1. Myeloma Research at the CCI/U of A 2019
Michael P. Chu
Medical Oncologist, CCI
Assistant Professor, U of A

2. Outline
Clinical Research
Basic Science Research

3. First…
Thank You!

4. Clinical Research
Current treatment paradigm splits patients between those who can vs cannot receive stem cell transplant
Ultimately, being incurable, most patients will see one or more members of particular drug families:
IMIDs: lenalidomide, pomalidomide
Proteasome inhibitors: bortezomib, carfilzomib, ixazomib
Targeted agents: selinexor, venetoclax, daratumumab

5. Clinical Research Combination and sequence studies
Each drug is active by itself
Can either combination with either drugs or earlier administration be more effective?
Ex: daratumumab combination studies

6. Clinical Research – BCMA
Newer compounds
Antibodies – targeting B-cell maturation antigen (BCMA)
Antibody-drug conjugates – also targeting BCMA but delivering potent chemotherapy (MMAE)
Bi-specific T-cell engagers

7. BiTEs – BCMA
Newer class of drugs that combine antibody therapy and immune therapy
Basic premise is different construct designs with two ends
One end = recognize cancer
Second end = bring and excite T-cells closer

8. BiTE – BCMA Spider plot of AMG 420, phase 1 clinical trial
Dose response demonstration that higher dose patients have strong responses that persisted
Multiple BiTEs in development
Pfizer
Celgene
Janssen

9. Clinical Research Myeloma Database Headed by Dr. Chris Venner
Creation of nation-wide pool of clinical and pathology information to create a library
Important for real world evidence of outcomes; direct impact on drug approvals

10. Clinical Research
Chimeric Antigen Receptor (CAR) T-cell therapy

11. CAR T-cell Function
Comparison of different immune therapy technologies

12. Myeloma CAR T-cell targets

13. Clinical Research CAR T-cells
Led to “breakthrough”, FDA designation for acute lymphoblastic leukemia, non-Hodgkin lymphoma
In myeloma, target is B-cell maturation antigen (BCMA)
Pioneer = bb2121
Additional 2 constructs in phase 1 or 2 studies (Legend/Janssen; Takeda)

14. Clinical Research CAR T-cells 2 prong approach locally
Creation of our own BCMA-CAR T-cell
Participation in industry-sponsored studies
Suggestion is that upcoming study will compare autologous stem cell transplant to CAR T-cells after induction therapy
Calgary participating on Celgene/Blue Bird Bio BB2121 study; set to launch this summer

15. Alberta Cellular and Immunotherapy (ACIT)
Provincial initiative to provide a research and clinical cellular therapy program
Pooling of infrastructure that already exists in Edmonton and Calgary
First project = Anti-CD19 CAR T-cells in relapsed/refractory Acute Lymphoblastic Leukemia (ALL) and aggressive Non-Hodgkin Lymphoma
Timeline = Aim for first patient screened for treatment by June/July 2019
Subsequent projects:
Myeloma
Glioblastoma Multiforme
Refractory lupus and scleroderma

16. T-Cell Expansion

17. Clinical Research Summary
Diagnostic and follow-up testing – minimal residual disease (marrow vs blood)
Database participation (MCRN initiative)
Therapeutic combinations (clinical trials)
Development of full suite immune therapy investigation
BiTEs/Duo-bodies
Creation and implementation of our own CAR T-cells

18. Basic Science Research
Evolving team
Ismail Ismail
Raymond Lai
Myself

19. Basic Science Research
Ismail lab
Examining the cancer stem cell and its vulnerabilities
Identified certain on-off gene signals that may impact sensitivity to melphalan (chemo given during transplant)

20. Basic Science Research
Raymond Lai Lab
Investigating the role of inner cell signaling
Specifically looking at mechanisms to inhibit
Ex: STAT3; similar idea to venetoclax
Developed a nano-particle delivery system to concentrate their drug at site of myeloma

21. Basic Science Research
Chu Lab
Prediction test development
MRD testing but in stem cells collected
Creation of new therapeutic antibody targeting a separate molecule from those currently being employed
Pre-clinical work with early development drugs (i.e. those not yet tried in humans or very minimally tried)
Development of novel CAR T-cells

22. Patient Prediction Model
Build on Linda Pilarski’s development of a 3D culture model
Linda and co demonstrated 3D cultures were more representative of drug activity and were better for studying myeloma as it more closely resembled bone marrow structure
We have adapted this to determine if we can use this in real time to predict patient responses at diagnosis to CyBorD

23. Patient Prediction Model
Clinical Response
Culture Response 1
43%
82% 2
92.7%
93% 3
89.7%
91% 4
24.3%
47% 5
82.3%
92%
Preliminary data
8 total patients; 3 excluded due to patients opting not to complete therapy (2 major infectious complications; 1 cardiac)
Aim = compare 12 patients who have completed at least 4 cycles CyBorD (i.e. through to transplant)

24. Minimal Residual Disease in Stem Cells

25. Minimal Residual Disease in Stem Cells
Developing microbead column with electrical engineer (Dr. Jie Chen)
Idea is to filter out any residual myeloma cells leaving behind only blood stem cells
Progress: prototype in development

26. Novel CAR T-cells Developing 2 CAR constructs
Dual targeted – BCMA and CD19
Armored CAR – BCMA alone
Looking at viral vs non-viral gene manipulation

27. Next Generations

28. National Collaboration

29. Basic Science Research
Pipeline of things to come
Testing of other immune-driven drugs – bi-specific T-cell engagers, antibody drug conjugates
Understanding resistance biology in real time
Noting changes in expression profile
Cross section of physiology, immunology and cancer biology – examining the physiologic impact of myeloma and determining how it affects patient outcomes and response to therapy

30. Basic Science Research Summary
Far reaching
Understanding myeloma biology
Targeting weak points
Creation of new therapeutics
Screening of these therapeutics in sensible models
Improved detection and diagnostics
Looking outside the box

31. Questions?