Harnessing Killer T Cells

Transcription

1 Harnessing Killer T Cells Julie Nielsen, PhD BC Cancer Agency May 2, 2015

2 Overview The immune response to cancer What T cells are & how they work Immune-based therapies for cancer Using T cells to target patient-specific mutations Targeting MYD88 with T cells

3 The immune system actively responds to cancer Tumor cells Killer T cells Helper T cells OvCa image courtesy of Katy Milne

4 % overall survival Tumor-infiltrating T cells are associated with patient survival Killer T cells present Killer T cells absent Years VGH/BCCA cohort HGSC OvCa optimally de-bulked n = 200 p = Clarke, B. et al Milne, K. et al. 2009

5 Basics of the immune system Includes many kinds of cells that help eliminate foreign invaders (e.g. viruses) and abnormal cells (e.g. cancer) Cells circulate throughout the body looking for trouble Each cell type uses a unique strategy Some cells produce antibodies (IgM) Others engulf foreign invaders Killer T cells directly destroy abnormal cells

6 How do killer T cells work? Components of cells or viruses are cut into fragments inside the cell These fragments are then taken to the cell surface where they are displayed for T cells to survey T cells recognize these fragments using their T cell receptor (lock & key) If T cells recognize something abnormal, they will kill the cell ~25 million different T cell receptors

7 How does cancer evade the immune system? Cancer cells are similar to normal cells in many ways this makes it difficult for the immune system to recognize cancer The immune system is tightly regulated to prevent autoimmunity cancer cells can take advantage of this & put the brakes on T cells

8 Strategies to enhance the immune response to cancer Rituximab Drugs that release the brakes on T cells T cell therapy Isolate T cells Identify T cells that recognize cancer Re-infuse T cells into patient Grow large numbers

9 CD19 CAR T cells CD19 is a protein found on WM & many other lymphomas & leukemias T cells can be engineered to recognize CD19 via a chimeric antigen receptor (CAR) CD19 CAR T cells have been used to treat ~100 patients with leukemia or lymphoma Clinical results demonstrated in many types of cancer (most effective in acute lymphoblastic leukemia) Numerous clinical trials underway One disadvantage: CD19 is also found on normal B cells, so they are also eliminated by CAR T cells

10 Tumor-specific targets Cancer is caused by accumulation of mutations (mistakes) in DNA Bad news: these mutations give cells abnormal growth properties Good news: T cells can detect these mutations and destroy cells that have them

11 Identifying T cells that recognize patient-specific mutations Recent advances in DNA sequencing make it possible to sequence tumors from many patients Some mutations are very common in specific types of cancer, but most mutations are unique to each patient Our research involves identifying mutations that are recognized by T cells in order to develop T cell-based therapies

12 Patients & controls Over 100 patients and 75 cancer-free controls enrolled in the study Sample requirements: Tumor samples for identifying mutations Annual blood samples (200ml/draw) for screening T cells Patients with WM or follicular lymphoma

13 Study overview Obtain tumor samples Identify tumor-specific sequences Assess T cell responses Every mutation has the potential to create a new T cell target Develop personalized T cell-based therapies

14 Not all mutations are recognized Mutated protein must be processed to generate fragment of interest Fragment must bind to the patient s MHC molecules on the cell surface T cells with the appropriate T cell receptor must exist

15 How do we determine which mutations are recognized? Obtain tumor & matched blood Identify mutations Mutant peptides T cells Peptides Test T cell 10 days 14 days responses 14 days

16 Number of patients T cells in follicular lymphoma 53 follicular lymphoma patients Looked for mutations in 10 genes known to have JS Nielsen et al., Figure 1 mutations in lymphomas Identified mutations in 80% of patients Somatic mutations in a cohort of FL patients 5 0 CREBBP EZH2 MEF2B FOXO1 CARD11 Mutant gene PIM1 EP300 IRF4 CCND3 CD79B

17 Spots per 10 6 cells T cells in follicular lymphoma Assessed T cell responses to proteins derived from mutations Identified T cells that recognized patient-specific mutations in 25% of patients IROL017 REP225 * Mock-transfected Irrelevant RNA WT MEF2B RNA Mutant MEF2B RNA DMSO (No antigen) Mutant MEF2B peptide

18 Targeting mutations in WM A mutation in MYD88 has been found in most patients with WM (Dr. Treon 2012 NEJM) We have identified T cells that recognize fragments of mutated MYD88 Individual peptides

19 10uM 1uM 100nM 10nM 1nM 100pM T cells specifically recognize mutated MYD88 Mutant WT Peptide concentration

20 T cells recognize mutated MYD88 in B cells

21 Future directions Can MYD88-specific T cells recognize WM? If so, develop & test T cell-based therapy Isolate patient s T cells MYD88 L265P - specific TCR Express TCR in patient s T cells & select MYD88- specific cells Re-infuse T cells into patient Expand T cells

22 Summary The immune system can recognize & eliminate tumors The presence of killer T cells in tumors is associated with increased patient survival Immune-based therapies are being tested in clinical trials (CAR T cells, strategies that remove the brakes from T cells) T cells can recognize proteins derived from patientspecific mutations T cells can recognize mutant MYD88 Future work will show whether T cells targeting MYD88 will be effective therapeutically

23 Acknowledgements Brad Nelson, PhD Nicol Macpherson, MD PhD Colin Sedgwick Andrew Chang Patients & controls Collaborators Ryan Morin, PhD Brian Berry, MD Steve Treon, MD PhD Joe Connors, MD Randy Gascoyne, MD Zabrina Brumme, PhD Marco Marra, PhD Funding BC Cancer Foundation International Waldenstrom s Macroglobulinemia Foundation Waldenstrom s Macroglobulinemia Foundation of Canada Canadian Cancer Society Research Institute Lymphoma Foundation Canada