David Ritchie is a professor and head of the bone marrow transplantation department at the Royal Melbourne Hospital in Australia. He holds appointments at the Royal Melbourne Hospital and Peter MacCallum Cancer Centre, and is co-head of the Haematology Immunology Translational Research Laboratory. His research focuses on the immunology and immunotherapy of blood cancers, myelodysplasia, acute and chronic leukemias, myeloma, and lymphoma, as well as the immunology of allogeneic transplantation.
Novel Immunotherapeutics in Acute Lymphocytic Leukemia
1. DAVID RITCHIE, MD, PhD
Melbourne, 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.
3. 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
4.
5.
6.
7.
8.
9.
10. T
DC
Attack
B Cells
Y
Y Y Y
Y Y
NK
NKT
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 cell
aGalCer adjuvants
Drug adjuvants
11. Why have these approaches been so weak?
Abnormal
Abnormal
Abnormal
Abnormal
Abnormal
12. Regulatory
T cells
Inflammatory
T cells
Monocyte Derived
Suppressor cells
Immune
Suppressing
Cytokines
Immune
Suppressing
Proteins
The tumor fought back.
Tumor Micro-environment
Prognostic
Predictive
Therapeutic
24. Responses
14 patients (82%) achieved a CR
3 did not respond
3 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.
25. 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.
26. Eligiblity
1. pre-emptively if MRD-positive (> 5 x 10-4 in BM) within the 1st year post-SCT or
2. 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 retreated
4 relapse
No CRS.
Subsequent cohort treated with prophylactic EBV LCL.
32. 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=116
Ph negative pre-B ALL, MRD positive CR
103 eligible for MRD assessment
Primary endpoint = MRD status after 1 28 day cycle
80% achieved MRD negativity
Grade 2 Adverse Events
pyrexia (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%).
33. 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=116
Ph negative pre-B ALL, MRD positive CR
103 eligible for MRD assessment
Primary endpoint = MRD status after 1 28 day cycle
80% achieved MRD negativity
Grade 2 Adverse Events
pyrexia (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%).
34. 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=116
Ph negative pre-B ALL, MRD positive CR
103 eligible for MRD assessment
Primary endpoint = MRD status after 1 28 day cycle
80% achieved MRD negativity
Grade 2 Adverse Events
pyrexia (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%).
35. To determine the optimal dose of blinatumomab in pediatric patients with
relapsed/refractory BCP-ALL.
36. 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.
37. 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.
39. 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
41. #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 ALL
Inotuzumab ozogamicin (IO) is a CD22 monoclonal antibody bound to calecheamicin
Single 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)
45. 4 deaths in CR
pneumonia complications (n=1),
sepsis and multiple organ failure (n=1),
gun shot wound (n=1),
renal failure and metabolic encephalopathy (n=1).
Conclusions
Results appear to be better than those achieved with a chemotherapy alone
May become the new standard of care for frontline treatment of older pts with ALL.
51. 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
Notas do Editor
Time to clinical relapse. The probability of relapse-free survival after initiation of blinatumomab treatment in all 20 evaluable patients is shown in blue. Median follow-up for relapse-free survival is 405 days (range, 78 to 655 days). The probability of relapse-free survival after initiation of blinatumomab treatment in all 12 evaluable patients who have not undergone allogeneic transplantation after completion of blinatumomab treatment is shown in yellow. Median follow-up for relapse-free survival is 276 days (range, 78 to 655 days). HSCT, hematopoietic stem-cell transplantation. Data as of June 15, 2010.