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  5. Development of Safe and Effective Tumor Vaccines and Gene Therapy Products
  1. Biologics Research Projects

Development of Safe and Effective Tumor Vaccines and Gene Therapy Products

Principal Investigator: Raj K. Puri, MD, PhD
Office / Division / Lab: OTAT / DCGT / TVBB

General Overview

Cancer is a very complex public health problem. According to American Cancer Society more than one million Americans are diagnosed with cancer each year and about half of these cancer patients die from this dreadful disease. Despite enormous efforts to find a cure, overall survival of cancer patients remains dismal and new therapeutic approaches are urgently needed. Recent advances in cancer immunotherapy has shown a remarkable potential to make cancer cure a reality.

Our laboratory is engaged in research in the areas of cancer vaccines, immunotherapy, cellular and gene therapy. We also investigate how advanced medical technologies such as genomics can contribute to the study and development of those products. Genomics is the study of the expression and function of thousands of different genes and microRNAs.

The issues raised by cancer vaccines as well as cellular and gene therapy products are extraordinarily complex, multifaceted, and subject to rapid change as the technology progresses. These therapies are rapidly evolving and continue to pose regulatory challenges to the FDA. Our laboratory is addressing some of these challenges by evaluating complex, emerging medical products and facilitating development of safe and effective therapies based on those products.

The FDA is reviewing numerous investigational cancer vaccines, immunotherapy and gene therapy products for investigational use. However, there are limited numbers of licensed products of this nature for clinical use. The main barriers to successful product development are a limited understanding of the biology of tumors, limited knowledge on unique targets on cancer and the lack of appropriate tests to determine unique characteristics, purity and potency of potential products. There is also a lack of reliable animal models that scientists can utilize to evaluate and predict the safety and efficacy of these promising products and methods to monitor meaningful tumor responses in patients. In addition, there is a severe paucity of biomarkers that can help in early diagnosis, predict prognosis and response to cancer therapy.

Our group is currently addressing these issues by developing in vitro and in vivo research programs to increase our understanding of how these products work in the body. Such knowledge will help FDA regulatory scientists conduct informed scientific evaluation of products, develop effective policies, and write documents that provide valuable guidance for industry in these areas. We will also be able to share this new knowledge by organizing workshops and providing education and outreach to numerous stakeholders. Altogether, our work will bring recognition and trust to FDA and its regulatory mission.

Scientific Overview

The overall aims of our research projects are to develop a better comprehension of tumor characteristics through identification and characterization of potential tumor-associated cell surface proteins. These surface proteins will aid in establishing the identity and potency of tumor vaccines (e.g., receptors for IL-13 and IL-4), and potentially lead to methods that link product characteristics with clinical outcome.

In addition, we are studying the mechanism of regulation of over-expressed receptors and tumor antigens and their involvement in other cellular or molecular pathways, such as ontogenesis and signal transduction. This work includes in vitro studies and in vivo animal models of human cancer to elucidate mechanisms of tumor invasion and metastasis that may facilitate identification of additional novel targets or biomarkers for detecting cancer and evaluating therapeutic responses. Furthermore, this work may benefit in the development of new release tests based on the discovery of new biomarkers for identity, potency, and stability for different types of cancer vaccines.

We have established various animal models including orthotopic models of human cancer that are used to evaluate the safety and efficacy of cancer vaccines, cell and gene therapy products. In addition, we are using genomics technology to identify characteristics of cellular cancer vaccines, stem cells and cell substrates used to manufacture cellular and gene therapy products. This technology identifies unique sets of genes that are highly differentially expressed, thus providing a molecular signature of tumors, stem cells, cancer stem cells, or blood cells. This high throughput approach will helps us identifying biomarkers for product characterization, patient safety, and surrogate markers of tumor response.

Our research studies are being conducted under two main projects:

Project 1. Cancer Vaccines and Immunotherapy

The following aims are studied under this project:

Aim 1. Identification, characterization, signaling through novel tumor antigens/receptors and targeting of these receptors for cancer therapy. These studies will potentially help in establishing the identity, purity and potency of cancer vaccines and cancer immunotherapy products. In addition, animal models of human cancer will help assessing safety and efficacy of tumor-targeted agents, cancer vaccines, and immunotherapy products as monotherapy or in combination therapy.

Aim 2. Development of safe and effective cancer vaccines including DNA plasmid or recombinant vaccinia viral vectors expressing human IL-13R2. In addition, molecular characterization of human immature and mature dendritic cells and identification of biomarker of antigen presentation when
pulsed with antigens/peptides as cancer vaccine.

Aim 3. Adoptive Immunotherapy of cancer using CAR-T or engineered TCR cells targeting IL-13 receptor alpha 2

Project 2. Application of Genomics technology: Characterization of Cell and Gene therapy and cancer vaccines products

The following aims are studied under this project:

Aim 1. Characterization of cell banks, cancer vaccines and stem cells by genomics technology to identify markers of purity, identity, potency and targets for therapy

Aim 2. Analysis of IL-4 receptors and IL-13 receptors as potential biomarkers of disease, prognosis and monitoring of tumor response by analyzing publically available The Cancer Genome Atlas (TCGA) database.


PLoS One 2019 May 23;14(5):e0217131
Subcellular compartmentalization of PKM2 identifies anti-PKM2 therapy response in vitro and in vivo mouse model of human non-small-cell lung cancer.
Suzuki A, Puri S, Leland P, Puri A, Moudgil T, Fox BA, Puri RK, Joshi BH

Immunotherapy 2019 Apr;11(6):483-96
Combination immunotherapy with IL-4 Pseudomonas exotoxin and IFN-alpha and IFN-gamma mediate antitumor effects in vitro and in a mouse model of human ovarian cancer.
Green DS, Husain SR, Johnson CL, Sato Y, Han J, Joshi B, Hewitt SM, Puri RK, Zoon KC

J Transl Med 2018 Dec 20;16(1):369
Identification of a novel role of IL-13Ralpha2 in human Glioblastoma multiforme: interleukin-13 mediates signal transduction through AP-1 pathway.
Bhardwaj R, Suzuki A, Leland P, Joshi BH, Puri RK

Stem Cells Transl Med 2018 Sep;7(9):664-75
Functional profiling of chondrogenically induced multipotent stromal cell aggregates reveals transcriptomic and emergent morphological phenotypes predictive of differentiation capacity.
Lam J, Bellayr IH, Marklein RA, Bauer SR, Puri RK, Sung KE

J Neurooncol 2018 Feb;136(3):463-74
Analysis of the cancer genome atlas (TCGA) database identifies an inverse relationship between interleukin-13 receptor alpha1 and alpha2 gene expression and poor prognosis and drug resistance in subjects with glioblastoma multiforme.
Han J, Puri RK

BMC Genomics 2017 Aug 11;18(1):605
MicroRNA expression in bone marrow-derived human multipotent Stromal cells.
Bellayr IH, Kumar A, Puri RK

Tissue Eng Part A 2017 Jun;23(11-12):471-3
Current status and challenges of three-dimensional modeling and printing of tissues and organs.
Husain SR, Ohya Y, Puri RK

BMC Infect Dis 2017 Apr 26;17(1):309
Differential host gene responses from infection with neurovirulent and partially-neurovirulent strains of Venezuelan equine encephalitis virus.
Gupta P, Sharma A, Han J, Yang A, Bhomia M, Knollmann-Ritschel B, Puri RK, Maheshwari RK

Stem Cells Dev 2016 Jun 1;25(11):861-73
Identification of predictive gene markers for multipotent stromal cell proliferation.
Bellayr IH, Marklein RA, Lo Surdo JL, Bauer SR, Puri RK

Stem Cells 2016 Apr;34(4):935-47
High content imaging of early morphological signatures predicts long term mineralization capacity of human mesenchymal stem cells upon osteogenic induction.
Marklein RA, Lo Surdo JL, Bellayr IH, Godil SA, Puri RK, Bauer SR

Blood Cells Mol Dis 2015 Dec;55(4):373-81
Gene expression profile of circulating CD34(+) cells and granulocytes in chronic myeloid leukemia.
Cokic VP, Mojsilovic S, Jaukovic A, Kraguljac-Kurtovic N, Mojsilovic S, Sefer D, Mitrovic Ajtic O, Milosevic V, Bogdanovic A, Dikic D, Milenkovic P, Puri RK

Cancer Gene Ther 2015 Dec;22(12):554-63
Gene therapy for cancer: regulatory considerations for approval.
Husain SR, Han J, Au P, Shannon K, Puri RK

Discov Med 2015 Nov;20(111):273-84
Identification, characterization, and targeting of IL-4 receptor by IL-4-Pseudomonas exotoxin in mouse models of anaplastic thyroid cancer.
Joshi BH, Suzuki A, Fujisawa T, Leland P, Varrichio F, Lababidi S, Lloyd R, Kasperbauer J, Puri RK

Cytokine 2015 Sep;75(1):79-88
Targeting of IL-4 and IL-13 receptors for cancer therapy.
Suzuki A, Leland P, Joshi BH, Puri RK

Mediators Inflamm 2015;2015:453020
Proinflammatory cytokine IL-6 and JAK-STAT signaling pathway in myeloproliferative neoplasms.
Cokic VP, Mitrovic-Ajtic O, Beleslin-Cokic BB, Markovic D, Buac M, Diklic M, Kraguljac-Kurtovic N, Damjanovic S, Milenkovic P, Gotic M, Raj PK

PLoS One 2015 Aug 14;10(8):e0135463
Microarray and proteomic analyses of myeloproliferative neoplasms with a highlight on the mTOR signaling pathway.
Cokic VP, Mossuz P, Han J, Socoro N, Beleslin-Cokic BB, Mitrovic O, Suboticki T, Diklic M, Lekovic D, Gotic M, Puri RK, Noguchi CT, Schechter AN

Cancer Med 2015 Jul;4(7):1060-8
Phase I trial of systemic intravenous infusion of interleukin-13-Pseudomonas exotoxin in patients with metastatic adrenocortical carcinoma.
Liu-Chittenden Y, Jain M, Kumar P, Patel D, Aufforth R, Neychev V, Sadowski S, Gara SK, Joshi BH, Cottle-Delisle C, Merkel R, Yang L, Miettinen M, Puri RK, Kebebew E

Urol Oncol 2015 Mar;33(3):133-6
Regulation of biologic oncology products in the FDA's Center for Biologics Evaluation and Research.
Bross PF, Fan C, George B, Shannon K, Joshi BH, Puri RK

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