DAVID RITCHIE, MD, PhDMelbourne, Australia• Professor and Head of Department, Bone Marrow

Transplantation, Royal Melbourne Hospital, Australia

• Dr. Ritchie holds a co-appointment as a Consultant Haematologist and BMT Physician at the Royal Melbourne Hospital (RMH) and Peter MacCallum Cancer Centre (PMCC). He is co-head of the Haematology Immunology Translational Research Laboratory (HITRL). He is the current President of the Haematology Society of Australia and New Zealand, and Chair of the BMT study group of the Australasian Lymphoma and Leukaemia Group (ALLG). His clinical and translational research is specifically on the immunology and immunotherapy of blood cancers and the immunology of new drug therapies in myelodysplasia (MDS), acute and chronic leukaemias, myeloma and lymphoma, and the immunology of allogeneic transplantation.

Immunotherapy in Acute Lymphoblastic Leukemia

Immunotherapies are part of the modern anti-cancer reality

Existing immune responses are the main drivers of immune therapies

Understanding the immune defects at presentation is critical for the rational design and application of immunotherapy

T

DC

Attack

B Cells

YY Y Y

Y Y

NKNKT

Attack

Attack

Abnormal

“Traditional”Immunotherapeutics

Monoclonal antibodies

Antigen Vaccines (Cellular and non-cellular)Adoptive T cell therapies (antigen expanded)Drug adjuvants (non-specific)

Adoptive NK cellaGalCer adjuvantsDrug adjuvants

Why have these approaches been so weak?

Abnormal

Abnormal

Abnormal

Abnormal

Abnormal

Regulatory T cells

InflammatoryT cells

Monocyte DerivedSuppressor cells

ImmuneSuppressingCytokines

ImmuneSuppressingProteins

The tumor fought back.

Tumor Micro-environmentPrognosticPredictiveTherapeutic

ImmuneSuppressingProteins

Immunological Synapse

Immunological Synapse

Inhibitory “checkpoint” proteins Checkpoint blockade anti-PD1; anti-CTLA4

T cell receptor More specific T cells CAR-T

T cell receptor Direct T cell engagement BiTE

T cell receptor Enhanced antigen expression Epigenetic drugs (Aza)

NK cell inhibitory ligands Inhibitory blockade anti-KIR (Lirilumab)

NK cell activating ligands Enhanced expression Epigenetic drugs (Aza)

NK cell targeting ADCC engineered MoAb Elotuzomab, Obinutuzumab

Cytokines andCytotoxic proteins ?promotion ???

Immunotherapies

Responses

14 patients (82%) achieved a CR3 did not respond3 ongoing evaluation

11/17 evaluable pts have ongoing BM CR with median follow up 2.6 mo (1.2-15 mo).

Three patients with a CR at 1 month have subsequently relapsed, 1 with CD19(-) disease.

ASH 2014 #383 Vaccination - a Novel Strategy to Improve the Persistence of CD19CAR Transduced T-Cells in Relapsed Paediatric ALL: Preliminary Results from the CD19TPALL Study

Martin Pule, Sara Ghorashian, MD, PhD, FRCPath, Laura Clifton-Hadley, PhD, BSc, Paul Smith, Soraya Saiagh, Paul Veys, FRCP, FRCPath, Nicholas Goulden, M.D. PhD, Gary Wright, Ettore Biagi, MD, PhD, Bianca Altvater, PhD, Brigitte Dreno, MD, Kim Champion, PhD, Michelle Cummins, MD, Rachael Hough, MD, BMBS, FRCP, FRCPath, Martin G. Sauer, MD, Claudia Rossig, MD Persis Amrolia

Post-allo immunotherapy

Donor-derived Epstein Barr virus (EBV)-specific T cells (CTL) transduced with a 1st generation CD19CAR.

Secondary expansion of CD19CAR T cells by vaccination with irradiated donor-derived, EBV transformed lymphoblastoid cell lines (LCL).

EBV-specific T cells were transduced with an SFG retroviral vector encoding a CD19CAR consisting of the FMC63 single chain Fv linked to a CD3ζ endodomain.

Eligiblity1. pre-emptively if MRD-positive (> 5 x 10-4 in BM) within the 1st year post-SCT or2. prophylactically at day 60-70 post-2nd SCT.

All patients received lymphodepletion with fludarabine 90 mg/m2. Patients with detectable residual disease received cytoreduction with vincristine/dexamethasone prior to CTL infusion.

20 patients have been recruited (14 pre-emptive, 6 prophylactic arm)7 patients treated (3 pre-emptive, 4 prophylactic).

2 patients treated remain in MRD negative CR at 3 and 17 months.1 relapse and retreated4 relapse

No CRS.

Subsequent cohort treated with prophylactic EBV LCL.

BiTE : Blinotumumab

BiTE technology

ImmunologicalSpeed-dating

Tumor Target T cell

Time to clinical relapse.

Topp M S et al. JCO 2011;29:2493-2498

©2011 by American Society of Clinical Oncology

Gökbuget N, Dombret H, Bonifacio M, et al. BLAST: A Confirmatory, Single-Arm, Phase 2 Study of Blinatumomab, a Bispecific T-Cell Engager (BiTE®) Antibody Construct, in Patients With Minimal Residual Disease B-Precursor Acute Lymphoblastic Leukemia. ASH 2014 Abstract 379

N=116Ph negative pre-B ALL, MRD positive CR103 eligible for MRD assessmentPrimary endpoint = MRD status after 1 28 day cycle80% achieved MRD negativity

Grade 2 Adverse Eventspyrexia (90%),tremor (29%), chills (28%), fatigue (24%), nausea (22%), vomiting (22%), diarrhea (20%).aphasia in 13%Grade ≥3 adverse events neutropenia (16%),pyrexia (7%),

tremor (5%).

Gökbuget N, Dombret H, Bonifacio M, et al. BLAST: A Confirmatory, Single-Arm, Phase 2 Study of Blinatumomab, a Bispecific T-Cell Engager (BiTE®) Antibody Construct, in Patients With Minimal Residual Disease B-Precursor Acute Lymphoblastic Leukemia. ASH 2014 Abstract 379

N=116Ph negative pre-B ALL, MRD positive CR103 eligible for MRD assessmentPrimary endpoint = MRD status after 1 28 day cycle80% achieved MRD negativity

Grade 2 Adverse Eventspyrexia (90%),tremor (29%), chills (28%), fatigue (24%), nausea (22%), vomiting (22%), diarrhea (20%).aphasia in 13%Grade ≥3 adverse events neutropenia (16%),pyrexia (7%),

tremor (5%).

Gökbuget N, Dombret H, Bonifacio M, et al. BLAST: A Confirmatory, Single-Arm, Phase 2 Study of Blinatumomab, a Bispecific T-Cell Engager (BiTE®) Antibody Construct, in Patients With Minimal Residual Disease B-Precursor Acute Lymphoblastic Leukemia. ASH 2014 Abstract 379

N=116Ph negative pre-B ALL, MRD positive CR103 eligible for MRD assessmentPrimary endpoint = MRD status after 1 28 day cycle80% achieved MRD negativity

Grade 2 Adverse Eventspyrexia (90%),tremor (29%), chills (28%), fatigue (24%), nausea (22%), vomiting (22%), diarrhea (20%).aphasia in 13%Grade ≥3 adverse events neutropenia (16%),pyrexia (7%),

tremor (5%).

To determine the optimal dose of blinatumomab in pediatric patients with relapsed/refractory BCP-ALL.

34 patients; total of 56 cycles.Six patients had refractory disease Six patients had >1 relapses.22 patients had relapsed after HSCT.

The MTD =15 µg/m²/day.

To reduce CRS 5 µg/m²/day for 7 days escalating to 15 µg/m²/day for the remainder of the first cycle and all following cycles

11 patients treated with 5/15 None developed CRS No grade 3 CNS-related adverse events (AEs) occurred.

Common AE•pyrexia (62%)•headache (35%)•anemia (29%)•hypertension (29%)

One patient treated at 5 µg/m²/day had a grade 3 seizure Responses across all dose levels, CR= 11 (32%) patients had complete remission PR= two (6%)

Responses all occurred within the first two treatment cycles.

Topp et al, ASCO 2014, Abstract 7005.

TOWER Study

A Phase 3, Randomized, Open Label Study Investigating the Efficacy of the BiTE Antibody Blinatumomab Versus SOC Chemoptherapy in Adult Subjects With Relasped/Refractory B-Precursor ALL

Inotuzumab Ozogamicin

#794 Inotuzumab Ozogamicin in Combination with Low-Intensity Chemotherapy (mini-hyper-CVD) As Frontline Therapy for Older Patients (≥60 years) with Acute Lymphoblastic Leukemia (ALL)

Elias Jabbour, MD, Susan O'Brien, M.D., Deborah A. Thomas, MD, Koji Sasaki, Guillermo Garcia-Manero, MD, Farhad Ravandi, MD, Gautam Borthakur, MD, Sergernne York, RN, Rebecca Garris, BSc, Jorge Cortes, MD, Hagop M. Kantarjian, MD

CD22 expression occurs in >90% of pts with ALLInotuzumab ozogamicin (IO) is a CD22 monoclonal antibody bound to calecheamicinSingle agent response rate in relapsed ALL = 57% (Katarjian Lancet Oncology 2012.

Mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses).

IO was given on day 3 of each of the first 4 courses

N= 27 (15 men)

96%

No Transplants

4 deaths in CRpneumonia complications (n=1), sepsis and multiple organ failure (n=1), gun shot wound (n=1), renal failure and metabolic encephalopathy (n=1).

ConclusionsResults appear to be better than those achieved with a chemotherapy aloneMay become the new standard of care for frontline treatment of older pts with ALL.

Check Point Blockade Inhibition??

Anti-PD1Anti-CTLA-4Anti-LAG3

Immunotherapy is here to stay…….lots of questions remain…..

• Understand baseline immunology biomarkers

• Auto vs Allo vs 3rd Party Allo for T cell sources

• Combination therapies

– To optimize response

– To consolidate of maintain responses

– To minimize toxicity