Learning Objectives: Explore and propose strategies that would support HBCUs as 5G Testbeds and Partners in deployment of 5G nationwide. Description: Broadband and 5G technology have created the conditions for the Fourth Industrial Revolution (4IR), whether it is the potential of blockchain for enabling key 5G technologies; or the impact IoT devices will have on health care, artificial intelligence innovations, or meeting the demands of increasing data-intensive applications. 4IR will have disruptive implications for the organizational structures of HBCUs and the economies within which they operate. HBCUs, as an integral part of America’s 5G-deployment strategy, are keys to the nation’s growth, productivity and competitiveness strategy. HBCU preparedness for the Fourth Industrial Revolution might well be a solution to the problem of a digitally bifurcated society. It has been predicted that from 2020 to 2035, the total contribution of 5G to real global GDP will be equivalent to an economy the size of India—currently the seventh largest economy in the world. HBCUs have the potential to be force multipliers in the contribution of 5G to both national and global GDP. At the end of this seminar, participants will be able to: 1. Offers suggestions that might lead to developing strategies for HBCUs to be key players in local, state and regional broadband/5G planning ecosystems; 2. Offer suggestions to ensure that HBCUs partner with federal government agencies and the telecommunications industry to be players in the 5G prototyping efforts for participation in 5G testbeds; 3. Develop some problem-solving heuristics for leadership to help re-position HBCUs as leaders in a global digital society and economy; 4. List strategies for how HBCUs can alter their organizational structures for 5G collective impact investing; 5. Suggest strategic steps to establish partnerships for Dynamic Spectrum Sharing; 6. Offer solutions for how HBCUs can participate in the Department of Defense and other federal agency 5G Strategies.

1. Dermawan
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2. Biotechnology for Immune Monitoring of
Glioblastoma Patients
Edjah Nduom, MD
Surgical Neurology Branch
National Institutes of Health

3. Disclosures
Receiving Drug-Only support from Bristol-Myers Squibb

4. Outline
Background
Checkpoint Inhibition for Glioblastoma
• Promise
• Challenges
Patient Expression of Immunosuppressive
markers
Improving clinical trials for the future
• Cytokine microdialysis
• Future directions

5. Take away point
We can improve our glioblastoma clinical trials by
measuring responses in the tissue

6. •GBM is the most aggressive and common primary
malignant brain tumor in adults characterized by
diffuse infiltration of the brain parenchyma
•Newly diagnosed GBM patients treated with
radiation and temozolomide have a time to
progression and median survival of 6.9 and 14
months respectively
•Barriers to therapy include heterogeneity of the
lesions, difficulty in delivery of therapeutics past the
blood brain barrier and resistance of these lesions to
conventional chemotherapeutics
Stupp et al., New England Journal of Medicine, 352(10):987-996, 2005.
Glioblastoma (GBM)

7. Surgery is not enough

8. significant cellularity,
atypia
Insular Lesion - high grade astrocytoma
increase in MIB1

9. Alternative Background Materials

10. Immune Checkpoints
Lynes, … Nduom. Frontiers in Oncology, 2018

11. Checkpoint inhibition for GBM
Lynes, … Nduom. Frontiers in Oncology, 2018

12. CTLA-4 blockade prolongs survival and
elicits increased tumor infiltration of CD8+
cells.
Peter E. Fecci et al. Clin Cancer Res 2007;13:2158-2167
©2007 by American Association for Cancer Research

13. Anti-PD-1 with SRS
Zeng et al., Int J Radiat Oncol Biol Phys, 2013

14. From: Long-term control and partial remission after initial pseudoprogression of glioblastoma by anti–PD-1
treatment with nivolumab
Neuro Oncol. 2016;19(3):454-456. doi:10.1093/neuonc/now265
Neuro Oncol | © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights
reserved. For permissions, please e-mail: journals.permissions@oup.com
Early checkpoint inhibitor success

15. Rationale for Checkpoint inhibition
Worked well in other tumors
Counters immune suppression in glioblastoma
Early success in preclinical models
Early success in patients
What could go wrong?

18. What went wrong?
How do we know if a patient has responded?
How do we determine which patients might
respond?

19. Measuring Immune Responses
Outcome in neuro-oncology trials typically
“Progression-free survival” or “Overall
Survival”
How do we measure these effectively?
Are there alternative methods?

20. Which recurrent lesion is a tumor?
Neither? Both? Left or right?

21. Immune response vs non-response
Patient 1 Patient 2
Unpublished data

22. Measuring Response to
Checkpoint Inhibition
What has been done in preclinical models?
What has been done in other cancers?

23. Figure 6. PD-L1 Blockade Prolongs Effector Function of OT-II T Cells after Antigen-Induced Arrest Representative contour plots (A)
and quantification (B) for IFN-γ production from OT-II T cells in the presence and absence of anti-PD-L1 antibody. DTH was
induced...
Honda et al., Immunity, 2014
IFN-γ production after
anti PD-L1 antibody

24. Functional consequences of PD-L1
expression for cytokine expression
and T-cell activation.
Sabine Wintterle et al. Cancer Res 2003;63:7462-7467
©2003 by American Association for Cancer Research

25. Checkpoint Inhibitors – systemic
immune effects
Das et al. Journal of Immunology, 2015
• 45 patients treated with ipilimumab, nivolumab or combination
• Changes in gene expression in T cells noted
• Increase in serum levels of IL-2Ra, IL-1a and CXCL 10

26. Rituparna Das et al. J Immunol 2015;194:950-959
Copyright © 2015 by The American Association of Immunologists, Inc.
• Patient treated with nivolumab and ipilimumab,
before and 3 weeks after treatment
Checkpoint Inhibitors – tumor-
infiltrating lymphocytes

27. Cytokines
These may hold the key to immune response in
glioma patients
We need a way to safely test these in glioma
patients
What evidence do we have in glioblastoma that
interferon gamma might be important?

28. Microdialysis
Use of special
catheters to sample
fluid in tissue
microenvironments
Slow perfusion of
isotonic solutes allow
diffusion into catheter
Safety well established

29. Cytokine Microdialysis in humans
• Early study
demonstrating increase
in IL-6 in the first few
days after severe TBI
• Microdialysis catheters
well tolerated with 10
days of monitoring
Hillman et al. Neurosurgery, 2005
Days after TBI

30. Cytokine microdialysis in
Brain tumor patients - radiation
Tabatabaei et al. Journal of Neuro-Oncology, 2017
• A significant increase of IL-8,
MCP-1 and MIP-1a were
detected in tumor tissue
after the first dose of
radiation and increased
further during 5 days of
radiation.
• IL-6 also increased after five
fractions of radiation.
• In brain adjacent to tumor,
the cytokine response was
modest with significant
increase of IL-8 after third
dose of radiation

31. Study scheme
Day 1
Day 3
Day 8
Lynes … Nduom, Neurosurgery, 2018
Nivolumab

32. Study timeline
Day 1
• Biopsy
• Lumbar
drain
• Blood
draw
• MD
catheter
placement
Day 3
Nivolumab
MD q6
CSF daily
Blood daily
Day 8
• Resection
• Catheters
removed
FU (Day
17+)
Nivolumab
• Anti-Lag 3
• MRI
Monthly
Lynes … Nduom, Neurosurgery, 2018
John Lynes, MD
Resident research
Fellow, 2017-2018

33. Potential outcomes
Some patients show IFN-γ response, others do not
• Follow patient outcomes
• Can these patients be identified prior to treatment?
All patients show IFN-γ response
• Are there other markers that discriminate patients
who might respond?
• Is IFN-γ enough for efficacy?
No patients show IFN-γ response
• Is interstitial fluid the best compartment to test?
• Do systemic markers show response while brain does
not?
• Is systemic delivery the right way to go in GBM?

34. Stereotactic biopsy

35. Incision for microdialysis placement

36. Pre-tunneling of catheter

37. Stylet for introduction of catheter

38. Two microdialysis catheters implanted
and tunneled

40. Slotted needle for introduction

41. Elekta slotted needle

42. Slotted needle with Suretrak
attached

43. Passing slotted needle to target
with Stealth guidance

44. Feeding catheter into rigid guide

45. Merged Preop MRI and Postop CT

46. MRI
Day 17 Day 8 Day 0

47. MRIs
Day 17 Day 8 Day 0

48. Pt 1 Course on Treatment
Day 17
Day 45
Day 73
Day 101
(on dex)

49. CD3
CD68 MIB-1
CD68
Day 8 resection

50. CD3 CD68 MIB-1
Day 101 resection

51. CD3
CD68
MIB-1
CD3 CD68 MIB-1
CD68
Day 8
Day 101

52. Status of trial
13 patients enrolled
6 have completed study procedures
4 failed screening/withdrew after enrollment, but before surgery
3 patients found to have pseudoprogression on pathology from Day 1 biopsy
No morbidity from microdialysis catheter placement
National recruitment ongoing

53. Conclusions
Verdict is still out on checkpoint inhibition in GBM
Additional biomarker-heavy studies are needed
Combinatorial approaches may harness findings
from existing studies

54. Acknowledgments
Surgical Neurology
Branch:
John Heiss
Kareem Zaghloul
Prashant Chittiboina
John Lynes
Arnold Obungu
Gifty Dominah
Victoria Sanchez
Niko Adamstein
Xiang Wang
Nancy Edwards
Abhik Ray-Chaudhury
Christi Hayes
Samantha Dill
Anthony Nwankwo
Isac Kunnath
Averie Kuek
Neuro-Oncology
Branch:
Mark Gilbert
Terri Armstrong
Sadhana Jackson
Jing Wu
Eric Burton
Marta Penas-Prado
National Institutes
of Health
NINDS:
Avi Nath
Dragan Maric
Kory Johnson
Pathology:
Drew Pratt
Osorio Lopes Abath Neto
Martha Quezado
Center for Human
Immunology:
John Tsang
Jinguo Chen
Richard Apps
NHLBI:
Chris Hourigan
Julie Thompson
NIAID:
Ron Germain
Andrea Radtke
NCI Surgery Branch:
Steve Rosenberg
Yong-Chen (William) Lu

55. Questions?