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RICHARD CHAMPLIN, MD
Houston, USA
• Professor and Chair of the Department of Stem Cell
Transplantation and Cellular Therap...
Cell Therapy for AML
Richard Champlin, MD
University of Texas- MD Anderson
Cancer Center
AML- Sensitivity to immunotherapy
• Allogeneic hematopoietic transplantation is
curative through the immune graft-vs-
leuk...
Problems
• Cancer cells are poorly immunogenic
• Cancer cells induce
hyporesponsiveness/tolerance
• Allogeneic transplanta...
Targets for Graft-vs.-Malignancy
Broadly expressed minor
histocompatibility antigen (GVHD)
Lineage restricted
minor histoc...
Chimeric antigen receptors (CARs)
vL
vH
CH1
CL
Antibody
Fab
vH vL
Chimeric antigen receptor
a b
TCR-complex
ge e d
z z
(Es...
Lessons from Anti CD19 CAR T-cells
• Effective against B-cell malignancies, ALL,
lymphoma, CLL
• Responders also eradicate...
Targeting AML with CAR- T cells
• Myeloid cell surface antigens
– CD123 (IL-3 receptor)
– CD33 (may be absent on leukemia ...
Targeting CD123 (IL-3Ra)
 a subunit of IL-3 receptor required for cell
proliferation, differentiation, and survival
Expr...
Chimeric Antigen Receptors
Cooper et al.
Major issue is separation of cytotoxicity AML , sparing
normal myeloid cells.
Pos...
Inducible Caspase 9 Self Destruct
Switch
12
CD123-CD28CAR CD123-41BBCAR
Conditional ablation of CAR+ T cells by chemical-
induced dimerization of iCaspase9
Redirected killing of CD123+ AML cells by
CAR+ T cells
CD123-CD28 CAR CD123-41BB CAR
CD123-41BB CARUntreated CD123-CD28 CAR
In vivo killing of AML tumor cells by
CAR+ T cells
Conclusions
CD123-specific CAR+ T cells co-expressing
iCaspase9 can be generated using approach
suitable for human applic...
(1) 8F4: A T cell receptor-like antibody
PR1
P3
NE
PR1-
CTL
TCR
PR1
P3 - Proteinase 3
NE - Neutrophil elastase
Lysis
AML, ...
(2) 8F4-CAR gene modified T cells
CD28
CD3z
sch8F4
8F4-CAR+
T cell
PR1
P3
NE
PR1-
CTL
TCR
AML, CML, & MDS
PR1
P3 - Protein...
Anti PR1-HLA A2 CAR T-cell
• Targets PR1 HLA A2 complex
• Should spare normal hematopoiesis
• If myelosuppressive, could u...
20
Alloreactive NK Cells and Haploidentical
Transplantation
Reduce GVHD
Reduce rejection
Reduce relapse
Manufacturing mbIL21-expanded NK cells
= 5 x 109
NK cells/kg
Cryopreserve in
aliquots
Antigen-specific proliferation of
CA...
mbIL21-expanded NK cells have increased
cytotoxicity, telomeres, and cytokine secretion
PLoSOne, Denman 2012 7:e30264
1
10...
NK Cell Clinical Trials
• We have initiated first in man phase I/II studies of ex vivo expanded
NK cells to augment GVL ef...
NK-cell Expansion and CAR
transduction
Antigen-specific
CAR+ NK cells
Expand NK cells on
clone 9
CB-NK culture with
cytoki...
Conclusions
• Cellular immunotherapy is a highly promising approach
to treatment of AML
• Leukemia antigens have been iden...
Cellular Therapy in Acute Myeloid Leukemia
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Cellular Therapy in Acute Myeloid Leukemia

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Cellular Therapy in Acute Myeloid Leukemia. Prof. Richard Champlin

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Cellular Therapy in Acute Myeloid Leukemia

  1. 1. RICHARD CHAMPLIN, MD Houston, USA • Professor and Chair of the Department of Stem Cell Transplantation and Cellular Therapy at the University of Texas MD Anderson Cancer Center • Dr. Richard Champlin has over 30 years of experience in clinical and translational research involving hematopoietic stem cell transplantation. He has been the President of the American Society of Blood and Marrow Transplantation as well as the Center for International Center for Blood and Marrow Transplantation Research. He was also the board Member of the National Marrow Donor Program and is a current member of the HRSA Advisory Committee for Cord and Stem Cell Transplantation at the MD Anderson Cancer Center. Professor Champlin chairs the Working Committee on Alternative Donors and Cell Sources of the International Bone Marrow Transplant Registry.
  2. 2. Cell Therapy for AML Richard Champlin, MD University of Texas- MD Anderson Cancer Center
  3. 3. AML- Sensitivity to immunotherapy • Allogeneic hematopoietic transplantation is curative through the immune graft-vs- leukemia effect – T-cells – NK cells • Major cause of treatment failure is relapse • Can we develop more effective cellular immune therapy with T- and NK- cells
  4. 4. Problems • Cancer cells are poorly immunogenic • Cancer cells induce hyporesponsiveness/tolerance • Allogeneic transplantation can provide nontolerized effector cells reactive against alloantigens as well as leukemia related targets.
  5. 5. Targets for Graft-vs.-Malignancy Broadly expressed minor histocompatibility antigen (GVHD) Lineage restricted minor histocompatibility antigen (G-vs-hematopoietic), or Redirected CAR T-cells vs CD19 Overexpressed normal cellular constituent (Proteinase 3, WT1, telomerase) Allo-Specific Malignancy Specific Idiotype, Fusion peptide of translocation (bcr-abl)
  6. 6. Chimeric antigen receptors (CARs) vL vH CH1 CL Antibody Fab vH vL Chimeric antigen receptor a b TCR-complex ge e d z z (Eshhar et al; PNAS 1993)
  7. 7. Lessons from Anti CD19 CAR T-cells • Effective against B-cell malignancies, ALL, lymphoma, CLL • Responders also eradicate normal B-cells • Patients can survive without B cells - IVIG • Cross reactivity and destruction of normal hematopoiesis is a major problem with CARs against AML – May ablate cells with suicide gene – Can give prior to hematopoietic transplantation
  8. 8. Targeting AML with CAR- T cells • Myeloid cell surface antigens – CD123 (IL-3 receptor) – CD33 (may be absent on leukemia stem cells) • Leukemia related antigens – WT1 – PR1 (derived from Proteinase 3)
  9. 9. Targeting CD123 (IL-3Ra)  a subunit of IL-3 receptor required for cell proliferation, differentiation, and survival Expression Over expressed on leukemic stem cells (AML, B- ALL, CML) and leukemic blasts Weak expression on monocytes, neutrophils, basophils, and megakaryocytes Absent on peripheral T cells, natural killer cells, platelets, red blood cells 10
  10. 10. Chimeric Antigen Receptors Cooper et al. Major issue is separation of cytotoxicity AML , sparing normal myeloid cells. Possible Targets CD123, CD33 Numeric expansion of CAR+ T cells on CD123+ aAPC with exogenous IL-2/21 Antigen-specific activation & proliferation of CAR+ T cells CD28 or CD137
  11. 11. Inducible Caspase 9 Self Destruct Switch 12
  12. 12. CD123-CD28CAR CD123-41BBCAR Conditional ablation of CAR+ T cells by chemical- induced dimerization of iCaspase9
  13. 13. Redirected killing of CD123+ AML cells by CAR+ T cells CD123-CD28 CAR CD123-41BB CAR
  14. 14. CD123-41BB CARUntreated CD123-CD28 CAR In vivo killing of AML tumor cells by CAR+ T cells
  15. 15. Conclusions CD123-specific CAR+ T cells co-expressing iCaspase9 can be generated using approach suitable for human application T cells showed anti-tumor efficacy in vitro and in vivo iCAR+ T cells conditionally ablated upon addition of dimerizer
  16. 16. (1) 8F4: A T cell receptor-like antibody PR1 P3 NE PR1- CTL TCR PR1 P3 - Proteinase 3 NE - Neutrophil elastase Lysis AML, CML, & MDS Anti-PR1/HLA-A2 monoclonal antibody (8F4) Molldrem et al Blood 2011 17
  17. 17. (2) 8F4-CAR gene modified T cells CD28 CD3z sch8F4 8F4-CAR+ T cell PR1 P3 NE PR1- CTL TCR AML, CML, & MDS PR1 P3 - Proteinase 3 NE - Neutrophil elastase Lysis 8F4 (anti-PR1/HLA-A2) CAR PR1/HLA-A2tetramer CD3 96.6% 18
  18. 18. Anti PR1-HLA A2 CAR T-cell • Targets PR1 HLA A2 complex • Should spare normal hematopoiesis • If myelosuppressive, could use in haploidentical transplants from HLA A2 negative donor • Limitation- only targets disease in HLA A2 positive recipients, but these cells can be produced against a panel of HLA antigens
  19. 19. 20 Alloreactive NK Cells and Haploidentical Transplantation Reduce GVHD Reduce rejection Reduce relapse
  20. 20. Manufacturing mbIL21-expanded NK cells = 5 x 109 NK cells/kg Cryopreserve in aliquots Antigen-specific proliferation of CAR+Tcells Cryopreservation Infusion Cell Culture Bags Volume Reduction Biosafe Sepax ells n Wave Bioreactor 0 7 14 21 28 35 100 101 102 103 104 105 106 107 108 WAVE GMP Validation Lab data, n=19 Days FoldExpansion Lee et al Plos One 2012 21
  21. 21. mbIL21-expanded NK cells have increased cytotoxicity, telomeres, and cytokine secretion PLoSOne, Denman 2012 7:e30264 1 10 100 1000 10000 IFNg TNF IL-2 IL-6IFNg TNF IL-2 IL-6 IFN Fresh mbIL15 mbIL21 Supernatant[pg/ml] Lysis of 721.221 targets by fresh vs. expanded NK cells 10:1 5:1 2.5:1 1.25:1 0.625:1 0.3125:1 0 20 40 60 80 100 Fresh NK cells mbIL15-expanded mbIL21-expanded E:T Ratio PercentSpecificLysis C lone 4 (m bIL15) C lone9.m bIL21 -20 -10 0 10 20 ***
  22. 22. NK Cell Clinical Trials • We have initiated first in man phase I/II studies of ex vivo expanded NK cells to augment GVL effects of allogeneic HSCT – Developed GMP procedure, completed validation, FDA IND – 2012-0819 tests addition of NK cells to HLA matched transplants 8 patients enrolled (Champlin, Lee) – 2012-0708 tests addition of NK cells to haploidentical transplants 3 patients enrolled (Ciurea, Champlin) – 2011-0943 NK cells with cord blood transplants- 4 patients enrolled (Hosing, Shpall) • All studies open in dose escalation phase. No NK cell related toxicities. Low rate GVHD. Too early to assess antileukemia effects. 23
  23. 23. NK-cell Expansion and CAR transduction Antigen-specific CAR+ NK cells Expand NK cells on clone 9 CB-NK culture with cytokine (IL-2 at 200 units/ml or IL-15 at 10ng/ml) and clone 9 Transduction of NK cells with retroviral vector
  24. 24. Conclusions • Cellular immunotherapy is a highly promising approach to treatment of AML • Leukemia antigens have been identified • Challenge is to avoid damage to normal hematopoiesis; may be overcome with suicide switch or use prior to HSCT • Targeting PR1, aberantly expressed on AML, may spare normal hematopoiesis • NK cells naturally target AML; NK CARs further increase cytotoxicity • Clinical trials using CAR T-cells, other antigen specific T- cells and NK cells are in progress

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