A5036944955- Immune cells in cancer
- Cancer Immunotherapy and Biomarkers
- Nanoplatforms for cancer theranostics
- CAR-T cell therapy research
- Tryptophan and brain disorders
- Cancer, Stress, Anesthesia, and Immune Response
- Cancer, Hypoxia, and Metabolism
- Adenosine and Purinergic Signaling
- Advancements in Semiconductor Devices and Circuit Design
- Histone Deacetylase Inhibitors Research
- T-cell and B-cell Immunology
- Chemokine receptors and signaling
- Peptidase Inhibition and Analysis
- Silicon Carbide Semiconductor Technologies
- Immune Cell Function and Interaction
- Melanoma and MAPK Pathways
- Protein Degradation and Inhibitors
- Viral Infectious Diseases and Gene Expression in Insects
- Virus-based gene therapy research
Cornell University
2019-2025
Weill Cornell Medicine
2019-2024
Swim Across America
2024
Parker Institute for Cancer Immunotherapy
2024
Memorial Sloan Kettering Cancer Center
2019-2023
Stony Brook University
2014
Patients with small cell lung cancer (SCLC) generally have a poor prognosis and median overall survival of only about 13 months, indicating the urgent need for novel therapies. Delta-like protein 3 (DLL3) has been identified as tumor-specific surface marker on neuroendocrine cancers including SCLC. In this study, we developed chimeric antigen receptor (CAR) against DLL3 that displays antitumor efficacy in xenograft murine SCLC models. CAR T expression proinflammatory cytokine interleukin-18...
Tumor reliance on glycolysis is a hallmark of cancer. Immunotherapy more effective in controlling glycolysis-low tumors lacking lactate dehydrogenase (LDH) due to reduced tumor efflux and enhanced glucose availability within the microenvironment (TME). LDH inhibitors (LDHi) reduce uptake growth preclinical models, but their impact tumor-infiltrating T cells not fully elucidated. have higher basal expression levels compared with infiltrating cells, creating therapeutic opportunity for...
Abstract Intravesical therapies have been the mainstay of bladder cancer (BC) management; however, their efficacy is limited by toxicities, recurrences, and supply shortages. Consequently, many patients are recommended cystectomy, which fraught with complications. Thus, bladder-sparing treatments present a major, unmet clinical need. Chimeric antigen receptor (CAR) T cell therapy, wherein cells engineered to express an artificial target, immunotherapeutic approach in hematologic...
MEK inhibitors (MEKi) have shown limited success as a treatment for MAPK/ERK pathway-dependent cancers due to various resistance mechanisms tumor cells can employ. CH5126766 (CKI27) is an inhibitor that binds and prevents release of RAF, reducing the relief negative feedback commonly observed with other MEKis. We CKI27 increased MHC expression in improved T cell-mediated killing. Yet, also decreased T-cell proliferation, activation, cytolytic activity by inhibiting pathway activated...
Chimeric antigen receptor (CAR) T-cell therapy has resulted in remarkable clinical success the treatment of B-cell malignancies. However, its efficacy solid tumors is limited, primarily by target heterogeneity. To overcome heterogeneity, we developed CAR T cells that overexpress LIGHT, a ligand both lymphotoxin-β on cancer and herpes virus entry mediator immune cells. LIGHT-expressing displayed antigen-directed cytotoxicity mediated antigen-independent killing through interaction LIGHT with...
<div>Abstract<p>MEK inhibitors (MEKi) have shown limited success as a treatment for MAPK/ERK pathway–dependent cancers due to various resistance mechanisms tumor cells can employ. CH5126766 (CKI27) is an inhibitor that binds MEK and prevents release of RAF, reducing the relief negative feedback commonly observed with other MEKis. We CKI27 increased MHC expression in improved T cell–mediated killing. Yet, also decreased T-cell proliferation, activation, cytolytic activity by...
<p>Supplemental Figure 11. The triple combination increases activation of CD8+ T cells and CD4+ Teffs while Tregs remain unaffected in LLC TDLN. (A) Schema tumor bearing mice treated with vehicle, CKI27, isotypes, GITR, and/or CTLA-4. All timepoints were harvested on day 21 (7 days post treatment). (B) Image TDLNs from mice. (C) Gating strategy for all vivo flow experiments. (D) Absolute number immune cell populations the TDLN; n=4-5. (E) Phenotypes n=9-10. Data are shown as mean±SEM....
<p>Supplementary Figure 2. MEK inhibition with CKI27 increases MHC and checkpoint ligand expression. Murine tumor cell lines were treated DMSO or for 72 hr either without IFNγ (5ng/mL) the last 24hr; n=3. FACS analysis of representative histograms MFI MHC-I (H2Kb/Kd H2Db/Dd), MHC-II, PD-L1, CD80 CD86 are shown.</p>
<p>Supplementary Figure 9. Intermittent CKI27 treatment and GITR engagement relieves suppressive effects of MEK inhibition on T cell proliferation, cytokine production, effector function. (A-C) Human PBMCs were labelled with CTV, sub-optimally stimulated 1:25 or 1:100 CD3/CD28 Dynabeads, treated DMSO, continuous (96hr), washout (24hr on, 72hr off), and/or GITR-L; n=2-3. (A) % proliferation CTVlow CD8+ CD4+ cells. (B) FACS analysis co-inhibitory, co-stimulatory, activation markers...
<p>Supplementary Figure 10. The triple combination reduces tumor growth, is T cell dependent, and protects from re-challenge in LLC CT26. (A-D) bearing mice were treated with vehicle, isotypes, GITR, CTLA-4, 5mg/kg 4on/3off CKI27, and/or CD8 for 4 weeks growth was monitored over time. (A) Average (volume, mm3) of immunocompetent mice. (B) immunodeficient (C) depleted (D) that re-challenged. (E-H) CT26 αCTLA-4, 2mg/kg αCD8 (E) (F) (G) (H) Two-way ANOVA test Bonferroni’s correction...
<p>(A) ELISA quantification of soluble LIGHT in cell culture media after 24 hours incubation. (B) Supernatant from LIGHT-CAR T cells and second-generation CAR were added to corresponding vitro cytolysis was assessed against AsPC1. Data is representative 2 independent experiments two different donors. (C) MIAPACA2. (D) Cytotoxicity assay with various mesothelin-directed constructs the addition recombinant 3 (E) Mesothelin-directed exhibited similar proliferation a repetitive antigen...
<p>(A) Violin plots showing quality metrics of single cells included in downstream analysis. nCount RNA: number RNA unique molecular identifiers (UMI); nFeature detected genes; nCount_ADT: antibody UMI; nFeature_ADT: antibodies; percent.mt: percentage mitochondrial gene expression; HTO_margin: difference between signals for the hashtag with highest signal and second signal. (B) (C) Weighted-nearest neighbor (WNN) UMAP colored by condition (CAR T cell construct timepoint) (top) CD4+ vs...
<p>Supplementary Figure 5. Intermittent CKI27 allows for immune cell recovery in the spleen, increases frequencies TDLN, and inhibits TILs similarly to continuous treatment. (A) Schema of LLC tumor bearing mice treated with vehicle, daily 2mg/kg CKI27, or intermittent 5mg/kg 4on/3off CKI27. Mice were a staggered schedule all timepoints harvested on day 23. (B-D) All fold changes calculated by normalizing DMSO. (B) Fold absolute number (cells/uL) spleen populations. (C) TDLN (D) weights...
<p>Supplementary Figure 1. MEK inhibition with CKI27 increases MHC and checkpoint ligand expression. (A-B) Murine tumor cell lines were treated DMSO or for 72 hr either without IFNγ (5ng/mL) the last 24hr; n=3. FACS analysis of (A) MHC-I (H2Kb/Kd H2Db/Dd) MHC-II (B) PD-L1, CD80 CD86 surface Median fluorescence intensity (MFI) values normalized to log transformed. Data are shown as mean±SEM.</p>
<p>Supplementary Figure 4. Intermittent CKI27 treatment partially relieves suppressive effects of MEK inhibition on T cell proliferation, cytokine production, and effector function. (A-C) Human PBMCs were labelled with CTV, sub-optimally stimulated 1:25 or 1:100 CD3/CD28 Dynabeads, treated DMSO, continuous (96hr) washout (24hr on, 72hr off); n=2-3. (A) Proliferation fold change CTVlow CD8+ CD4+ cells was calculated by normalizing to DMSO. (B) FACS analysis co-inhibitory,...
<p>Supplementary Figure 7. Intermittent CKI27 treatment and GITR co-stimulation relieves expression of co-stimulatory markers. Representative dot plot data for FACS analysis markers expressed by CD8+ T cells.</p>
<p>Supplementary Figure 6. Intermittent CKI27 treatment and GITR co-stimulation relieves expression of co-inhibitory markers. (A) Gating strategy for all T cell activation assays. (B) Representative dot plot data FACS analysis markers expressed by CD8+ cells.</p>
<p>Supplementary Figure 8. Intermittent CKI27 treatment and GITR co-stimulation relieves expression of activation markers. Representative dot plot data for FACS analysis markers expressed by CD8+ T cells.</p>
<p>Supplementary Figure 3. MEK inhibition with CKI27 increases HLA and checkpoint ligand expression. (A-B) Human tumor cell lines were treated DMSO or for 72hr either without IFNγ (10ng/mL) the last 24hr; n=3. FACS analysis of (A) HLA-ABC HLA-DR (B) PD-L1, CD80 CD86 surface MFI values are shown as mean±SEM.</p>
<p>Supplementary Figure 12. The triple combination increases activation of CD8+ T cells, CD4+ Teffs, and Tregs in CT26 TDLN. (A) Schema tumor bearing mice treated with vehicle, CKI27, isotypes, GITR, and/or CTLA-4. All timepoints were harvested on day 21 (7 days post treatment). (B) Absolute number immune cell populations the TDLN; n=4-5. (C) Phenotypes cells from Data are shown as mean±SEM. One-way ANOVA test Bonferroni’s correction for multiple comparisons was used all panels....
<p>(A) Flow cytometric analysis of LTβR expression MIAPACA2 cells after CRISPR knockout (KO). KO were also transduced with non-signaling without intracellular signaling portion (tLTBR). (B) healthy human donor-derived mesothelin-targeted CAR T cocultured tumor expressing GFP and firefly luciferase at different effector to ratios. Bioluminescence was measured 72 hours later plotted as a percentage the signal detected in coculture non-functional Meso-DEL-CAR cells. Plots represent 3...
<p>(A) CAR T cells infiltration and expression of LIGHT at the tumor site was quantified by flow cytometric analysis on day 14 post cell treatment. (B) (C) Quantification per gram AsPC1 mass Plot is representative 4 to 5 mice treatment group. Immunohistochemistry staining mesothelin-negative cancer line, Panc1. Negative control. (D) mesothelin-positive MDA-MB-231. Positive (E) various PDX slides samples validate their mesothelin expression. (F) Flow in PDAC2, one selected for vivo...