Browsing by Subject "Immunotherapy"
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Item AB1-42 Antibody Producing Plasma Cells in DNA AB42 Trimer Immunized Mice Reside Predominantly in the Bone Marrow(2013-01-22) Zacharias, Tresa; Langworthy, Suzanna; Fu, Min; Anderson, Larry; Stuve, Olaf; Rosenburg, Roger; Lambracht-Washington, DorisAlzheimer's disease (AD) is the most common form of age-related dementia and affects nearly 40 million people worldwide. Immunotherapy provides a possible avenue for prophylaxis of AD, but a clinical trial (AN1792) in which patients with early AD were immunized with Aβ1-42 peptide was halted after the occurrence of meningoencephalitis in 6% of the immunized people which was attributed to a T cell autoimmune response. DNA vaccination has been shown to have a polarized Th2 immune response that lacks many of the features responsible for inflammation seen in peptide immunizations. In this study, we show a new feature of the DNA Aβ42 trimer elicited B cell immune response and present data for the presence of a long lived plasma cell pool residing within the bone marrow in DNA immunized mice but not in peptide immunized mice. Two groups of mice were analyzed: one group of B6C3F1 mice (n=20) were studied 4 months after the last DNA vaccination, and a second group of BALB/c mice (n=14), which received DNA or peptide immunizations, were analyzed 10 days following the last immunization. The comparison of antibody producing cells in bone marrow and spleen for the DNA and peptide immunized mice with an Antibody Forming Cell (AFC) ELISPOT assay and subsequent ELISAs showed that bone marrow plasma cells from DNA immunized mice produced more anti-Aβ42 IgG producing cells and higher levels of secreted IgG antibodies. In peptide immunized mice, more IgG antibody producing cells were found to reside in the spleen. These data indicate that the bone marrow may be an important reservoir for B cells following DNA Aβ42 immunization and is in line with studies showing that the bone marrow represents an excellent niche for the survival of long lived plasma cells and a lifetime source for antibody producing B cells which are independent of continuous antigen specific stimulation. Further studies are needed to show whether it is possible to define additional phenotypic characteristics for the antigen specific B cell immune response in DNA Aβ42 trimer immunized mice or differences in the TH subsets directly involved in initial signaling events to B cells in the germinal center reactions.Item Chronic lymphocytic leukemia: from "chemo"-therapy to "chronic" therapy(2020-07-24) Awan, Farrukh T.Item Development of an IL12 Prodrug to Treat Solid Tumors with Minimal Toxicity(2022-05) Moon, Benjamin Ik; Gao, Jinming; Hammers, Hans; Li, Bo; Fu, Yang-Xin; Qiao, JianCytokines are secreted molecules that guide the immune system to respond correctly to various challenges. Among all cytokines, IL12 is perhaps the most powerful at polarizing the immune response into a Type 1, cell-mediated phenotype. Cell-mediated immunity plays a critical role in cancer immunoediting, allowing CTLs to recognize and kill aberrant cells. Because of this, IL12 has been tested in many different preclinical and clinical studies for its potential use as an anti-tumor therapeutic agent. However, IL12 also causes severe, dose-limiting systemic toxicity due to on-target, off-tumor activation of peripheral immune cells. Newer attempts at IL12-mediated delivery focus on restricting IL12 activity to within the tumor as much as possible, but they each have their own limitations. To address these problems, we developed a novel IL12 prodrug, pro-IL12, that is actively blocked until it is preferentially activated within the TME. We achieved this by using portions of the IL12 receptor attached with a flexible linker to sterically block the active site of IL12. The linker contains a substrate site that can be cleaved by tumor-specific proteinases, thereby releasing the blocker and activating the prodrug. Pro-IL12 successfully maintained anti-tumor efficacy with reduced toxicity compared to its non-prodrug counterpart. We determined that the mechanism of anti-tumor immunity was predominantly through pre-existing, intratumor CD8+ T cells that produce IFNγ after direct binding of the prodrug to cell surface IL12 receptor complexes. Pro-IL12 also worked in combination with TKI and ICB to achieve even more potent tumor control. In a follow up study, I propose that a higher dose of pro-IL12 might use distinct cellular and molecular mechanisms. Indeed, high dose pro-IL12 more effectively controls large tumors at the cost of reintroducing systemic toxicity. Mechanistically, this dose used a broader, T cell-dependent mechanism that was independent of IFNγ. Further analysis determined that IFNγ was responsible for all manifestations of toxicity and that IFNγ blockade given concurrently with pro-IL12 could limit toxicity with no effect on efficacy. Additionally, the absence of IFNγ signaling on T cells had no effect on their phenotype or ability to control the tumor. As a whole, these studies document the development of a next generation, IL12 immunotherapy for the treatment of solid tumors with an emphasis on its mechanisms of tumor control that are distinct from toxicity.Item Germ warfare(1978-03-23) Mackowiak, Philip A.Item A hard nut to crack: unraveling novel food allergy therapies(2024-05-31) Bird, J. AndrewItem Immune checkpoint inhibitor related endocrinopathies(2018-10-26) Ali, SadiaItem Immunotherapy in kidney cancer: the past, present and future(2016-07-15) Hammers, HansItem Immunotherapy in lung cancer treatment: a new paradigm still in revision(2019-10-11) Kim, JamesItem Immunotherapy: a new era in cancer treatment(2015-07-10) Nijhawan, DeepakItem The Integrated Stress Response Pathway Regulates PD-L1 Translation in Human Lung Cancer(2019-04-12) Suresh, Shruthy; Zhu, Hao; O'Donnell, Kathryn A.; Brekken, Rolf A.; Kliewer, Steven A.Large-scale sequencing studies have comprehensively identified genomic alterations in human cancers, but they lack the ability to distinguish between cancer driver and passenger mutations. Unbiased genetic screens are a complementary approach for identifying novel cancer driving genes and establishing functional significance of clinically observed mutations. My thesis projects demonstrate how powerful this approach can be in identifying novel therapeutic targets for human cancer treatment. Recent studies have demonstrated that human lung cancer cells express high levels of Programmed Death Ligand 1 (PD-L1), a ligand of the Programmed Death 1 (PD-1) receptor on T-cells, which allows them to directly suppress T-cell proliferation and function. Monoclonal antibodies disrupting this pathway have yielded remarkable clinical results. However, the mechanisms of PD-L1 regulation in tumor cells remain incompletely understood. I used CRISPR-based screening to identify novel regulators of PD-L1 in human lung cancer cells, revealing potent induction of PD-L1 upon disruption of the heme biosynthesis pathway. Impairment of heme production activates the Integrated Stress Response (ISR), allowing bypass of inhibitory upstream open reading frames in the PD-L1 5'UTR, resulting in enhanced PD-L1 translation and immune suppression. I further demonstrated that ISR-dependent translation of PD-L1 requires the translation initiation factor EIF5B. EIF5B overexpression, which is frequent in human lung cancers and is associated with poor prognosis, is sufficient to induce PD-L1. These findings uncover a new mechanism of immune checkpoint activation and suggest novel targets for therapeutic intervention. Additionally, I have also worked on characterizing Steroid Receptor Coactivator-2, previously identified from a forward genetics screen, as a tumor suppressor in MYC-mediated liver tumorigenesis.Item Live Donor Renal Transplantation in India: Outcome and Comparison of Different Induction Therapies with a Focus on Gender Bias in Live Donor Renal Transplantation(2018-03-23) Khan, Maryam Idrees; Nwariaku, Fiemu; Rajora , Nilum; Tanriover , BekirBACKGROUND: As of 2014, an estimated 9% of the global population aged 18+ years was affected by diabetes. The World Health Organization (WHO) also estimated around 2.5% of deaths were attributed to diabetes in 2012 and more than 80% of those deaths occurred in low-middle income countries. It is apparent that diabetes and its complications are becoming a global issue as an increasing common, preventable, non-communicable disease. Along with cardiovascular disease, blindness, and neuropathy, end stage renal disease (ESRD) is one of the serious complications that can develop as a result of diabetes. Diabetes is the leading cause of ESRD in both developed countries like the United States and developing countries like India. India is a particularly interesting country to observe given their vast population base, rapid growing economy, genetic predisposition to diabetes and increased insulin resistance. It is estimated that 100,000 patients develop ESRD each year in India with diabetes as the main underlying cause (44% of all ESRD cases). Once a patient develops ESR, renal replacement therapy (RRT) is required to sustain life. RRT consists of three options: 1) hemodialysis (HD), 2) peritoneal dialysis (PD), or 3) renal transplant (RT). Of the three options, renal transplant is considered the best in terms of quality of life and cost effectiveness, but only about 5% of Indian patients with ESRD end up receiving RT. Most RT in India come from living donors rather than cadaveric donors like in the United States. Induction therapy with interleukin-2 receptor alpha chain (IL2-RA) is recommended as a first line agent in LRT however comparative outcomes of induction therapy remains controversial in Indian LRT population. OBJECTIVE: To evaluate patient survival and allograft function in LRT with a specific focus on the Indian population between 2010 and 2014 and to access the impact of different induction therapies on the outcomes of Indian LRT patients. METHODS: A single center (Medanta Medicity, Gurgaon, India) dataset was retrospectively studies for patients receiving LRT from 2010 to 2014 (N=901) to compare effectiveness of IL2-RA to other induction options (no-induction and rabbit anti-thymocyte globulin [r-ATG]). IL2-RA and no induction were chosen for immunologically low risk patients. R-ATG was primarily given to the recipient with PRA>20% and HLA mismatch >5 antigen out of 6. Patient paper charts were analyzed for dates not included in the Medanta database which included follow-up dates with corresponding creatinine levels (at 3 months, 6 months, 1 year, and last follow up), date and type of rejection if applicable, graft loss and death. Patients included in the data set had their last follow up at Medanta within the last 6 months from the time data was collected. The patient data was used to calculate rejection rate, graft failure, and hazard ratio (HR) for overall graft failure. The main outcomes were the risk of acute rejection at one-year and overall allograft failure (graft failure or death) post-transplantation through the end of follow-up. RESULTS: Similar Kaplan Meier curves for overall graft survivals were observed among induction categories. Rejection rate was higher in no-induction and IL2-RA groups (~25%) compared to r-ATG induction. On univariate Cox analysis, compared to no-induction therapy, overall allograft failure was similar among induction categories. Most of the rejections were borderline or Banff Type I acute cellular rejections. CONCLUSION: Compared to no-induction therapy, IL2-RA induction was not associated with better outcomes in Indian LRT recipients. R-ATG appears to be an acceptable and possibly preferred induction alternative for IL2-RA in high rejection risk Indian patients.Item Modeling Tumor Neoantigens for Predicting Patients' Clinical Outcomes(December 2021) Lu, Tianshi; Hoshida, Yujin; Wang, Tao; Xiao, Guanghua; Ahn, Chul; Aguilera, Todd A.Tumor neoantigens are critical targets of the host antitumor immune response and their presence play an important role in affecting tumor progressions and immunotherapy treatment response. Neoantigens showed a lot of potential of being applied to clinical treatment. However, systematic study of neoantigens' impact on tumors and patients is still challenging due to the huge diversity of neoantigens, heterogeneity within tumors, and the model to study the pairing between neoantigen-MHC and T cells to identify the neoantigens that truly elicit T cell response. To study the impact of neoantigen-T cell interaction on tumorigenesis, I developed a Bayesian hierarchical model to infer the history of neoantigen-cytotoxic T cell interactions in tumors.Item Modulating SIRP-alpha, a Myeloid-Specific Immune Checkpoint, for Immunotherapeutic Treatment of Malignancy(2016-04-01) Ring, Nan Guo; Weissman, Irving; Laccetti, Andrew; Nijhawan, Deepak; Wang, RichardBACKGROUND: CD47 is a "don't-eat-me" signal upregulated by many types of cancer that signals through its receptor SIRPα to inhibit macrophage-mediated destruction. Recent studies have demonstrated the efficacy of anti-CD47 blockade in synergizing with traditional monoclonal antibodies (mAbs) to enhance phagocytosis of cancer cells. We proposed targeting SIRPα as an alternative strategy and as a bridge to creating a single format bispecific macrophage-enhancing antibody (BiME). OBJECTIVE: The focus of this project was to test the therapeutic efficacy of SIRPα-blockade in combination treatment with other anti-tumor mAbs and in a single agent format as BiMEs. METHODS: We created KWAR23, a SIRPα-blocking monoclonal antibody, and from it, we derived several BiMEs in the dual-variable-domain immunoglobulin format to target CD20, Her2, and CD70. We tested these agents in high-throughput phagocytosis assays. We have also begun testing the therapeutic efficacy of KWAR23 in combination with rituximab in a xenograft mouse model of B cell lymphoma. RESULTS: KWAR23 significantly enhanced the efficacy and potency of phagocytosis of mAb-opsonized cancer cells when compared to the mAbs alone in B cell lymphoma and breast adenocarcinoma. BiMEs resulted in greater efficacy of phagocytosis of cancer cells when compared to their parent mAbs for B cell lymphoma, breast adenocarcinoma, and renal cell carcinoma. SIRPα-blockade in combination with rituximab also appeared to significantly reduce tumor burden in mice engrafted with a B cell lymphoma cell line. CONCLUSIONS: The therapeutic role of check-point inhibitors has become increasingly apparent and important in the treatment of cancer in recent years, but the role played by macrophages remains unclear. We have now demonstrated multiple strategies for targeting the CD47-SIRPα pathway to harness macrophages in antibody-mediated cell killing. This research may further benefit the field of immunotherapy as we learn more about the intricate interplay between innate and adaptive immunity in cancer biology.Item "My cancer treatment is a pain in the neck": immune checkpoint inhibitor therapy: a rheumatologist's perspective(2018-06-22) Bermas, Bonnie L.Item [News](1981-01-05) Rutherford, SusanItem [News](1987-11-20) Bosler, Tommy JoyItem [News](1987-11-18) Bosler, Tommy JoyItem Potentiating Antibody Therapy by Targeting Complement on Cancer Cells(2017-04-03) Carstens, Elizabeth Jane; Wiestner, Adrian; Dunbar, Cynthia; Choti, MichaelBACKGROUND: Monoclonal antibodies (mAb) are a key component of treatment regimens for hematologic malignancies, but mAb-induced antigen loss on tumor cells can lead to treatment failure. Loss of cell surface CD20 can occur in the treatment of lymphoid malignancies with anti-CD20 antibodies (mAbs) (eg rituximab, ofatumumab) through trogocytosis. This is a frustrated form of phagocytosis, where the target CD20 antigen is removed with a piece of target cell plasma membrane by the immune effector cell, thus creating "escape variants", which are no longer sensitive to the anti-CD20 therapy. In a clinical trial we initiated with anti-CD20 mAb ofatumumab in chronic lymphocytic leukemia (CLL), we observed that these escape variants carried covalently bound complement activation fragments, especially C3d. Indeed, C3d opsonized CLL cells persisted for weeks in circulation. (Beurskens et al., 2012). At final restaging after combined ofatumumab and chemotherapy treatment, many patients had CD20 negative, but C3d positive disease. This suggests that a single mAb is insufficient to deplete cancer cells due to antigen escape. OBJECTIVE: C3d may constitute a neoantigen that could be exploited to re-target cells that have escaped from anti-CD20 mAb therapy. METHODS: To target complement opsonized cells we generated a human IgG1 mouse chimera mAb specific to C3d that is not competed by full length C3 in serum. To test whether targeting C3d can eliminate escape variants after anti-CD20 therapy, we collected blood samples from CLL patients before (Day 1) and 24 hours after administration of ofatumumab (Day2). To demonstrate that anti-C3d targeting was able to effectively circumvent antigen loss in vitro, we tested the anti-C3d mAbs ability to perform complement dependent cytotoxicity (CDC), antibody dependent cytotoxicity (ADCC), apoptosis and phagocytosis on Day 2 CLL cells. To test CDC, Day 2 CLL and previously treated CD20+ cell lines were incubated with anti-C3d mAb and normal human serum and stained for cell death. Similarly, ADCC was tested by coincubating Day 2 cells with an NK cell line in the presence of mAb. To evaluate phagocytosis, CLL cells were incubated with macrophages for six hours in the presence of antibody and imaged using flow cytometry to evaluate degree of internalization. We also tested the efficacy of the anti-C3d mAb in vivo, using two mouse models. First, we transferred peripheral blood mononuclear cells obtained from CLL patients on Day 2 into NSG mice. Mice were treated with either isotype antibody, ofatumumab or anti-C3d mAb. Mice were sacrificed and tumor burden was quantified in peripheral blood and spleen. To evaluate impact on survival, we subcutaneously xenografted HBL2 cells, a CD20+ mantle cell lymphoma (MCL) line, into SCID mice. All mice received an injection of human C3 and either anti-CD20 mAb (rituximab or ofatumumab) alone, anti-CD20 and anti-C3d mAb or isotype control. Caliper measurements of the tumor longest dimension and survival were measured. RESULTS: Anti-C3d mAb did not bind CLL cells obtained pre-treatment but bound cells obtained on Day 2. Day 2 CLL was effectively killed through CDC, NK cell mediated ADCC, and phagocytosis but not apoptosis. Phagocytosis of Day 2 CLL cells in response to anti-C3d treatment was two-fold higher than that observed on Day 1 CLL treated with ofatumumab. Importantly, non B lymphocytes were neither bound nor killed by the anti-C3d mAb, consistent with the highly targeted and selective deposition of C3d on CD20+ cells by ofatumumab in vivo. Our anti-C3d mAb effectively reduced tumor burden in both peripheral blood and spleen of the mice relative to mice treated with isotype control in the CLL primary NSG model. Our anti-C3d antibody extended time to tumor development and also prolonged survival in the MCL model differentially from CD20 targeting alone. CONCLUSION: Collectively, our results identify C3d as a marker for leukemic cells that have escaped in vivo antibody treatment and provide proof of principle evidence for the clinical utility of C3d-targeting. In essence, we present an approach to utilize endogenous complement molecules as targets for immunotherapy. This approach relies on prior treatment with monoclonal antibodies that activate the complement cascade and thus covalently link complement component C3d to tumor cells. We conclude that anti-C3d mAbs can potentiate the anti-tumor activity of complement-fixing antibodies and eliminate antigen loss variants that survive after antibody therapy.Item [Southwestern News](2002-08-13) Echeverria, IoneItem Toward the Rational Design of Better Antivirals: The Development of cGAMP as an HIV-1 Anti-Retroviral and the Genetic Surveillance of WNV Evolution(2017-04-17) Aroh, Chukwuemika Nnabuike; Pasare, Chandrashekar; Wakeland, Edward K.; Yan, Nan; Schoggins, John W.; Pfeiffer, Julie K.The innate immune response is the first line of defense against pathogens and thus represents the first hurdle viruses must overcome to cause severe disease in humans. Understanding the consequences of viral evolution can give insights to mechanisms of viral pathogenesis as well as the development of novel therapeutics. Here I studied two clinically important viruses: Human Immunodeficiency Virus (HIV) and West Nile Virus (WNV). HIV-1 has evolved several mechanisms to evade immune detection by the cGAS-STING cytosolic DNA sensing pathway. A small cyclic di-nucleotide, cGAMP, activates the same pathway by directly binding STING. Treatment with cGAMP, delivered by ultra-pH sensitive nanoparticles or by liposomes, in human peripheral blood mononuclear cells (PBMCs) induced potent and long-acting protection against replication of several laboratory-adapted and clinical HIV-1 isolates in contrast to the short-lasting effect of current anti-retroviral therapy (ARTs). These results present the first evidence for potentially developing cGAMP or other STING agonists as a long-acting antiretroviral immunotherapy. West Nile Virus (WNV) is a mosquito-borne Flavivirus which was introduced to North America in 1999 and is currently the leading cause of viral encephalitis. The lack of specific therapeutics or human vaccines makes WNV an ongoing public health threat. Now endemic, WNV is steadily evolving, but the contribution of positively-selected mutations to human disease remains unclear. In 2012 the second largest outbreak of human West Nile disease occurred in the U.S., with one-third of the cases happening in Texas. The outbreak was associated with groups of WNV carrying positively-selected mutations. By sequencing WNV in Texas from 2012-2015, we show that positively-selected mutations in WNV mediate increased circulation and over-wintering in the environment, which may promote increases of human disease. Additionally, we show evidence that the WNV population is still evolving new alleles. These results advance our understanding of the impact of WNV evolution to human disease, and may afford insights to the evolution of other invading flaviviruses, such as Dengue and Zika virus. Altogether, these results show that understanding the consequences of viral evolution can be harnessed towards overcoming challenges to the development of more effective therapeutics.