Induction of Anti-Cancer Effects by Targeting Alloreactive Intentionally Mismatched T Cells and NK Cells to Tumor Cells Using Bi-Specific Trifunctional Antibodies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3245-3245
Author(s):  
Shoshana Morecki ◽  
Horst Lindhofer ◽  
Elena Yacovlev ◽  
Yael Gelfand ◽  
Shimon Slavin
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Tumor Cell ◽  
Nk Cells ◽  
Tumor Cells ◽  
Bispecific Antibody ◽  
Tumor Inoculation ◽  
Anti Cancer ◽  
Second Tumor ◽  
Donor Lymphocytes

Abstract Engraftment of donor stem cells induces host vs graft unresponsiveness thus allowing durable engraftment of donor lymphocytes which can induce graft vs malignancy (GVM) effects following transplantation of MHC compatible donor stem cells. Unfortunately, graft vs host disease (GVHD) frequently results in major toxicity and mortality and limits the clinical efficacy of cell therapy. Although the intensity of GVM effects can be improved by using mismatched donors GVM effects cannot be induced in recipients of haploidentically mismatched allografts because of anticipated lethal GVHD. We have attempted to induce GVM effects by intentionally mismatched donor lymphocytes by targeting donor derived T cells and NK cells activated by rIL-2 to cancer cells, in order to improve the efficacy of the GVL effects on the one hand and prevent or minimize GVHD by targeting alloreactive cells to the tumor cells that need to be eliminated using bispecific tri-functional antibodies, on the other. A trifunctional bispecific antibody (BiLu) directed against murine CD3 and human epithelial-cell adhesion molecule (EpCAM), was administered concomitantly with naïve or IL-2 activated donor splenocytes to mice inoculated with a murine model of melanoma cells transfected with human EpCAM (B16-EpCAM). A total of 10/20 and 32/38 mice treated with BiLu and naïve or IL-2 activated donor splenocytes, respectively, were tumor-free survivors without GVHD for >250 days following tumor inoculation. Out of 28 of the disease free survivors (DFS) without GVHD, treated with IL-2 activated splenocytes and BiLu, 24 mice were resistant to a second tumor inoculum (104) given >250 days following the first tumor inoculation. In contrast, only 8 of the 18 DFS mice treated with naïve splenocytes and BiLu, and 5 of the 10 DFS controls treated with BiLu only, resisted the second tumor challenge. Induction of anti-tumor immunity by IL-2 activated cells and BiLu was more efficient and long-lasting in mice previously injected with a lethal first tumor cell dose (5×104) than in mice inoculated with a sub-lethal tumor cell dose (5×103). Interestingly, a similar infusion of donor cells labeled with bi-specific anti-EpCAM and anti-CD3 following allogeneic stem cell transplantation for metastatic breast cancer did not result in augmentation of GVHD. In conclusion, concomitant inoculation of alloreactive donor lymphocytes and trifunctional bispecific antibody can be effective for targeting of killer T and NK cells to tumor cells while avoiding GVHD, as well as for induction of long-lasting anti-cancer immunity, most likely due to presentation of tumor antigen to T cells by antigen presenting cells (dendritic cells) expressing Fc receptor binding to the Fc portion of the bi-specific antibody.

NK Cells Derived from Human Embryonic Stem Cells Demonstrate More Effective In Vivo Clearance of Xenografted Human Tumor Cells Compared to NK Cells Derived from Cord Blood.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2745-2745 ◽  
Author(s):  
Petter S. Woll ◽  
Rebecca Marcus ◽  
Dan S. Kaufman
Keyword(s):  
Stem Cells ◽  
Nk Cells ◽  
Tumor Cells ◽  
Human Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Human Tumor ◽  
Cytolytic Activity ◽  
Tumor Inoculation ◽  
Human Tumor Cells

Abstract The derivation of both myeloid and lymphoid cells from human embryonic stem cells (hESCs) clearly establish hESCs as an important model system to study human hematopoietic ontogeny. However, the potential for clinical applications of hESC-derived hematopoietic cells still remain poorly characterized. Here we have analyzed the efficacy of hESC-derived natural killer (NK) cells in a model of anti-tumor immunotherapy. hESC-derived NK cells were compared to NK cells derived from human umbilical cord blood (UCB) for ability to clear both established human tumors and metastatic disease in an in vivo model. Using a two-step differentiation process, we have demonstrated effective derivation of NK cells from hESCs. The hESC-derived NK cells express activating and inhibitory receptors similar to NK cells derived from UCB. These receptors include C-type lectin-like receptors, natural cytotoxicity receptors, CD16 and diverse killer-cell Ig-like receptors. More importantly, the hESC-derived NK cells also demonstrate cytokine production and potent direct cytolytic activity against multiple types of tumors, including leukemia, lymphoma, glioma, testicular cancer and breast cancer cells lines. This in vitro cytolytic activity is similar to what found for UCB-derived NK cells cultured in identical conditions. To advance these studies to a more relevant pre-clinical model, we have now investigated the in vivo activity of hESC-derived NK cells in a xenogeneic mouse model. Here, K562 erythroleukemia cells stably expressing firefly luciferase (luc) were injected subcutaneously into sub-lethally irradiated NOD/SCID mice. The luc+ K562 cells allows serial bioluminescent imaging to follow growth of the tumor cells non-invasively over a prolonged time course, as well as sensitive detection of micro-metastasis. Three days after tumor-inoculation, mice received one of three treatment courses: NK cells derived from hESCs, NK cells derived from UCB, or no cells. Each group received ip injections of IL-15 every 2–3 days for the first 7 days after treatment, then IL-2 every 2–3 days for an additional 2 weeks. In this model, mice that received cytokine treatment but did not receive NK cells (n=11) consistently developed large tumors within three weeks. Remarkably, all mice treated with hESC-derived NK cells demonstrated complete clearance of the primary tumor two weeks after tumor inoculation (n=8). In contrast, mice treated with UCB-derived NK cells had significantly less anti-tumor activity in vivo, with only 50% tumor-free animals treated with UCB-derived NK cells (n=8). Some mice treated with hESC-derived NK cells were monitored up to 8 weeks with no evidence of tumor development. Furthermore, liver, lungs, spleen and kidneys were harvested at the time of sacrifice and analyzed for presence of micro-metastasis by detection of luc. In animals receiving cytokines alone, 50% of the organs analyzed displayed metastatic presence of luc+ cells. However, there was a significant reduction of metastases in UCB-NK-treated (9%) and hESC-NK-treated (4%) animals. These results suggest that hESC-derived NK cells are capable of clearing human tumor cells in vivo more effectively than UCB-derived NK cells. Current studies are underway to investigate in vivo activity of hESC-derived NK cells in other tumor models, and to evaluate specific mechanisms that might regulate improved in vivo activity of hESC- compared to UCB-derived NK cells, focusing on in vivo cell migration, cell survival and proliferation.

scholarly journals A bispecific antibody agonist of the IL-2 heterodimeric receptor preferentially promotes in vivo expansion of CD8 and NK cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Katherine E. Harris ◽  
Kyle J. Lorentsen ◽  
Harbani K. Malik-Chaudhry ◽  
Kaitlyn Loughlin ◽  
Harish Medlari Basappa ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Bispecific Antibody ◽  
T Regulatory Cells ◽  
Tumor Regression ◽  
Interleukin 2 ◽  
In Vivo Studies ◽  
Preferential Binding

AbstractThe use of recombinant interleukin-2 (IL-2) as a therapeutic protein has been limited by significant toxicities despite its demonstrated ability to induce durable tumor-regression in cancer patients. The adverse events and limited efficacy of IL-2 treatment are due to the preferential binding of IL-2 to cells that express the high-affinity, trimeric receptor, IL-2Rαβγ such as endothelial cells and T-regulatory cells, respectively. Here, we describe a novel bispecific heavy-chain only antibody which binds to and activates signaling through the heterodimeric IL-2Rβγ receptor complex that is expressed on resting T-cells and NK cells. By avoiding binding to IL-2Rα, this molecule circumvents the preferential T-reg activation of native IL-2, while maintaining the robust stimulatory effects on T-cells and NK-cells in vitro. In vivo studies in both mice and cynomolgus monkeys confirm the molecule’s in vivo biological activity, extended pharmacodynamics due to the Fc portion of the molecule, and enhanced safety profile. Together, these results demonstrate that the bispecific antibody is a safe and effective IL-2R agonist that harnesses the benefits of the IL-2 signaling pathway as a potential anti-cancer therapy.

scholarly journals Single-cell evaluation reveals shifts in the tumor-immune niches that shape and maintain aggressive lesions in the breast

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Vidya C. Sinha ◽  
Amanda L. Rinkenbaugh ◽  
Mingchu Xu ◽  
Xinhui Zhou ◽  
Xiaomei Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Mouse Model ◽  
Transition State ◽  
Tumor Cell ◽  
Single Cell ◽  
Tumor Cells ◽  
Breast Lesions ◽  
Aggressive Tumor ◽  
Insight Into

AbstractThere is an unmet clinical need for stratification of breast lesions as indolent or aggressive to tailor treatment. Here, single-cell transcriptomics and multiparametric imaging applied to a mouse model of breast cancer reveals that the aggressive tumor niche is characterized by an expanded basal-like population, specialization of tumor subpopulations, and mixed-lineage tumor cells potentially serving as a transition state between luminal and basal phenotypes. Despite vast tumor cell-intrinsic differences, aggressive and indolent tumor cells are functionally indistinguishable once isolated from their local niche, suggesting a role for non-tumor collaborators in determining aggressiveness. Aggressive lesions harbor fewer total but more suppressed-like T cells, and elevated tumor-promoting neutrophils and IL-17 signaling, disruption of which increase tumor latency and reduce the number of aggressive lesions. Our study provides insight into tumor-immune features distinguishing indolent from aggressive lesions, identifies heterogeneous populations comprising these lesions, and supports a role for IL-17 signaling in aggressive progression.

scholarly journals Cellular cytotoxicity is a form of immunogenic cell death

2020 ◽  
Vol 8 (1) ◽  
pp. e000325 ◽  
Author(s):  
Luna Minute ◽  
Alvaro Teijeira ◽  
Alfonso R Sanchez-Paulete ◽  
Maria C Ochoa ◽  
Maite Alvarez ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Dendritic Cells ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Immunogenic Cell Death ◽  
Cell Debris ◽  
Tumor Cell Death ◽  
Mhc Multimer

BackgroundThe immune response to cancer is often conceptualized with the cancer immunity cycle. An essential step in this interpretation is that antigens released by dying tumors are presented by dendritic cells to naive or memory T cells in the tumor-draining lymph nodes. Whether tumor cell death resulting from cytotoxicity, as mediated by T cells or natural killer (NK) lymphocytes, is actually immunogenic currently remains unknown.MethodsIn this study, tumor cells were killed by antigen-specific T-cell receptor (TCR) transgenic CD8 T cells or activated NK cells. Immunogenic cell death was studied analyzing the membrane exposure of calreticulin and the release of high mobility group box 1 (HMGB1) by the dying tumor cells. Furthermore, the potential immunogenicity of the tumor cell debris was evaluated in immunocompetent mice challenged with an unrelated tumor sharing only one tumor-associated antigen and by class I major histocompatibility complex (MHC)-multimer stainings. Mice deficient inBatf3,Ifnar1andSting1were used to study mechanistic requirements.ResultsWe observe in cocultures of tumor cells and effector cytotoxic cells, the presence of markers of immunogenic cell death such as calreticulin exposure and soluble HMGB1 protein. Ovalbumin (OVA)-transfected MC38 colon cancer cells, exogenously pulsed to present the gp100 epitope are killed in culture by mouse gp100-specific TCR transgenic CD8 T cells. Immunization of mice with the resulting destroyed cells induces epitope spreading as observed by detection of OVA-specific T cells by MHC multimer staining and rejection of OVA+EG7 lymphoma cells. Similar results were observed in mice immunized with cell debris generated by NK-cell mediated cytotoxicity. Mice deficient inBatf3-dependent dendritic cells (conventional dendritic cells type 1, cDC1) fail to develop an anti-OVA response when immunized with tumor cells killed by cytotoxic lymphocytes. In line with this, cultured cDC1 dendritic cells uptake and can readily cross-present antigen from cytotoxicity-killed tumor cells to cognate CD8+T lymphocytes.ConclusionThese results support that an ongoing cytotoxic antitumor immune response can lead to immunogenic tumor cell death.

Engineered immunostimulatory cells can convert PBMCs from chronic lymphocytic leukemia (CLL) patients into potent tumor killing immune cells.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7517-7517
Author(s):  
Joshua W. Keegan ◽  
Frank Borriello ◽  
Stacey M. Fernandes ◽  
Jennifer R. Brown ◽  
James A. Lederer
Keyword(s):  
T Cells ◽  
B Cells ◽  
Tumor Cell ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Killing Activity ◽  
Tumor Killing ◽  
Tumor Cell Killing ◽  
Potent Tumor

7517 Background: Alloplex Biotherapeutics has developed a cellular therapeutic that uses ENgineered Leukocyte ImmunoSTimulatory cell lines called ENLIST cells to activate and expand populations of tumor killing effector cells from human peripheral blood mononuclear cells (PBMCs). This process leads to a 300-fold expansion of NK cells, CD8+ T cells, NKT cells, and TCRγδ T cells that are called SUPLEXA cells, which will be cryopreserved and transferred back into patients as an autologous immune cell therapy for cancer. In this study, PBMCs from CLL patients were used to generate SUPLEXA cells as a first approach to comparatively profile SUPLEXA cells from cancer patients and normal healthy volunteers (NHVs). Methods: ENLIST cell lines were engineered by expressing curated immunomodulatory proteins in the SK-MEL-2 melanoma cell line. Two million (M) PBMCs from 10 CLL patients or 2 NHVs were incubated with 0.4 M freeze/thaw killed ENLIST cells for 5 days in XVIVO-15 medium with 2% heat-inactivated human AB serum (XAB2) and then split 1:15 in XAB2 containing IL-7 and IL-15 to expand. After 9 days, SUPLEXA cells were harvested and cryopreserved. Results: Original PBMCs and matched SUPLEXA cells from each donor were thawed and characterized by mass cytometry (CyTOF) using a 47-marker antibody panel. CyTOF staining results of PBMCs from CLL patients demonstrated approximately 95% leukemia cells and few T cells, NK cells, B cells, and monocytes. CyTOF staining of SUPLEXA cells from all 10 CLL patients showed expansion of NK cells (17%), CD8 T cells (11%), and CD4 T cells (7.5%) that were similar in phenotype to SUPLEXA cells from NHVs showing high expression of granzymes and perforin that are indicative of potent tumor cell killing activity. Cancer cells in the original CLL PBMC samples were reduced to 0.78%. However, a population of non-T/non-B cells (60% ± 9.5%) was detected in SUPLEXA cells from all CLL patients that require further characterization. Next, SUPLEXA cells from CLL and NHV patients were comparatively tested for tumor cell killing activity at 2:1, 1:1, and 1:2 effector to target cell (MEL-14 melanoma cells expressing RFP) ratios. Percent killing of tumor cells by SUPLEXA cells prepared from CLL patients (77.8% ± 2.6% at 2:1) and NHVs (81.5% ± 0.3% at 2:1) were nearly identical at all effector to target ratios. Conclusions: We demonstrate for the first time that PBMCs from CLL patients can be converted into SUPLEXA cells despite low numbers of normal immune cells at baseline and the known immunologic impairment present in CLL patients. Importantly, SUPLEXA cells derived from CLL patients acquire potent tumor killing activity that is indistinguishable from SUPLEXA cells prepared from NHVs. Taken together, these findings support the feasibility of converting PBMCs from CLL patients with low percentages of NK and T cells into an autologous cellular therapy for cancer.

scholarly journals Participation of the H-2 antigens of tumor cells in their lysis by syngeneic T cells.

1976 ◽  
Vol 143 (3) ◽  
pp. 601-614 ◽  
Author(s):  
J W Schrader ◽  
G M Edelman
Keyword(s):  
T Cells ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Target Cell ◽  
Cytotoxic T Cells ◽  
Hybrid Origin ◽  
Target Cells ◽  
Cytotoxic Lymphocytes ◽  
Effector Cells

Cytotoxic T lymphocytes were generated in vitro against H-2 compatible or syngeneic tumor cells. In vitro cytotoxic activity was inhibited by specific anti-H2 sera, suggesting that H-2 antigens are involved in cell lysis. Two observations directly demonstrated the participation of the H-2 antigens on the tumor cells in their lysis by H-2-compatible T cells. First, coating of the H-2 antigens on the target tumor cell reduced the number of cells lysed on subsequent exposure to cytotoxic T cells. Second, when cytotoxic T cells were activated against an H-2 compatible tumor and assayed against an H-2-incompatible tumor, anti-H-2 serum that could bind to the target cell, but not to the cytotoxic lymphocyte, inhibited lysis. H-2 antigens were also shown to be present on the cytotoxic lymphocytes. Specific antisera reacting with these H-2 antigens, but not those of the target cell, failed to inhibit lysis when small numbers of effector cells were assayed against H-2-incompatible target cells or when effector cells of F1-hybrid origin and bearing two H-2 haplotypes were assayed against a tumor cell of one of the parental strains. These findings suggest that it is the H-2 antigens on the tumor cell and not those on the cytotoxic lymphocytes that are important in cell-mediated lysis of H-2-compatible tumor cells.

scholarly journals A Nuclear-Directed Ribonuclease Variant Targets Cancer Stem Cells and Inhibits Migration and Invasion of Breast Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4350
Author(s):  
Jessica Castro ◽  
Giusy Tornillo ◽  
Gerardo Ceada ◽  
Beatriz Ramos-Neble ◽  
Marlon Bravo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cell Lines ◽  
Breast Cancer Cells ◽  
Migration And Invasion ◽  
Tumor Cell Lines

Despite the significant advances in cancer research made in recent years, this disease remains one of the leading causes of death worldwide. In part, this is due to the fact that after therapy, a subpopulation of self-renewing tumor cells can survive and promote cancer relapse, resistance to therapies and metastasis. Targeting these cancer stem cells (CSCs) is therefore essential to improve the clinical outcome of cancer patients. In this sense, multi-targeted drugs may be promising agents targeting CSC-associated multifocal effects. We have previously constructed different human pancreatic ribonuclease (RNase) variants that are cytotoxic for tumor cells due to a non-classical nuclear localization signal introduced in their sequence. These cytotoxic RNases affect the expression of multiple genes involved in deregulated metabolic and signaling pathways in cancer cells and are highly cytotoxic for multidrug-resistant tumor cell lines. Here, we show that these cytotoxic nuclear-directed RNases are highly selective for tumor cell lines grown in 3D, inhibit CSCs’ development and diminish the self-renewal capacity of the CSCs population. Moreover, these human RNase variants reduce the migration and invasiveness of highly invasive breast cancer cells and downregulate N-cadherin expression.

Abstract 4077: ATOR-1144 is a tumor-directed CTLA-4 x GITR bispecific antibody that acts by depleting Tregs and activating effector T cells and NK cells

2019 ◽  
Author(s):  
Sara Fritzell ◽  
Mattias Levin ◽  
Ida Åberg ◽  
Maria Johansson ◽  
Magnus Winnerstam ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Bispecific Antibody ◽  
Effector T Cells

Abstract 4077: ATOR-1144 is a tumor-directed CTLA-4 x GITR bispecific antibody that acts by depleting Tregs and activating effector T cells and NK cells

2019 ◽  
Author(s):  
Sara Fritzell ◽  
Mattias Levin ◽  
Ida Åberg ◽  
Maria Johansson ◽  
Magnus Winnerstam ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Bispecific Antibody ◽  
Effector T Cells

scholarly journals P01.08 Beyond PD-1: characterization of new checkpoints restricting function of cytotoxic lymphocytes infiltrating human carcinoma

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A11.2-A12
Author(s):  
AS Herbstritt ◽  
PU Prinz ◽  
M Maxwell ◽  
M Kadiyala ◽  
D Yan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cell ◽  
Nk Cells ◽  
Solid Tumors ◽  
Principal Investigator ◽  
Tumor Control ◽  
Research Support ◽  
Part Time ◽  
Research Grant

BackgroundT and NK cells from human renal cell carcinoma (RCC) are functionally non-responsive. Analysis of the TCR signaling cascade required for effector function identified that proximal signaling molecules were activated whereas activation of downstream ERK was blocked. Further investigation showed increased diacylglycerol kinase alpha (DGK-α) levels in T and NK cells from the RCC tumor microenvironment (TME). These cells were refractory to stimulation showing no degranulation or IFN-γ production. Using a small molecule DGK–α inhibitor (R59022), the function of tumor-infiltrating lymphocytes was restored ex vivo. A correlation of high DGK-α and loss of function was also observed in an experimental mouse model of adoptive therapy where CAR T cells that had lost their activity after infiltrating into solid tumors were found to have increased DGK-α.1 Blockade of the Programmed cell death protein 1 (PD-1) with monoclonal antibodies is used in the clinic enabling some patients to achieve tumor control. However, not all patients respond. DGK-α activity is positioned downstream of PD-1 and should, if overactive, curb T cell function even if PD-1 inhibition is released. Thus, we hypothesize that dual inhibition of PD-1 and DGK–α might be required to fully unleash the T cell’s potential in the TME. Current DGK-α inhibitors are not suitable for clinical application. Therefore, we investigated alternative means using an RNA interference (RNAi) approach to target DGK-α alone as well as in combination with PD-1 in T and NK cells.Material and MethodsKnockdown is performed by RNAi using INTASYLTM compounds developed by Phio Pharmaceuticals. INTASYLTM compounds incorporate drug-like properties into the siRNA, resulting in enhanced uptake in the presence of serum with no need for further transfection reagents. Knockdown is analyzed by RT-qPCR and flow cytometry. Functional assays include cytotoxicity, degranulation and cytokine production in tumor mimicking environments.ResultsA tumor mimicking in vitro system was developed which allows for the demonstration of functional restoration or prevention of functional loss of cell activity. Using T cell/tumor cell co–cultures at high tumor cell density, functional suppression could be induced in T and NK cells comparable to those observed in the TME. Testing of DGK-α targeting INTASYLTM compounds, silencing of DGK-α was observed in human U2OS osteosarcoma cells. Using a fluorescently labeled compound, highly efficient transfection of human primary immune cells was seen. Combinations of PD-1 and DGK-α targeting compounds are being tested and evaluated for synergism in experimental models.ConclusionsStrong activity of specific T and NK cells is necessary for tumor control. Dual targeting of PD-1 and DGK-α may be required to fully enable T and NK cell reactivity in the TME. Current DGK-α inhibitors do not exhibit the desirable pharmacokinetic/pharmacodynamic (PK/PD) properties for clinical development. The tested self-delivering RNAi technology represents a promising approach to targeting intracellular immune checkpoints such as DGK-α.ReferenceMoon EK, Wang L-C, Dolfi DV, Wilson CB, Ranganathan R, Sun J, et al. Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors. Clin Cancer Res 2014; 20(16):4262–73Disclosure InformationA.S. Herbstritt: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; Phio Pharmaceuticals. C. Other Research Support (supplies, equipment, receipt of drugs or other in-kind support); Significant; Phio Pharmaceuticals. P.U. Prinz: None. M. Maxwell: A. Employment (full or part-time); Significant; Phio Pharmaceuticals. M. Kadiyala: A. Employment (full or part-time); Significant; Phio Pharmaceuticals. D. Yan: A. Employment (full or part-time); Significant; Phio Pharmaceuticals. E. Noessner: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; Phio Pharmaceuticals. C. Other Research Support (supplies, equipment, receipt of drugs or other in-kind support); Significant; Phio Pharmaceuticals.

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