Darell Bigner

Overview:

The Causes, Mechanisms of Transformation and Altered Growth Control and New Therapy for Primary and Metastatic Tumors of the Central Nervous System (CNS).

There are over 16,000 deaths in the United States each year from primary brain tumors such as malignant gliomas and medulloblastomas, and metastatic tumors to the CNS and its covering from systemic tumors such as carcinoma of the lung, breast, colon, and melanoma. An estimated 80,000 cases of primary brain tumors were expected to be diagnosed last year. Of that number, approximately 4,600 diagnosed will be children less than 19 years of age. During the last 20 years, however, there has been a significant increase in survival rates for those with primary malignant brain tumors.

For the last 44 years my research has involved the investigation of the causes, mechanism of transformation and altered growth control, and development of new methods of therapy for primary brain tumors and those metastasizing to the CNS and its coverings. In collaboration with my colleagues in the Preston Robert Tisch Brain Tumor Center, new drugs and those not previously thought to be active against CNS tumors have been identified. Overcoming mechanisms of drug resistance in primary brain tumors are also being pursued.

As the founding Director of the Preston Robert Tisch Brain Tumor Center, I help coordinate the research activities of all 37 faculty members in the Brain Tumor Center. These faculty members have projects ranging from very basic research into molecular etiology, molecular epidemiology, signal transduction; translational research performing pre-clinical evaluation of new therapies, and many clinical investigative efforts. I can describe any of the Brain Tumor Center faculty member’s research to third year students and then direct them to specific faculty members with whom the students would like a discussion.

We have identified through genome-wide screening methodology several new target molecules selectively expressed on malignant brain tumors, but not on normal brain. These include EGFRwt, EGFRvIII, and two lacto series gangliosides, 3'-isoLM1 and 3',6'-isoLD1 and chondroitin proteoglycan sulfate. We raised conventional and fully human monoclonal antibodies against most of these targets as well as having developed single fragment chain molecules from naïve human libraries.

My personal research focuses on molecularly targeted therapies of primary and metastatic CNS tumors with monoclonal antibodies and their fragments. Our study we conducted was with a molecule we discovered many years ago, the extracellular matrix molecule, Tenascin. We have treated over 150 malignant brain tumor patients with excellent results with a radiolabeled antibody we developed against Tenascin. We are collaborating with Dr. Ira Pastan at NIH to develop tumor-targeted therapies by fusing single fragment chain molecules from monoclonal antibodies or from naïve human libraries to the truncated fragment of pseudomonas exotoxin A. One example of this is the pseudomonas exotoxin conjugated to a single fragment chain antibody that reacts with wild type EGFR and EGFRvIII, two overexpressed proteins on glioblastoma. The immunotoxin, called D2C7-IT, is currently being investigated in an FDA dose-escalation study, in which patients undergoing treatment of this investigational new drug are showing positive responses. My laboratory is also working with Matthias Gromeier, creator of the oncolytic poliovirus - a re-engineered poliovirus that is lethal to cancer cells, but not lethal to normal cells. The oncolytic poliovirus therapeutic approach has shown such promising results in patients with glioblastoma, that it was recently featured on a on a special two-segment program of 60 Minutes. The next clinical step will be to combine both the virus and the immunotoxin with anti-PD1, an immune checkpoint blockade inhibitor and with anti-CD40, a fully human monoclonal antibody which converts tumor stimulant macrophages into tumor suppressive macrophages. We believe that regional tumor-targeted cytotoxic therapies, such as oncolytic poliovirus and the D2C7 immunotoxin, not only specifically target and destroy tumor cells, but in the process, initiate immune events that promote an in situ vaccine effect. That immune response can be amplified by human checkpoint blockade to engender a long-term systemic immune response that effectively eliminates recurrent and disseminated GBM cells. Ultimately, all three agents may be used together, providing different antigenic targets and cytotoxicity mechanisms.

We have identified through genome-wide screening methodology several new target molecules selectively expressed on malignant brain tumors, but not on normal brain. These include glycoprotein non-metastatic B (GPNMB), a molecule shared with malignant melanoma; MRP3, a member of the multidrug resistant family; and two lacto series gangliosides, 3'-isoLM1 and 3',6'-isoLD1 and chondroitin proteoglycan sulfate. We are raising conventional monoclonal antibodies against all of these targets as well as developing single fragment chain molecules from naïve human libraries. When necessary, affinity maturation in vitro is carried out and the antibodies and fragments are armed either with radioactive iodine, radioactive lutetium, or radioactive Astatine-211. Other constructs are evaluated for unarmed activity and some are armed with Pseudomonas exotoxin. After development of the constructs, they are evaluated in human malignant glioma xenograft systems and then all studies necessary for Investigational New Drug Permits from the Food and Drug Administration are carried out prior to actual clinical trial.

I was senior author on a New England Journal of Medicine paper that was the first to show markedly increased survival in low to intermediate grade gliomas with an isocitrate dehydrogenase mutation.

The first fully funded Specialized Research Center on Primary and Metastatic Tumors to the CNS funded by the National Institutes of Health, of which I was Principal Investigator, was funded for 30 years at which time the type of grant was discontinued. My NCI MERIT Award, which ranked in the upper 1.2 percentile of all NIH grants at the time of its last review, is currently in its 40th year of continuous funding. It is one of the few MERIT awards awarded three consecutive times, and it is the longest continually funded grant of the NCI Division of Cancer Diagnosis and Treatment. My last NCI Award was an Outstanding Investigator Award from 2014 to 2022.

In addition to the representative publications listed, I have made national presentations and international presentations during the past year.

My laboratory has trained over 50 third year medical students, residents, Ph.D. students, and postdoctoral fellows and I have a great deal of experience in career development with some students having advanced all the way from fellowship status to endowed professorships. A major goal with third year medical students is to perform work that can be presented in abstract form at national or international meetings and to obtain publication in major peer-reviewed journals.

Positions:

E. L. and Lucille F. Jones Cancer Distinguished Research Professor, in the School of Medicine

Neurosurgery
School of Medicine

Professor of Neurosurgery

Neurosurgery
School of Medicine

Chief, Division of Experimental Pathology

Pathology
School of Medicine

Professor of Surgery

Surgery
School of Medicine

Professor of Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1965

Duke University

Ph.D. 1971

Duke University

Intern, Surgery

Duke University

Fellow, Neurological Surgery

Duke University

Clinical Associate, Medical Neurology

National Institutes of Health

Grants:

Enhancing dendritic cell migration to drive potent anti-tumor immune responses

Administered By
School of Medicine
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Targeting EGFRvIII in Brain Tumors with Bispecific Antibodies

Administered By
School of Medicine
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Nuclear EGFR Signaling Network in Human Cancer

Administered By
Surgery, Surgical Sciences
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

The Role of CD155 in Leptomeningeal Dissemination and Oncolytic Virus Susceptibility in the Medulloblastoma Microenvironment

Administered By
Neurosurgery
Awarded By
Department of Defense
Role
Mentor
Start Date
End Date

Phase-1 clinical trial of PVSRIPO oncolytic immunotherapy in pediatric HGG

Administered By
Neurosurgery
Awarded By
Solving Kids' Cancer
Role
Co Investigator
Start Date
End Date

Publications:

Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy.

Several immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits in 10-20% of patients. Here we perform genomic analysis of tumor tissue from recurrent WHO grade IV glioblastoma patients acquired prior to immunotherapy intervention. We report that very low tumor mutation burden is associated with longer survival after recombinant polio virotherapy or after immune checkpoint blockade in recurrent glioblastoma patients. A relationship between tumor mutation burden and survival is not observed in cohorts of immunotherapy naïve newly diagnosed or recurrent glioblastoma patients. Transcriptomic analyses reveal an inverse relationship between tumor mutation burden and enrichment of inflammatory gene signatures in cohorts of recurrent, but not newly diagnosed glioblastoma tumors, implying that a relationship between tumor mutation burden and tumor-intrinsic inflammation evolves upon recurrence.
Authors
Gromeier, M; Brown, MC; Zhang, G; Lin, X; Chen, Y; Wei, Z; Beaubier, N; Yan, H; He, Y; Desjardins, A; Herndon, JE; Varn, FS; Verhaak, RG; Zhao, J; Bolognesi, DP; Friedman, AH; Friedman, HS; McSherry, F; Muscat, AM; Lipp, ES; Nair, SK; Khasraw, M; Peters, KB; Randazzo, D; Sampson, JH; McLendon, RE; Bigner, DD; Ashley, DM
MLA Citation
Gromeier, Matthias, et al. “Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy.Nat Commun, vol. 12, no. 1, Jan. 2021, p. 352. Pubmed, doi:10.1038/s41467-020-20469-6.
URI
https://scholars.duke.edu/individual/pub1471754
PMID
33441554
Source
pubmed
Published In
Nature Communications
Volume
12
Published Date
Start Page
352
DOI
10.1038/s41467-020-20469-6

ANALYSIS OF IMMUNE SIGNATURES IN PEDIATRIC GLIOBLASTOMAS FOR PATIENT STRATIFICATION TO IMMUNOTHERAPY

Authors
Chandramohan, V; Evangelous, T; Lipp, ES; Hora, B; Bigner, DD; McLendon, RE; Ashley, DM
MLA Citation
Chandramohan, Vidyalakshmi, et al. “ANALYSIS OF IMMUNE SIGNATURES IN PEDIATRIC GLIOBLASTOMAS FOR PATIENT STRATIFICATION TO IMMUNOTHERAPY.” Neuro Oncology, vol. 22, 2020, pp. 365–365.
URI
https://scholars.duke.edu/individual/pub1473564
Source
wos-lite
Published In
Neuro Oncology
Volume
22
Published Date
Start Page
365
End Page
365

GENETICALLY STABLE POLIOVIRUS VECTOR CARRYING H3.3K27M ANTIGEN FOR TREATMENT OF DIFFUSE MIDLINE GLIOMA BY INTRAMUSCULAR INJECTION

Authors
Mosaheb, M; Landi, D; Dobrikova, E; Brown, M; Yang, Y; Cable, J; Okada, H; Nair, S; Bigner, D; Ashley, D; Gromeier, M
MLA Citation
URI
https://scholars.duke.edu/individual/pub1473629
Source
wos-lite
Published In
Neuro Oncology
Volume
22
Published Date
Start Page
472
End Page
472

ONCOLYTIC POLIOVIRUS AS A PROBE FOR MECHANISMS OF IMMUNE RESISTANCE IN GLIOBLASTOMA

Authors
MLA Citation
Yang, Yuanfan, et al. “ONCOLYTIC POLIOVIRUS AS A PROBE FOR MECHANISMS OF IMMUNE RESISTANCE IN GLIOBLASTOMA.” Neuro Oncology, vol. 22, 2020, pp. 231–231.
URI
https://scholars.duke.edu/individual/pub1467989
Source
wos-lite
Published In
Neuro Oncology
Volume
22
Published Date
Start Page
231
End Page
231

302 A phase I trial of intratumoral PVSRIPO in patients with unresectable treatment refractory melanoma

<jats:sec><jats:title>Background</jats:title><jats:p>While PD-1/PD-L1 antagonists have improved the prognosis for many patients with melanoma, the majority fail therapy. PVSRIPO is a novel immunotherapy consisting of a non-neurovirulent rhinovirus:poliovirus chimera that activates innate immunity to facilitate a targeted anti-tumor immune response. Preclinical data show that PVSRIPO plus anti-PD-1 therapy leads to a greater anti-tumor response than either agent alone, warranting clinical investigation.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>An open-label phase I trial of intratumoral PVSRIPO in patients with unresectable melanoma (AJCC version 7 stage IIIB, IIIC, or IV) was performed. Eligible patients failed at least prior anti-PD-1 and BRAF/MEK (if BRAF mutant) therapy. The primary objective was to characterize the safety and tolerability of PVSRIPO. 12 patients in 4 cohorts received a total of 1, 2 (into 2 different lesions) or 3 (same lesion 3x or 3 different lesions) injections of PVSRIPO monotherapy, 21 days apart.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>PVSRIPO injections were well tolerated with no SAEs or DLTs reported; all TEAEs were grade (G) 1 or 2 (grade 1 pruritus most common at 58%), with all but 2 PVSRIPO-related TEAEs localized to the injected or adjacent lesions ( n=1 G1 hot flash, n=1 G1 fatigue). Despite the limited number of PVSRIPO treatments relative to the overall lesion burden (67% patients &gt;5 lesions), 4 of 12 patients (33%) achieved an objective response per irRC, including 4/6 (66%) who received 3 injections (maximum administered). Pathologic complete response (ie, no viable tumor detected in injected and non-injected lesions biopsied) was observed in 2 of 4 (50%) patients with in-transit disease. PVSRIPO response relative to time since prior anti-PD-1 exposure is summarized in table 1. Following study completion/PVSRIPO therapy, 10/12 patients (83%) again received immune checkpoint inhibitor (ICI)-based therapy and 6/12 patients (50%) remained progression free at the data cutoff.</jats:p><jats:table-wrap id="T1" position="float" orientation="portrait"><jats:label>Abstract 302 Table 1</jats:label><jats:caption><jats:p>PVSRIPO anti-tumor response relative to ICI administration and post-study disease status</jats:p></jats:caption><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="ABS_302_T001" position="float" orientation="portrait" /></jats:table-wrap></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Intratumoral PVSRIPO was well tolerated. When taken together with preclinical data, the anti-tumor responses observed relative to prior or subsequent ICI therapy suggests that PVSRIPO, either alone or in combination with anti-PD-1, may be an effective treatment in anti-PD-1 refractory melanoma. An amendment exploring higher PVSRIPO dose levels is ongoing and a phase 2 study with and without anti-PD-1 in the refractory population is initiating.</jats:p></jats:sec><jats:sec><jats:title>Ethics Approval</jats:title><jats:p>This study (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT03712358">NCT03712358</jats:ext-link>) was approved by WIRB; ID 20181772.</jats:p></jats:sec>
Authors
Beasley, G; Farrow, N; Landa, K; Seilm, MA; Jung, S-H; Bigner, D; Kelly, AT; Nair, S; Gromeier, M; Salama, A
MLA Citation
Beasley, Georgia, et al. “302 A phase I trial of intratumoral PVSRIPO in patients with unresectable treatment refractory melanoma.” Journal for Immunotherapy of Cancer, vol. 8, no. Suppl 3, BMJ, 2020, pp. A329–A329. Crossref, doi:10.1136/jitc-2020-sitc2020.0302.
URI
https://scholars.duke.edu/individual/pub1475414
Source
crossref
Published In
Journal for Immunotherapy of Cancer
Volume
8
Published Date
Start Page
A329
End Page
A329
DOI
10.1136/jitc-2020-sitc2020.0302