Shahnawaz Imam’s Role in the Project: Principal Investigator, with 15% effort

Leona M. and Harry B. Helmsley Charitable Trust - 129353-01 (Shahnawaz Imam and Juan C Jaume): 12/1/2021 to 5/31/2023

Helmsley Foundation  

Normalizing arginine metabolism with sepiaptein for immunostimulatory-shift of HER2+ breast cancer- $353,419                                                    

Shahnawaz Imam's Role in the Project: Consultant

R01 - 248304 (Saori Furuta) 03/04/2020 -- 02/28/2025

NCI - National Cancer Institute

Sample Collection for Clinical Performance Evaluation of Elecsys Anti-TPO II - $25,000

Protocol/Study No: CIM RD005629 – ICON 0165/0677 (Award Notification): Co-PI

Sponsor(s): Roche Diagnostics Operations, Inc.

Generation of human CAR-Treg cells for inducing immunological tolerance against diabetogenic T cells in the pancreatic islets of recent onset LADA patients - $25,000

Shahnawaz Imam's Role in the Project: Principal Investigator

Sponsor(s): deArce-Koch Memorial Endowment Fund, University of Toledo (07/01/2023 -06/30/2024)

Pancreatic islets rescue in Type 1 Diabetes using immunomodulators- $50,000

Shahnawaz Imam's Role in the Project: Principal Investigator

Sponsors(s): Regional Pilot/Feasibility Grant 2023-24 (N-130630-01) (12/01/2023 -11/30/2024)

Department of Medicine, COMLS Startup Fund- $100,000

Shahnawaz Imam's Role in the Project: Principal Investigator

Dr. Saira Saeed Khan, Ph.D. (01/29/2024-01/28/2025) Fulbright Fellow Trainees (Mentored Scholarship)- $40,275

Shahnawaz Imam's Role in the Project: Mentor  

Sponsor(s): The Bureau of Educational and Cultural Affairs, Department of State, with the Cooperation of Institute of International Education, United States, J William Fulbright Foreign Scholarship Award

Ahmad Aldasouqi, Undergraduate Student (University of Toledo): 2021-2024 (Awarded with UGR4910, Summer Research Fellowship, 2023 and 2024)- $3,000/year

Shahnawaz Imam's Role in the Project: Mentor  

 

1. US Patent US11974552B2: “Transgenic C57BL6-BTBR mouse with a humanized MHC II gene that expresses GAD65” University of Toledo, Office of Technology Transfer. 05/07/2024.  

Background: Although the NOD mouse is the current standard for studies on type I diabetes (T1D), no curative therapies resulting from this model have passed clinical trials. Knock-in/out models cannot mimic the total pathophysiology of diabetes. To develop a cure for T1D, there is a need for an animal model of human T1D that resembles human disease and, as such, exhibits the complications of diabetes.  

Invention Description:  Researchers at the University of Toledo have developed a triple transgenic mouse model of type 1 diabetes (T1D) in which human GAD65 is expressed in pancreatic beta cells, and human MHC II (DQ8) is expressed in antigen-presenting cells with human T1D susceptibility that closely resembles the human disease and its complications. These mice express all three human transgenes simultaneously at β-cells of the pancreas, and human beta cell autoantigens are presented to effector T cells simulating human diabetes. Applications: (i) Animal model for autoimmune diabetes disease mechanisms.  (ii) Animal model for the development of antigen-specific immune interventions.  (iii) Animal model for the hyperglycemic complications of diabetes such as nephropathy, neuropathy, and retinopathy.

Imam, S., Alfonso-jaume, M., Jaume, J.C. (2024). Transgenic C57BL6-BTBR mouse with a humanized MHC II gene that expresses GAD65. United States Patent Number US11974552B2 dated 05/07/2024.

Transgenic C57BL6-BTBR mouse with a humanized MHC II gene that expresses GAD65

2. United States Patent # US12144829B2, dated 12/10/2024: Immunosuppressive antigen-specific chimeric antigen receptor Treg cells for prevention and/or treatment of autoimmune and alloimmune disorders: University of Toledo, Office of Technology Transfer 2024.

Background: The therapeutic application of regulatory T cells (Tregs) for treating autoimmune diseases is limited by the scarcity of antigen-specific Tregs. If antigen-specific Tregs could be produced on demand against a desired autoimmune target, antigen-specific immune suppression of autoimmune diseases would be achievable. One approach to endow effector T cells with a desired antigen specificity uses chimeric T cell antigen receptors with antibody-type specificity. Cellular therapies with antibody-type specific chimeric antigen receptor (CAR)-redirected cytotoxic T cells have shown efficacy in treating malignancies. Accordingly, employing such chimeric immune receptors to redirect Tregs to sites of autoimmune attack would be a useful therapeutic approach to alleviate a broad scope of diseases in which an uncontrolled autoimmune response plays a major role.

Invention Description: We have developed pancreatic beta cell-specific CAR Tregs with preventive and therapeutic capacity against type 1 diabetes (T1D).  Our disclosure describes CAR technology as a means of generating potent, functional, and stable GAD65 antigen-specific CAR Tregs that can prevent and treat T1D. Applications: (i) A composition comprising pancreatic beta cell-specific chimeric antigen receptor (CAR) regulatory T cells (Tregs) useful for the prevention and treatment of type 1 diabetes (T1D). (ii) A method for preventing and treating diabetes, comprising administering an amount effective to treat diabetes to a diabetic or prediabetic subject.  Advantages: (i) Target-specific immune suppression with preservation of host immune function (immune tolerance) to prevent and treat T1D.

a) Jaume JC, Imam S (2024) Immunosuppressive antigen-specific chimeric antigen receptor Treg cells for prevention and/or treatment of autoimmune and alloimmune disorders. United States Patent US12144829B2, dated 12/10/2024,

Immunosuppressive antigen-specific chimeric antigen receptor Treg cells for prevention and/or treatment of autoimmune and alloimmune disorders

 

3. US Patent Application # US20230105011A1: Stratifying risk of malignancy in indeterminate thyroid nodules and immuno-genomic markers for early detection of thyroid cancer: University of Toledo, Office of Technology Transfer. 2024.

Background:     Thyroid cancer is the most common endocrine cancer globally, with an increasing incidence from 2.4 to 9.4% annually over the last three decades. Approximately 600,000 fine needle aspirations (FNAs) are performed annually in the US, and almost a fifth of those (i.e., 120,000 nodules) carrying features consistent with atypia of undetermined significance are suspicious for follicular neoplasms or thyroid malignancy.   However, only 15-30% of thyroid nodules with indeterminate diagnosis are diagnosed malignant, rendering the majority (~70%) of thyroid gland removal surgeries unnecessary. Therefore, it becomes imperative to identify thyroid cancer diagnostic strategies, which could enhance our predictive capabilities and reduce the number of unnecessary thyroidectomies. 

Invention Description: The FNA samples were subjected to cellular profiling and cytokine/chemokine analysis to produce a comprehensive biomarker. DN T cells are a subset of CD3+ T cells having either αβ or γδ T cell receptors, devoid of mature T cell markers (CD3+CD4-CD8-CD56-). These cells constitute approximately 1-5% of circulating T cells. These cells were found to be 20 times more abundant than classic Tregs (CD3+CD4+CD25+ FoxP3+) in thyroid cancer samples than in non-cancerous cases, which implies that DN T cells are highly specialized cells that help cancerous cells in immune evasion. Furthermore, our studies reveal that patients with DN T cell proportion >9.14% in the thyroid cancer microenvironment are at higher risk of developing thyroid cancers. The criterion of 9.14% cut-off at 100% specificity highlights the ability to predict benign nodules and identifies this test as a “rule-out test.”  Additionally, DN T cells were increased in malignant pleural effusions in lung cancer and positively correlated with tumor metastasis in melanoma.

The novelty of this patent technology is the longitudinal analysis and the integration of a multitude of cellular and humoral cues relevant to the disease at the time of diagnosis and during the progression of thyroid cancer. This data also includes the most recent advances in micro-RNA (miRNA) analysis and expression profiling (RNA-Seq) of immune cells present in the microenvironment of thyroid cancer to pinpoint the mechanism(s) involved in the onset and/or progression of the disease.

Imam, S., Jaume, J.C. (2024). Stratifying risk of malignancy in indeterminate thyroid nodules and immuno-genomic markers for early detection of thyroid cancer. United States Patent Application# US20230105011A1. 

Stratifying risk of malignancy in indeterminate thyroid nodules and immuno-genomic markers for early detection of thyroid cancer

 

4. United States Patent Application No. US20240148789A1: Synergistic Inhibition of eIF5A and Notch Signaling. University of Toledo, Office of Technology Transfer. 2024.

Invention Description: Simultaneous inhibition of eIF5A and Notch pathways is a multipronged approach that addresses the underlying immune dysfunction in T1D, enriches Tregs, alleviates β-cell ER stress, and regulates β-cell maturity and proliferation. This unique approach can potentially leverage the benefits of both immunomodulation and cell dedifferentiation strategies to produce superior physiological outcomes. Methods for inducing plasticity in effector T cells to exhibit a regulatory T cell phenotype, treating an autoimmune disease, enriching Treg cells, and preparing a subject for an organ transplant are described.

Advantage: 1) Co-stimulation with GC7+anti-DLL4 suppresses diabetogenic T cells by inducing plasticity in CD4+ expressing Foxp3+IL-17+IFN-γ+ towards the Treg cell phenotype. 2) enriching the Treg population in the pancreatic microenvironment of T1D mice and restraining the CTL-mediated destruction of β-cells.

Imam, S., Jaume, J.C. (2024). Synergistic Inhibition of eIF5A and Notch Signaling. United States Patent Application# US20240148789A1. 

Synergistic Inhibition of eIF5A and Notch Signaling

 

5. United States Patent Application No. US20240148789A1: Synergistic Inhibition of eIF5A and Notch Signaling in Intermediate Tregs. University of Toledo, Office of Technology Transfer. 2024.

Invention Description: In T1D, unfit/low Tregs lead to increased Th1, Th17, and FoxP3+IL-17+IFN-γ+ cells that culminate in cytotoxic T cells (CTLs), destroying the β-cells.  Therefore, the balance between FoxP3+ expressing Treg cells (anti-inflammatory), and proinflammatory T effector cells (FoxP3+IL-17+, FoxP3+IFN-γ+, FoxP3+IL-17+IFN-γ+, IL-17+IFN-γ+, Th1, Th17 cells, and CTLs) could be the determining factor for maintaining homeostasis or promoting inflammation. We characterized a unique population of proinflammatory cytokines expressing intermediate Tregs (CD4+CD25-IFNg+IL17+FOXP3+) in T1D/LADA patients and found to be significantly increased compared to age-matched healthy adults. We report that simultaneous inhibition of eIF5a and Notch pathways using GC7 and anti-DLL4 could induce Treg phenotype in Treg-deficient CD4+ T cells and CD4-deficient PBMCs from T1D/LADA patients.  

Advantage: 1) Co-stimulation with GC7+anti-DLL4 suppresses diabetogenic T cells by inducing plasticity in CD4+ expressing Foxp3+IL-17+IFN-γ+ towards the Treg cell phenotype. 2) enriching the Treg population in the pancreatic microenvironment of T1D mice and restraining the CTL-mediated destruction of β-cells.

Imam, S., Rafiqi, S.I (2024). Synergistic Inhibition of eIF5A and Notch Signaling in Intermediate Tregs. United States Patent Application# US20240307532A1.

Synergistic Inhibition of eIF5A and Notch Signaling in Intermediate Tregs

 

6. United States Provisional Patent # 63/666,449 filed July 1, 2024: Islet antigen-specific CAR-T therapy for pancreatic cancer. University of Toledo, Office of Technology Transfer 2024, technology file# TECH-2024-11.

Invention Description: We have developed pancreatic islet beta cell-specific CAR T CD8 T cells with therapeutic capacity against pancreatic ductal adenocarcinoma (PDAC).  Our disclosure describes CAR technology to generate potent, functional, and stable GAD65 antigen-specific CAR CD8 T cells that can create a pro-inflammatory microenvironment in PDAC.  Immunotherapy based on CAR-N-CD8 T cells can create an IFN-γ dominated pancreatic microenvironment in vivo GAD65-specific humanized mice model, break the tumor barrier, and activate indigenous CD4 and CD8 T cells. These cells can invade the tumor-associated barrier and interact with cancer cells. This foundation work will pave the way for developing a strategy against PDAC.  

Applications: (i) A composition comprising pancreatic beta cell-specific chimeric antigen receptor (CAR) CD8 T cells functional for treating PDAC.

Shahnawaz Imam, 2024, University of Toledo, Office of Technology Transfer 2024, technology file# TECH-2024-11. United States Provisional Patent # 63/666,449 filed July 1, 2024.

Synergistic Inhibition of eIF5A and Notch Signaling in Intermediate Tregs