Recent Updates in Cancer Immunotherapy

Recent Updates in Cancer Immunotherapy H. Miles Prince Epworth Healthcare Peter MacCallum Cancer Centre

How do we choose? What is the next new flavour? Where does immunotherapy fit in?

St Sebastian Archilles versus

Immune mechanisms to attack haematological cancers Monoclonal antibodies

ADCC: Antibody-dependent Cell Cytotoxicity

Immune mechanisms to attack haematological cancers Monoclonal antibodies Allogeneic transplantation Immune stimulants Interferon hairy cell leukemia, follicular lymphoma,myeloma Immunomodulatory Drugs (thalidomide, lenalidomide, pomalidomide) Myeloma, follicular lymphoma, myelodysplasia

Cereblon Non- cereblon targets =new drugs

Immune mechanisms to attack cancer Monoclonal antibodies Allogeneic transplantation Immune stimulants Interferon Immunomodulatory Drugs thalidomide, lenalidomide, pomalidomide Chimeric Antigen Receptor (CAR) T cells Bi-specific antibodies antibodies that bind target and T cells Checkpoint inhibitors CTLA4, PD1 axis

The future beyond chemotherapy

The future beyond chemotherapy Monoclonal antibodies Immune stimulants Interferon Immunomodulatory Drugs thalidomide, lenalidomide, pomalidomide Allogeneic transplantation CAR T cells Bi-specific antibodies antibodies that bind target and T cells Checkpoint inhibitors CTLA4, PD1 axis VS Small molecules Tyrosine Kinase Inhibitors bcr-abl (CML) BTK (CLL, lymphomas) FLT3 (AML) JAK2i (myeloproliferative) Epigenetic targets Demethylating agents Readers/Writers/Erasors HDACi, BETi Mutations EZH2, IDH Pro-apoptotic BH3-mimetcs, MCLi

B cell target A story of CD19/CD20 for lymphoma/leukaemia

Rituximab in B cell NHL Induction Diffuse large B cell Lymphoma Follicular Lymphoma Marginal zone lymphoma Burkitt s lymphoma Chronic Lymphocytic Leukemia Maintenance Low grade NHL Salvage/Re-treatment

Radio-immunotherapy B cell NHL Effective Cumbersome process Utilization is falling Competing therapies are taking the market share BH3 mimetics Ease of use is critical to utilization

Second-generation CAR used in current clinical studies at Penn and CHOP Shannon L. Maude et al. Blood 2015;125:4017-4023 2015 by American Society of Hematology

Antigen Antigen Antigen

Targeting CD19

CAR-T in ALL UPen: CTL019 CAR-T cells Children (n = 25) and adults (n=5) CTL019 proliferated in vivo detected in blood, marrow and CSF CR in 27 (90%) All pts had cytokine release syndrome severe = 27% Predicted 6m EFS = 67% OS = 78% persistence of T cells = 68% B cell aplasia = 73%

Event-free survival in 30 children and adults treated with CTL019 therapy. Shannon L. Maude et al. Blood 2015;125:4017-4023

CLL

Summary of CAR T-cells in lymphoproliferative diseases 2 nd generation CAR-T Against CD19 currently ALL high + deep response rate prolonged remissions CLL - effective in smaller proportion: will this have a place with new targeted therapies? NHL under investigation MM promising: why are CD19 effective? Cytokine Release Syndrome predicts response Responding patients had persistence of CAR T cells more than several months post-rx Persistence of CAR-T required to maintain response Patients with persistence of CAR T cells had B cell aplasia

Where can the process be modified? Patient Selection

Where can the process be modified? cytokine cocktail

Where can the process be modified? Vector construct

Where can the process be modified? Number and phenotype: CRS

Where can the process be modified? Tumour bulk reduction Immune suppression Checkpoint inhibitors Immunostimulants

Next steps

40 New Parkville facility 2016/17 U U D C B D C B A A Peter Mac s (and CTPL s) new home 10 clean rooms fully PIC/S compliant Most steps in grade A & B zones Substantial amounts of in-process testing and PD in grade C Scale-up and validation areas Segregation of EM testing Biosafety Levels 2 and 3

Bi-specific T cell engagers BiTe

Bi-specific T cell engagers BiTe Long infusions Toxicities Non-persistence: relapse and retreatment ALL, NHL

The fate of peripheral T cells Effector memory - EM Central memory - CM Terminal memory - TM

Emma Whitehead refractory relapse of B-ALL The elephant in the room Leukemia Patients Remain in Remission More Than Two Years After Receiving Genetically Engineered T Cell Therapy University of Pennsylvania Researchers Report on Results of Trial in 12 Patients, Including Two Children ATLANTA Nine of twelve leukemia patients who received infusions of their own T cells after the cells had been genetically engineered to attack the patients tumors responded to the therapy, which was pioneered by scientists in the Perelman School of Medicine at the University of Pennsylvania. Penn Medicine researchers will present the latest results of the trial today at the American Society of Hematology s Annual Meeting and Exposition. cers, included 10 adult patients with chronic lymphocytic leukemia treated at the Hospital of the University of Pennsylvania (HUP) and two children with acute lymphoblastic leukemia treated at the Children s Hospital of Philadelphia. Two of the first three patients treated with the protocol at HUP whose cases were detailed in the New England Journal of Medicine and Science Translational Medicine in August 2011 remain healthy and in full remissions more than two years after their treatment, with the engineered cells still circulating in their bodies. The findings reveal the first successful and sustained demonstration of the use of gene transfer therapy to turn the body s own immune cells into weapons aimed at cancerous tumors. Our results show that chimeric antigen receptor modified T cells have great promise to improve the treatment of leukemia and lymphoma, says the trial s leader, Carl June, MD, the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine and director of Translational Research in Penn s Abramson Cancer Center. It is possible that in the future, this approach may reduce or replace the need for bone marrow transplantation. The results pave the way for a potential paradigm shift in the treatment of these types of blood cancers, which in advanced stages have the possibility of a cure only with bone marrow transplants. That procedure requires a lengthy hospitalization and carries at least a 20 percent mortality risk - - and even then offers only a limited chance of cure for patients whose disease has not responded to other treatments. Three abstracts about the new research will be presented during the ASH meeting. David Porter, MD, director of Blood and Marrow Transplantation in the Abramson Cancer Center, will give an oral presentation of Abstract #717 on Monday, Dec. 10, at 5 PM in the Thomas Murphy Ballroom 4, Level 5, Building B of the Georgia World Congress Center. Michael Kalos, PhD, director of the Translational and Correlative Studies Laboratory at Penn, will give an oral presentation on Abstract #756 on Monday, Dec. 10, at 5:45 PM in C208- C210, Level 2, Building C. Stephan Grupp, MD, PhD, director of Translational Research in the Center for Childhood Cancer Research at the Children's Hospital of Philadelphia, will present a poster of Abstract #2604 on Sunday, Dec. 9, at 6 PM in Hall B1- B2, Level 1, Building B. The protocol for the new treatment involves removing patients' cells through an apheresis process similar to blood donation, and modifying them in Penn's cell and vaccine production facility. Scientists there reprogram the patients T cells to target tumor cells through a gene modification technique using a HIV- derived lentivirus vector. The vector encodes an antibody- like protein, called a chimeric antigen receptor (CAR), which is expressed on the surface of the T cells and designed to bind to a protein called CD19. The modified cells are then infused back into the patient's body following lymphodepleting chemotherapy. Once the T cells start expressing the CAR, they focus all of their killing activity on cells that express CD19, which includes CLL and ALL tumor cells, and normal B cells. All of the other cells in the patient that do not express CD19 are ignored by the modified T cells, which limits systemic side effects typically experienced during www.uphs.upenn.edu/news/news_releases/2012/12/tcell/print.html 1/2 I ve told the team that resources are not an issue. Speed is the issue. Novartis Chief Executive Joseph Jimenez Versus

The competition

Pro-apoptotic agents BH3-mimetics

Targeting the B cell receptor pathway TKI Ibrutinib CLL, NHL Idelalisib CLL, NHL

Archilles

Targeting the B cell receptor pathway TKI Ibrutinib CLL, NHL Idelalisib CLL, NHL

Assessing mutations can predict response to BTK inhibitors Next Gen sequencing now becoming standard investigation

Drug effectiveness is dependent on sutype of Diffuse Large Cell Lymphoma

Effectiveness is dependent on mutation status of Diffuse Large Cell Lymphoma

Immunomodulatory agents in lymphoma (lenalidomide) Standard therapy in myeloma Effective in follicular lymphoma Responses achieved Synergystic with rituximab Not effective in maintenence Ongoing trials Some effect in large cell lymphoma (Activated B cell only)

Drug effectiveness is dependent on sutype of Diffuse Large Cell Lymphoma

St Sebastian

The immune synapse T cell Target -Virus -Bacteria -Cancer

Checkpoint = suppressed immune system

Checkpoint inhibitors

Change From Baseline in Tumor Size, % Pembrolizumab Monotherapy Has Shown Activity in 20 Tumors Melanoma 1 100 NSCLC 2 H&N 3 Urothelial 4 TNBC 5 Gastric 6 chl 7 0-100 NHL PMBCL 8 Mesothelioma 9 Ovarian 10 SCLC 11 Esophageal 12 NPC 13 Anal 14 Biliary Tract 15 Colorectal 16 ER + /HER2 BC 17 Cervical 18 Thyroid 19 Salivary 20 100 0-100 1. Daud A et al. ASCO 2015; 2. Garon EB et al. ESMO 2014; 3. Seiwert T et al. ASCO 2015; 4. Plimack E et al. ASCO 2015; 5. Nanda R et al. SABCS 2014; 6. Bang YJ et al. ASCO 2015 ; 7. Moskowitz C et al. ASH 2014; 8. Zinzani PL et al. ASH 2015; 9. Alley EA et al. AACR 2015; 10. Varga A et al. ASCO 2015; 11. Ott PA et al. 2015 ASCO; 12. Doi T et al. ASCO 2015; 13. Hsu C et al. ECC 2015; 14. Ott PA et al. ECC 2015; 15. Bang Y-J et al. ECC 2015; 16. O Neil B et al. ECC 2015; 17. Rugo HS et al. SABCS 2015; 64 18. Frenel JS et al. ASCO 2016; 19. Mehnert JM et al. ASCO 2016; 20. Cohen R et al. ASCO 2016.

PD1 inhibitors in Hodgkin s disease

PD-1 axis inhibitors Melanoma Non-small-cell lung cancer Renal-cell cancer Hodgkin lymphoma (NHL, T cell lymphoma, myeloma)

Summary of responses

Duration of response Median PFS: 17.4 months (95% CI, 11.7 18.8)

Microenvironment in Lymphoma

Lymphoma Microenvironment Many lymphomas evolve from a polyclonal response to infectious and auto-antigens Tumor cells retain microenvironment dependency Tumor cells use microenvironment for immunosuppression Microenvironment mediates therapy resistance

Fowler et al. Haematologica 2016 Lymphoma Microenvironment Model Interactions

Follicular Lymphoma: Immune Response Signatures Dave et al. NEJM 2004

Follicular Lymphoma: Role of Treg Infiltration Farinha et al. Blood 2010

Fowler et al, Haematologica 2016 Lymphoma Microenvironment: Targeted Approaches

Hitting the target (immunologically) Hodgkin Lymphoma Mediastinal B cell lymphoma CD30 Anaplastic T cell lymphoma Cutaneous T cell lymphoma

Hitting the target (immunologically) Expression of CD30 Hodgkin Lymphoma +++++ +++++ Mediastinal B cell lymphoma CD30 Anaplastic T cell lymphoma +++++ Cutaneous T cell lymphoma +

Hitting the target (immunologically) Expression of CD30 Efficacy of Brentuximab vedotin Hodgkin Lymphoma +++++ +++++ Mediastinal B cell lymphoma CD30 Anaplastic T cell lymphoma +++++ Cutaneous T cell lymphoma +

Probability of PFS Progression-free survival (ITT population) 1.0 0.9 0.8 Log-rank test p-value: <0.001 Hazard ratio (95% CI): (0.169, 0.430) Median (months): BV: 16.7 MTX or Bex: 3.5 Number of events: BV: 36 MTX or Bex: 50 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Brentuximab vedotin Methotrexate or bexarotene Censored Censored Number of patients at risk: Brenuximab vedotin Methotrexate or bexarotene 1 0 1 2 3 4 5 6 7 8 9 1011121314151617181920212223242526272829303132333435 64 59 58 54 51 50 48 47 46 64 54 42 34 24 17 13 12 11 43 8 Time from randomization (months) 38 8 38 7 29 7 27 6 27 6 23 5 19 5 17 5 13 4 12 4 12 4 11 10 8 3 1 1 7 7 7 6 3 3 3 1 1 Assessed by independent review Bex, bexarotene; MTX, methotrexate Prince et al. Lancet 2017

Hitting the target (immunologically) Expression of CD30 Efficacy Hodgkin Lymphoma +++++ +++++ Mediastinal B cell lymphoma CD30 Anaplastic T cell lymphoma +++++ What target? Microenvironment? Cutaneous T cell lymphoma +

Immunotherapy in the future delivery Ease of delivery Length of treatment Cost Cytokine release Immunosupression Neurotoxicity Combination capacity toxicity Biology Target expression Pathways (NFkB) Smart combinations Mutation targets