Myeloma Research at the CCI/U of A 2019

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 • 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?