Purna Krishnamurthy
A5004379340- Dermatology and Skin Diseases
- IL-33, ST2, and ILC Pathways
- PARP inhibition in cancer therapy
- Asthma and respiratory diseases
- Eosinophilic Esophagitis
- Ion Channels and Receptors
- Immune Cell Function and Interaction
- Cancer, Stress, Anesthesia, and Immune Response
- Acne and Rosacea Treatments and Effects
- Cytokine Signaling Pathways and Interactions
- Brain Metastases and Treatment
- Cancer Cells and Metastasis
- Atherosclerosis and Cardiovascular Diseases
- Exercise and Physiological Responses
- Cancer, Lipids, and Metabolism
- CAR-T cell therapy research
- Adipokines, Inflammation, and Metabolic Diseases
- Immunotherapy and Immune Responses
- Electrostatic Discharge in Electronics
- Wound Healing and Treatments
- Eosinophilic Disorders and Syndromes
- Advancements in Semiconductor Devices and Circuit Design
- Allergic Rhinitis and Sensitization
- Contact Dermatitis and Allergies
- Adipose Tissue and Metabolism
Baylor College of Medicine
2025
Indiana University – Purdue University Indianapolis
2013-2017
Indiana University School of Medicine
2013-2017
Indiana University
2016
Center for Children
2016
Riley Hospital for Children
2013-2014
Indiana University Indianapolis
2014
// Riesa M. Burnett 1 , Kelly E. Craven 2 Purna Krishnamurthy Chirayu P. Goswami 4 Sunil Badve 3 Peter Crooks 5 William Mathews 6 Poornima Bhat-Nakshatri and Harikrishna Nakshatri 1,2,4 Department of Surgery, Indiana University School Medicine, Indianapolis, IN, USA Biochemistry Molecular Biology, Pathology Laboratory Center for Computational Biology Bioinformatics, Arkansas, Little Rock, AR, Leuchemix, Inc., Woodside, CA, Correspondence to: Nakshatri, email: Keywords : breast cancer, brain...
Abstract The efficacy of CAR T-cells (CART) in solid tumors is limited by immune inhibition. In our study, we observed that effector cytokines mediated the upregulation PD-L1 immune-checkpoint primary glioblastoma (GBM). To offset inhibitory signal, engineered PD-1 checkpoint reversal receptors (CPR) with a CD28 or 41BB co-stimulatory endodomain and co-expressed them first-generation CD28-containing second-generation HER2-specific (CPR/CART) using bicistronic vectors. We found bipartite...
<p>Analysis of CAR immune synapse (CARIS) with HER2+ GBM cells.</p>
<p>Immunophenotype and immune-checkpoint receptor expression in patient-derived CPR/CART cells.</p>
<p>Expression of CAR/CPR on T cells and HER2/PD-L1 tumor cells.</p>
<p>Summary of CPR/CART design and characterization CARζ co-expressing CPR containing CD28 or 4-1BB signaling.</p>
<p>Assessment of PD-L1 expression and CARζ/CPR41BB cell cytotoxic function in osteosarcoma.</p>
<p>Immunophenotype and functional profile of CARζ/CPR41BB in comparison to CAR41BBζ cells.</p>
<p>Analysis of CAR immune synapse (CARIS) formation by CARζ/CPR41BB and CAR41BBζ cells with wild-type PD-L1 KO LN229-GBM cells.</p>
<p>Assessment of mitochondrial metabolism in CARζ/CPR41BB cells.</p>
<p>PD-L1 expression in GBM and PD-1 recruitment to the CARIS with GBM. <b>A,</b> Constitutive (UPN01) inducible (UPN06) surface of PD-L1 primary cells after 24–48 hours IFN-γ exposure. Representative results from two samples shown. UPN, unique patient number. <b>B,</b> median fluorescent intensity (MFI) on (<i>n</i> = 14) before at 48 (10 ng/mL) exposure; ***, <i>P</i> < 0.001, Wilcoxon signed-rank test. <b>C,</b>...
<div>Abstract<p>The efficacy of chimeric antigen receptor T cells (CART) in solid tumors is limited by immune inhibition. In our study, we observed that effector cytokines mediated the upregulation PD-L1 checkpoint primary glioblastoma. To offset inhibitory signal, engineered PD-1 reversal receptors (CPR) with a CD28 or 41BB costimulatory endodomain and coexpressed them first-generation CD28-containing second-generation HER2-specific CAR (CPR/CART) using bicistronic vectors. We...
<p>Dynamics of CARζ/CPR41BB T-cell activation and CARIS formation in comparison with CAR41BBζ cells. <b>A,</b> cells (<i>n</i> = 3 donors) demonstrated significantly lower IL-2 IFN-γ release compared at 24 hours coculture LN229-GBM cells, CAR28ζ consistently showing the higher Th1 cytokine production. Data are shown as mean ± SD. **, <i>P</i> < 0.000; ****, 0.0001; two-way ANOVA Tukey multiple comparisons test. <b>B,</b> Western blot...
<p>Metabolomic parameters of CARζ/CPR41BB cells in comparison with CAR41BBζ cells. <b>A,</b> OCR measurements resting (cultured media containing IL-7 and IL-15) (<i>n</i> = 3 donors; 200,000 T per well) under basal metabolic conditions after the addition mitochondrial inhibitors. <b>B,</b> Comparison maximal respiration between at baseline (day 0). <i>P</i> 0.059, Student two-tailed <i>t</i> test. <b>C,</b> Basal...
<p>Effect of decoupling signal 2 from the CAR on T-cell function. <b>A,</b> Illustration depicting bipartite activation through 1 delivery engaging HER2 antigen and binding CPR with PD-L1 (or PD-L2). <b>B,</b> Percent increase in IFN-γ production by CAR28ζ/CPR28 CARζ/CPR28 compared CAR28ζ cells (50,000 T cells/well) at 24 hours coculture autologous GBM (<i>n</i> = 5 patients). Effector (100,000 cells) to target ratio 1:1. **, <i>P</i>...
<p>Design and functional screening of PD-1<sub>TR</sub> CPR28 molecules. <b>A,</b> Schematic representation the bicistronic vectors encoding for HER2-CAR with truncated PD-1 (PD-1<sub>TR</sub>) or CPR28. The CPR28<sup>dimer</sup> included a membrane proximal extracellular cysteine residue (C141) required CD28 homodimerization, as indicated. <b>B,</b> Flow cytometry analysis showing coexpression CPR on T cells. CAR28ζ NT cells...
<p><i>In vivo</i> antitumor activity of locoregionally delivered CARζ/CPR41BB cells in an orthotopic GBM model. <b>A,</b> Experimental schema for <i>in functional testing a LN229-GBM xenograft Mice were injected with eGFP.FFluc-expressing tumor on day 0 and randomized to treatment groups 11. Treatment consisted two intracranial T-cell injections days 13 21. Tumors monitored by BLI. <b>B,</b> Comparison volumes between control after...
<p>Immunohistochemistry and histopathology findings in a metastatic osteosarcoma model after treatment with CARζ/CPR41BB cells.</p>
<p>PD-L1 expression in glioblastoma (GBM) cells and PD-1 upregulation CART.</p>
<p>In vivo function of systemically administered CARζ/CPR41BB cells in a metastatic osteosarcoma model.</p>
<p>Phenotypic and functional profile of CART receiving bipartite activation signals through CPR41BB costimulation. <b>A,</b><i>In vivo</i> screening CARζ CAR28ζ cells coexpressing CPR28 or against orthotopic xenografts HER2<sup>+</sup>PD-L1<sup>+</sup> U373-GBM in SCID mice (<i>n</i> = 5 per group). <b>B,</b> Fold change tumor burden after treatment relative to the volume before intratumoral injection T (day 0),...