Publications by authors named "M Kazim Panjwani"

17 Publications

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Establishing a model system for evaluating CAR T cell therapy using dogs with spontaneous diffuse large B cell lymphoma.

Oncoimmunology 2020 23;9(1):1676615. Epub 2019 Oct 23.

Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Multiple rodent and primate preclinical studies have advanced CAR T cells into the clinic. However, no single model accurately reflects the challenges of effective CAR T therapy in human cancer patients. To evaluate the effectiveness of next-generation CAR T cells that aim to overcome barriers to durable tumor elimination, we developed a system to evaluate CAR T cells in pet dogs with spontaneous cancer. Here we report on this system and the results of a pilot trial using CAR T cells to treat canine diffuse large B cell lymphoma (DLBCL). We designed and manufactured CD20-targeting, second-generation canine CAR T cells for functional evaluation and using lentivectors to parallel human CAR T cell manufacturing. A first-in-species trial of five dogs with DLBCL treated with CAR T was undertaken. Canine CAR T cells functioned in an antigen-specific manner and killed CD20+ targets. Circulating CAR T cells were detectable post-infusion, however, induction of canine anti-mouse antibodies (CAMA) was associated with CAR T cell loss. Specific selection pressure on CD20+ tumors was observed following CAR T cell therapy, culminating in antigen escape and emergence of CD20-disease. Patient survival times correlated with product expansion. Altering product manufacturing improved transduction efficiency and skewed toward a memory-like phenotype of canine CAR T cells. Manufacturing of functional canine CAR T cells using a lentivector is feasible. Comparable challenges to effective CAR T cell therapy exist, indicating their relevance in informing future human clinical trial design.
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http://dx.doi.org/10.1080/2162402X.2019.1676615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959441PMC
October 2019

Checkpoint Blockade Reverses Anergy in IL-13Rα2 Humanized scFv-Based CAR T Cells to Treat Murine and Canine Gliomas.

Mol Ther Oncolytics 2018 Dec 28;11:20-38. Epub 2018 Aug 28.

Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

We generated two humanized interleukin-13 receptor α2 (IL-13Rα2) chimeric antigen receptors (CARs), Hu07BBz and Hu08BBz, that recognized human IL-13Rα2, but not IL-13Rα1. Hu08BBz also recognized canine IL-13Rα2. Both of these CAR T cell constructs demonstrated superior tumor inhibitory effects in a subcutaneous xenograft model of human glioma compared with a humanized EGFRvIII CAR T construct used in a recent phase 1 clinical trial (ClinicalTrials.gov: NCT02209376). The Hu08BBz demonstrated a 75% reduction in orthotopic tumor growth using low-dose CAR T cell infusion. Using combination therapy with immune checkpoint blockade, humanized IL-13Rα2 CAR T cells performed significantly better when combined with CTLA-4 blockade, and humanized EGFRvIII CAR T cells' efficacy was improved by PD-1 and TIM-3 blockade in the same mouse model, which was correlated with the levels of checkpoint molecule expression in co-cultures with the same tumor . Humanized IL-13Rα2 CAR T cells also demonstrated benefit from a self-secreted anti-CTLA-4 minibody in the same mouse model. In addition to a canine glioma cell line (J3T), canine osteosarcoma lung cancer and leukemia cell lines also express IL-13Rα2 and were recognized by Hu08BBz. Canine IL-13Rα2 CAR T cell was also generated and tested by co-culture with canine tumor cells and in an orthotopic model of canine glioma. Based on these results, we are designing a pre-clinical trial to evaluate the safety of canine IL-13Rα2 CAR T cells in dog with spontaneous IL-13Rα2-positive glioma, which will help to inform a human clinical trial design for glioblastoma using humanized scFv-based IL-13Rα2 targeting CAR T cells.
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http://dx.doi.org/10.1016/j.omto.2018.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174845PMC
December 2018

Feasibility and Safety of RNA-transfected CD20-specific Chimeric Antigen Receptor T Cells in Dogs with Spontaneous B Cell Lymphoma.

Mol Ther 2016 09 12;24(9):1602-14. Epub 2016 Jul 12.

Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Preclinical murine models of chimeric antigen receptor (CAR) T cell therapy are widely applied, but are greatly limited by their inability to model the complex human tumor microenvironment and adequately predict safety and efficacy in patients. We therefore sought to develop a system that would enable us to evaluate CAR T cell therapies in dogs with spontaneous cancers. We developed an expansion methodology that yields large numbers of canine T cells from normal or lymphoma-diseased dogs. mRNA electroporation was utilized to express a first-generation canine CD20-specific CAR in expanded T cells. The canine CD20 (cCD20) CAR expression was efficient and transient, and electroporated T cells exhibited antigen-specific interferon-gamma (IFN-γ) secretion and lysed cCD20+ targets. In a first-in-canine study, autologous cCD20-ζ CAR T cells were administered to a dog with relapsed B cell lymphoma. Treatment was well tolerated and led to a modest, but transient, antitumor activity, suggesting that stable CAR expression will be necessary for durable clinical remissions. Our study establishes the methodologies necessary to evaluate CAR T cell therapy in dogs with spontaneous malignancies and lays the foundation for use of outbred canine cancer patients to evaluate the safety and efficacy of next-generation CAR therapies and their optimization prior to translation into humans.
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http://dx.doi.org/10.1038/mt.2016.146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5113111PMC
September 2016

Efficacy of palifermin in the hematopoietic stem cell transplant setting.

Authors:
Muneera Panjwani

J Adv Pract Oncol 2013 Mar;4(2):89-100

Yale University School of Nursing, New Haven, Connecticut.

Palifermin is a recombinant human keratinocyte growth factor that stimulates proliferation and differentiation of epithelial cells. Palifermin's biological activity exerts cytoprotective and healing effects that decrease cell injury caused by chemotherapy and radiation therapy. In randomized, placebo-controlled trials, palifermin significantly reduced the incidence and duration of severe oral mucositis. Based on these findings, the US Food and Drug Administration approved palifermin for patients with hematologic malignancies undergoing myeloablative therapy followed by hematopoietic stem cell transplant (HSCT). However, researchers testing the efficacy of palifermin in postapproval studies using various conditioning regimens have debated the extrapolation of palifermin dosage and dosing frequency used in the registration study as inappropriate for less mucotoxic agents. In addition, modifying the dosing intervals and frequency of palifermin has been proposed to decrease adverse events and achieve the highest clinical benefits for less mucotoxic regimens. The incidence and severity of oral mucositis vary significantly across different conditioning regimens. Hence, cost-effectiveness and the clinical benefits of palifermin among various conditioning regimens have also been debated. This article reviews the published literature on the efficacy of palifermin and makes evidence-based recommendations for the use of palifermin in the HSCT setting.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4093413PMC
March 2013

Membranous glomerulonephritis associated with inflammatory demyelinating peripheral neuropathies.

Am J Kidney Dis 1996 Feb;27(2):279-83

Department of Medicine, Baylor College of Medicine, Houston, TX 77030-3498, USA.

A 55-year-old man with chronic inflammatory demyelinating polyradiculoneuropathy developed the nephrotic syndrome. Renal biopsy showed stage I membranous glomerulonephritis. Review of the literature revealed the association of these two rare syndromes, considered to be due to immunologic dysfunction, in two other cases, as well as several cases of the acute form of demyelinating peripheral polyradiculoneuropathy. The nephrotic syndrome appears to be persistent in the chronic form of the peripheral neuropathy but reversible in its acute form following immunosuppressive therapy. The possibility of a common immunopathogenesis in the association of membranous glomerulonephritis and inflammatory demyelinating peripheral neuropathies deserves further scrutiny.
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http://dx.doi.org/10.1016/s0272-6386(96)90554-5DOI Listing
February 1996

Hepatoblastoma in early infancy.

Indian J Pediatr 1984 Jul-Aug;51(411):501-3

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http://dx.doi.org/10.1007/BF02776441DOI Listing
April 1985

Antihistaminase activity of some alkaloids of Rauwolfia serpentina and their derivatives.

Arch Int Pharmacodyn Ther 1965 Sep;157(1):14-21

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September 1965

Reversal of priscol block by antihistamine drugs.

Indian J Med Res 1961 Sep;49:775-80

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September 1961

The action of diacetylmonoxime (DAM) on ciliary activity.

Arch Int Pharmacodyn Ther 1961 Apr;131:107-15

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April 1961