Herbert Lyerly

Overview:

Positions:

George Barth Geller Distinguished Professor of Immunology

Surgery, Surgical Sciences
School of Medicine

Professor of Surgery

Surgery, Surgical Sciences
School of Medicine

Professor in Immunology

Immunology
School of Medicine

Professor of Pathology

Pathology
School of Medicine

Affiliate, Duke Global Health Institute

Duke Global Health Institute
Institutes and Provost's Academic Units

Core Faculty Member, Duke-Margolis Center for Health Policy

Duke - Margolis Center For Health Policy
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Regeneration Next Initiative

Regeneration Next Initiative
School of Medicine

Education:

M.D. 1983

University of California - Los Angeles

Grants:

A Cancer Rainbow Mouse for the Simultaneous Assessment of Multiple Oncogenes

Administered By
Cell Biology
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Inhibition of Wnt/B-Catenin Signaling in Colorectal Cancer Therapy

Administered By
Medicine, Gastroenterology
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

A Molecular Framework for Understanding DCIS

Awarded By
Department of Defense
Role
Principal Investigator
Start Date
End Date

Advancing Immunology in Dogs with Naturally-occurring Invasive Bladder Cancer, a Relevant Model to Improve Immunotherapy Across Molecular Cancer Subtypes in Humans

Awarded By
Purdue University
Role
Principal Investigator
Start Date
End Date

Preclinical Development Of Rna Decoys

Awarded By
National Institutes of Health
Role
Co-Principal Investigator
Start Date
End Date

Publications:

Changes in peripheral blood regulatory T cells, and IL-6 and IL-10 levels predict response of pediatric medulloblastoma and germ cell tumors with residual or disseminated disease to craniospinal irradiation.

PURPOSE: Radiotherapy modulates immune cells and cytokines resulting in both clinically beneficial and detrimental effects. The changes in peripheral blood T lymphocyte subsets and cytokines during radiotherapy for pediatric brain tumors and the association of these changes with therapeutic outcomes have not been well described. METHODS AND MATERIALS: The study population consisted of children (n=83, ages 3∼18) with primary brain tumors (medulloblastoma, glioma, germ cell tumors, and CNS embryonal tumor-NOS), with or without residual or disseminated (R/D) diseases who were starting standard post-operative focal or craniospinal-irradiation (CSI). Peripheral blood T lymphocyte subsets collected before and 4 weeks after radiotherapy were enumerated by flow cytometry. Plasma levels of IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, and IL-17A were measured by cytometric bead array. RESULTS: Patients with R/D lesions receiving CSI (n=32) had a post-radiotherapy increase in the frequency of CD3+T cell and CD8+T cells, a decrease in CD4+ T cells, and an increase in Tregs and CD8+CD28- suppressor cells which were predominantly seen than other groups. In such R/D lesions exposed to CSI group, consisting of patients with medulloblastoma and germ cell tumors, 19 experienced a complete response (CR) and 13 experienced a partial response (PR) on imaging at 4 weeks following radiotherapy. The post/pre-radiotherapy ratio of Tregs (P =0.0493), IL-6 (P=0.0111) and IL-10 (P=0.0070) was lower in the CR group than the PR group. Multivariate analysis revealed that the post/pre-radiotherapy ratios of Treg, IL-6 and IL-10 were independent predictors of CR (P<0.0001, P=0.018, P<0.0001, respectively). The areas under the receiver operating curves (ROC) and confidence intervals were 0.7652 (0.5831ཞ0.8964), 0.7794 (0.5980ཞ0.9067), 0.7085 (0.5223ཞ0.8552) for IL-6, IL-10 and Treg respectively. The sensitivities of IL-6, IL-10 and Treg to predict radiotherapeutic responses were 100%, 92.3%, and 61.5% and specificity was 52.6%, 57.9%, and 84.2% respectively. CONCLUSIONS: CSI treatment to those with R/D lesions exerted a predominantly effect on anti-tumor immune response compared with both R/D lesions-free but exposed to focal or CSI radiotherapy and with R/D lesions for focal radiotherapy. Such CSI with R/D lesions group experiencing CR is more likely to have a decrease in immunoinhibitory molecules and cells than patients who only achieve PR. Measuring peripheral blood Treg, IL-6 and IL-10 levels could be valuable for predicting radiotherapeutic responses of pediatric brain tumors with R/D lesions with CSI for medulloblastoma and intracranial germ cell tumors.
Authors
Song, L; Wang, S; Fang, T; Qiu, X; Wang, X; Zhou, X; Morse, MA; Hobeika, A; Wu, W; Yang, H; Ren, J; Lyerly, HK
URI
https://scholars.duke.edu/individual/pub1481989
PMID
33974888
Source
pubmed
Published In
Int J Radiat Oncol Biol Phys
Published Date
DOI
10.1016/j.ijrobp.2021.04.041

Intratumoral Plasmid IL12 Expands CD8+ T Cells and Induces a CXCR3 Gene Signature in Triple-negative Breast Tumors that Sensitizes Patients to Anti-PD-1 Therapy.

PURPOSE: Triple-negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Antibodies targeting programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) have entered the therapeutic landscape in TNBC, but only a minority of patients benefit. A way to reliably enhance immunogenicity, T-cell infiltration, and predict responsiveness is critically needed. PATIENTS AND METHODS: Using mouse models of TNBC, we evaluate immune activation and tumor targeting of intratumoral IL12 plasmid followed by electroporation (tavokinogene telseplasmid; Tavo). We further present a single-arm, prospective clinical trial of Tavo monotherapy in patients with treatment refractory, advanced TNBC (OMS-I140). Finally, we expand these findings using publicly available breast cancer and melanoma datasets. RESULTS: Single-cell RNA sequencing of murine tumors identified a CXCR3 gene signature (CXCR3-GS) following Tavo treatment associated with enhanced antigen presentation, T-cell infiltration and expansion, and PD-1/PD-L1 expression. Assessment of pretreatment and posttreatment tissue from patients confirms enrichment of this CXCR3-GS in tumors from patients that exhibited an enhancement of CD8+ T-cell infiltration following treatment. One patient, previously unresponsive to anti-PD-L1 therapy, but who exhibited an increased CXCR3-GS after Tavo treatment, went on to receive additional anti-PD-1 therapy as their immediate next treatment after OMS-I140, and demonstrated a significant clinical response. CONCLUSIONS: These data show a safe, effective intratumoral therapy that can enhance antigen presentation and recruit CD8 T cells, which are required for the antitumor efficacy. We identify a Tavo treatment-related gene signature associated with improved outcomes and conversion of nonresponsive tumors, potentially even beyond TNBC.
Authors
Telli, ML; Nagata, H; Wapnir, I; Acharya, CR; Zablotsky, K; Fox, BA; Bifulco, CB; Jensen, SM; Ballesteros-Merino, C; Le, MH; Pierce, RH; Browning, E; Hermiz, R; Svenson, L; Bannavong, D; Jaffe, K; Sell, J; Foerter, KM; Canton, DA; Twitty, CG; Osada, T; Lyerly, HK; Crosby, EJ
MLA Citation
Telli, Melinda L., et al. “Intratumoral Plasmid IL12 Expands CD8+ T Cells and Induces a CXCR3 Gene Signature in Triple-negative Breast Tumors that Sensitizes Patients to Anti-PD-1 Therapy.Clin Cancer Res, vol. 27, no. 9, May 2021, pp. 2481–93. Pubmed, doi:10.1158/1078-0432.CCR-20-3944.
URI
https://scholars.duke.edu/individual/pub1474844
PMID
33593880
Source
pubmed
Published In
Clinical Cancer Research
Volume
27
Published Date
Start Page
2481
End Page
2493
DOI
10.1158/1078-0432.CCR-20-3944

Targeting the glucagon receptor signaling pathway as a novel strategy to counteract PI3K inhibitor induced hyperglycemia while sustaining tumor PI3K inhibition.

Authors
Wang, J; Osada, T; Morse, MA; Calzone, F; Yan, H; Thai, D; Lyerly, HK
MLA Citation
URI
https://scholars.duke.edu/individual/pub1474786
PMID
33576297
Source
pubmed
Published In
Leuk Lymphoma
Published Date
Start Page
1
End Page
6
DOI
10.1080/10428194.2021.1881504

Intratumoral delivery of tavokinogene telseplasmid (plasmid IL-12) and electroporation induces an immune signature that predicts successful combination in patients

Authors
Crosby, EJ; Nagata, H; Telli, ML; Acharya, CR; Wapnir, I; Zablotsky, K; Browning, E; Hermiz, R; Svenson, L; Bannavong, D; Malloy, K; Canton, DA; Twitty, CG; Osada, T; Lyerly, HK
URI
https://scholars.duke.edu/individual/pub1477078
Source
wos-lite
Published In
Cancer Research
Volume
81
Published Date

Targeting the Glucagon Receptor Signaling Pathway As a Novel Strategy to Counteract PI3K Inhibitor Induced Hyperglycemia While Sustaining Tumor PI3K Inhibition

<jats:p>Pathologic activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is an oncogenic driver for many malignancies, including lymphomas1. Although validated as a therapeutic oncologic target, the PI3K signaling pathway is also implicated in normal glucose homeostasis. Specifically, since the PI3K subunit p110α is chiefly responsible for downstream insulin receptor (INSR) signaling, PI3K signaling inhibition that includes p110α leads to severe hyperglycemia. Both compensatory endogenous insulin release as well as treatment of hyperglycemia with exogenous insulin/insulin mimetics activate INSR-associated PI3K signaling, ultimately limiting blockade of tumor associated PI3K signaling2. Aggressive lymphomas driven by pathologic PI3K signaling respond to combined PI3Kα and δ/γ inhibition, but this is likely submaximal due to endogenous insulin feedback, and more intense dosing is difficult to achieve safely due to severe hyperglycemia3. Therefore, a novel strategy to maintain blockade of tumor associated PI3K signaling while reducing hyperglycemia is needed. We hypothesized that inhibition of glucagon receptor (GCGR) signaling, a pathway that does not depend on PI3K, may normalize PI3K inhibitor induced hyperglycemia without disrupting antitumor PI3K blockade. GCGR blockade with a GCGR specific monoclonal antibody (REMD-477, a human anti-GCGR antibody, or REMD2.59c, a murine equivalent) may allow for the safer use of more potent PI3K inhibitors or more intensive dosing schedules in the treatment of aggressive lymphomas.</jats:p> <jats:p>The effect of GCGR blockade on PI3K inhibitor induced hyperglycemia was first evaluated in a non-tumor bearing mouse model using REMD2.59c. The PI3K inhibitor copanlisib was administered by tail vein injection to CB17 SCID mice in the control group every other day at the reported MTD of 15 mg/kg. REMD2.59c was administered by intraperitoneal injection to the treatment group intermittently on the day prior to copanlisib injection. Blood glucose levels were measured 2 hours after copanlisib injection. Significant hyperglycemia was observed after copanlisib treatment, and this was corrected by REMD2.59c pretreatment, confirming the effectiveness of GCGR blockade (Figure A-B).</jats:p> <jats:p>Having demonstrated that GCGR blockade controls hyperglycemia caused by PI3K inhibition with copanlisib in a mouse model, we next treated a 54 year old non-diabetic woman with relapsed and refractory peripheral T cell lymphoma (PTCL) on an IRB-approved clinical pilot study of copanlisib in combination with REMD-477. Following copanlisib 60mg IV alone, glucose increased from a baseline of 100mg/dl to a maximum of 592 mg/dl at 5 hours. For the following weekly doses of copanlisib, she was pre-treated with 70mg REMD-477 SQ, and copanlisib induced hyperglycemia was significantly ameliorated (Figure C). The patient tolerated treatment with REMD-477 well without significant episodes of hypoglycemia.</jats:p> <jats:p>With improved glycemic control on REMD-477, our patient did not require dose reductions or treatment delays, and experienced clinical improvement in lymphadenopathy on copanlisib. She had previously progressed through 6 lines of therapy, including duvelisib, a selective PI3K δ/γ inhibitor which necessitated dose reduction due to gastrointestinal toxicity. Our study of the GCGR mAb REMD-477 as a novel strategy to counteract PI3K inhibitor induced hyperglycemia and insulin feedback is an important advance that may allow for more effective and safer use of potent PI3K inhibitors in the treatment of aggressive lymphomas.</jats:p> <jats:p>References</jats:p> <jats:p>1. Alzahrani AS. PI3K/Akt/mTOR inhibitors in cancer: At the bench and bedside. Semin Cancer Biol. 2019;59(April):125-132. doi:10.1016/j.semcancer.2019.07.009</jats:p> <jats:p>2. Hopkins BD, Pauli C, Du X, et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature. 2018;560(7719):499-503. doi:10.1016/j.physbeh.2017.03.040</jats:p> <jats:p>3. Cheson BD, O'Brien S, Ewer MS, et al. Optimal Management of Adverse Events From Copanlisib in the Treatment of Patients With Non-Hodgkin Lymphomas. Clin Lymphoma, Myeloma Leuk. 2019;19(3):135-141. doi:10.1016/j.clml.2018.11.021</jats:p> <jats:p>Figure 1.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>Calzone: REMD Biotherapeutics: Current equity holder in private company. Yan:REMD Biotherapeutics: Current Employment, Current equity holder in private company. Thai:REMD Biotherapeutics: Current Employment, Current equity holder in private company. Lyerly:REMD Biotherapeutics: Consultancy, Current equity holder in private company.</jats:p> </jats:sec> <jats:sec> <jats:title>OffLabel Disclosure:</jats:title> <jats:p>Copanlisib in the treatment of peripheral T cell lymphoma</jats:p> </jats:sec>
Authors
Wang, J; Morse, M; Calzone, F; Yan, H; Thai, Z; Osada, T; Lyerly, H
MLA Citation
Wang, Jie, et al. “Targeting the Glucagon Receptor Signaling Pathway As a Novel Strategy to Counteract PI3K Inhibitor Induced Hyperglycemia While Sustaining Tumor PI3K Inhibition.” Blood, vol. 136, no. Supplement 1, American Society of Hematology, 2020, pp. 4–5. Crossref, doi:10.1182/blood-2020-140576.
URI
https://scholars.duke.edu/individual/pub1475010
Source
crossref
Published In
Blood
Volume
136
Published Date
Start Page
4
End Page
5
DOI
10.1182/blood-2020-140576