relative abundances of the various interstellar species detected reveal that the ISM of M82 probed by SN 2014J consists of a mixture of diffuse atomic and molecular clouds characterized by a wide range of physical/environmental conditions. Decreasing N(Na I)/N(Ca II) ratios and increasing N(Ca I)/N(K I) ratios with increasing velocity are indicative of reduced depletion in the higher-velocity material. Significant component-to-component scatter in the N(Na I)/N(Ca II) and N(Ca I)/N(Ca II) ratios may be due to variations in the local ionization conditions. An apparent anti-correlation between the N(CH+)/N(CH) and N(Ca I)/N(Ca II) ratios can be understood in terms of an opposite dependence on gas density and radiation field strength, while the overall high CH+ abundance may be indicative of enhanced turbulence in the ISM of M82. The Li abundance also seems to be enhanced in M82, which supports the conclusions of recent gamma-ray emission studies that the cosmic-ray acceleration processes are greatly enhanced in this starburst galaxy.Comment: 32 pages, 6 figures, accepted to ApJ; added table giving single-epoch equivalent widths; improved discussion regarding the lack of temporal variations; improved analysis of the Li I regio

Effect of epigallocatechin-3-gallate on graft-versus-host disease

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is often complicated by alloreactive donor T cell-mediated graft-versus-host disease (GvHD). The major polyphenol of green tea, epigallocatechin-3-gallate (EGCG), is an inhibitor of both DNA methyltransferase 1 (DNMT1) and signal transducer and activator of transcription 1 (STAT1), which are essential for induction of GvHD. Thus, in this report, we examine if in vivo administration of EGCG mitigates GvHD in several different animal models. While we concede that refinement of EGCG treatment might result in GvHD prevention, our results suggest that EGCG treatment might not be an effective therapy against GvHD in the clinic

Liposomal phytohemagglutinin: In vivo T-cell activator as a novel pan-cancer immunotherapy

Immunotherapy is an attractive approach for treating cancer. T-cell engagers (TCEs) are a type of immunotherapy that are highly efficacious; however, they are challenged by weak T-cell activation and short persistence. Therefore, alternative solutions to induce greater activation and persistence of T cells during TCE immunotherapy is needed. Methods to activate T cells include the use of lectins, such as phytohemagglutinin (PHA). PHA has not been used to activate T cells in vivo, for immunotherapy, due to its biological instability and toxicity. An approach to overcome the limitations of PHA while also preserving its function is needed. In this study, we report a liposomal PHA which increased PHA stability, reduced toxicity and performed as an immunotherapeutic that is able to activate T cells for the use in future cancer immunotherapies to circumvent current obstacles in immunosuppression and T-cell exhaustion

CD7-deleted hematopoietic stem cells can restore immunity after CAR T cell therapy

Targeting T cell malignancies with universal CD7-targeting chimeric antigen receptor T cells (UCART7) can lead to profound immune deficiency due to loss of normal T and NK cells. While a small population of endogenous CD7- T cells exists, these cells are unlikely to be able to repopulate the entire immune repertoire after UCART7 treatment, as they are limited in number and proliferative capacity. To rescue T and NK cells after UCART7, we created hematopoietic stem cells genetically deleted for CD7 (CD7-KO HSCs). CD7-KO HSCs were able to engraft immunodeficient mice and differentiate into T and NK cells lacking CD7 expression. CD7-KO T and NK cells could perform effector functions as robustly as control T and NK cells. Furthermore, CD7-KO T cells were phenotypically and functionally distinct from endogenous CD7- T cells, indicating that CD7-KO T cells can supplement immune functions lacking in CD7- T cells. Mice engrafted with CD7-KO HSCs maintained T and NK cell numbers after UCART7 treatment, while these were significantly decreased in control mice. These studies support the development of CD7-KO HSCs to augment host immunity in patients with T cell malignancies after UCART7 treatment

Ablation of VLA4 in multiple myeloma cells redirects tumor spread and prolongs survival

Multiple myeloma (MM) is a cancer of bone marrow (BM) plasma cells, which is increasingly treatable but still incurable. In 90% of MM patients, severe osteolysis results from pathological interactions between MM cells and the bone microenvironment. Delineating specific molecules and pathways for their role in cancer supportive interactions in the BM is vital for developing new therapies. Very Late Antigen 4 (VLA4, integrin

Antibody-drug conjugates plus Janus kinase inhibitors enable MHC-mismatched allogeneic hematopoietic stem cell transplantation

Despite the curative potential of hematopoietic stem cell transplantation (HSCT), conditioning-associated toxicities preclude broader clinical application. Antibody-drug conjugates (ADCs) provide an attractive approach to HSCT conditioning that minimizes toxicity while retaining efficacy. Initial studies of ADC conditioning have largely focused on syngeneic HSCT. However, to treat acute leukemias or induce tolerance for solid organ transplantation, this approach must be expanded to allogeneic HSCT (allo-HSCT). Using murine allo-HSCT models, we show that pharmacologic Janus kinase 1/2 (JAK1/2) inhibition combined with CD45- or cKit-targeted ADCs enables robust multilineage alloengraftment. Strikingly, myeloid lineage donor chimerism exceeding 99% was achievable in fully MHC-mismatched HSCT using this approach. Mechanistic studies using the JAK1/2 inhibitor baricitinib revealed marked impairment of T and NK cell survival, proliferation, and effector function. NK cells were exquisitely sensitive to JAK1/2 inhibition due to interference with IL-15 signaling. Unlike irradiated mice, ADC-conditioned mice did not develop pathogenic graft-versus-host alloreactivity when challenged with mismatched T cells. Finally, the combination of ADCs and baricitinib balanced graft-versus-host disease and graft-versus-leukemia responses in delayed donor lymphocyte infusion models. Our allo-HSCT conditioning strategy exemplifies the promise of immunotherapy to improve the safety of HSCT for treating hematologic diseases

CS1 CAR-T targeting the distal domain of CS1 (SLAMF7) shows efficacy in high tumor burden myeloma model despite fratricide of CD8+CS1 expressing CAR-T cells

Despite improvement in treatment options for myeloma patients, including targeted immunotherapies, multiple myeloma remains a mostly incurable malignancy. High CS1 (SLAMF7) expression on myeloma cells and limited expression on normal cells makes it a promising target for CAR-T therapy. The CS1 protein has two extracellular domains - the distal Variable (V) domain and the proximal Constant 2 (C2) domain. We generated and tested CS1-CAR-T targeting the V domain of CS1 (Luc90-CS1-CAR-T) and demonstrated anti-myeloma killing in vitro and in vivo using two mouse models. Since fratricide of CD8 + cells occurred during production, we generated fratricide resistant CS1 deficient Luc90- CS1- CAR-T (ΔCS1-Luc90- CS1- CAR-T). This led to protection of CD8 + cells in the CAR-T cultures, but had no impact on efficacy. Our data demonstrate targeting the distal V domain of CS1 could be an effective CAR-T treatment for myeloma patients and deletion of CS1 in clinical production did not provide an added benefit using in vivo immunodeficient NSG preclinical models