Relapse is the leading cause of treatment failure post-hsct. Can we prevent or treat disease relapse?

Transcription

1 Relapse is the leading cause of treatment failure post-hsct Can we prevent or treat disease relapse?

2 Options at relapse - Second transplant - DLI (un manipulated or manipulated) - Leukaemia-specific T cells - Genetically engineered cellular therapies

3 Outcome after HSCT2 (n=170) LFS Relapse Bosi A et al. JCO 2001;19:

4 First BMT-relapse interval is a major factor for LFS Bosi A et al. JCO 2001;19:

5 An alternative donor at HSCT2 improves OS (n=179) Christopeit M et al. JCO 2013;31:

6 Disease relapse after allografting Appelbaum et al. Nature 2001

7 Donor lymphocyte infusions (DLI): exploiting the graft-versus-leukaemia effect to treat relapse post-allograft T Diagnosis Post-BMT Relapse Post-DLI

8 Escalating dose regimen at the HH First dose SIB VUD (CD3 cells/kg) (CD3 cells /Kg) Second dose Third dose Fourth dose 5x x Median time between infusions = 23 weeks

9 Donor T cell/cml cell ratios at different disease stages. CML Donor T cells 1/1500 1/3 7/1 MolRel CyRel HRel

10 Mol/Cyto-rel require lower ECD than haem-rel Simula et al, Leukemia 2007

11 The cell dose affects response rate Simula et al, Leukemia 2007

12 Fozza et al, Br J Haematol 2007

13 AGVHD and BMT-DLI interval Days BMT-DLI Acute GVHD Grade 0-I < (57%) > (84%) Grade II-IV 6 (43%) 7 (15%) Total 14 (100%) 46 (100%) p = 0.028

14 King s College Hospital DLI Study 116 patients Krishnamurthy, Potter et al, BBMT,2013 Pre-emptive DLI: pdli (n= 64) DLI instituted for : Donor CD3 <50% or Fall in donor CD3 >20% within 1 month Therapeutic DLI: tdli (n=52) Chemotherapy and DLI: n=35 DLI alone: n=14 Data missing: n=3 Escalating dose DLI 6-8 week interval

15 Early administration of pre-emptive DLI correlates with durable AML/MDS remission 64 patients pre-emptive DLI to correct falling donor CD3 chimerism (median time 164 days) Overall 5 year survival after pre-emptive DLI 80% Superior event-free 5 year survival after pre-emptive DLI 65% GvHD incidence 31% (19% chronic extensive) after pre-emptive DLI Krishnamurthy P, et al, Biol Blood Marrow Transplant (in press)

16 Pre-emptive DLI for relapse of AML/MDS after RIC HSCT KCH retrospective analysis: OS of 80% and EFS of 65% GvHD (31%): Acute in 4 (6%) Chronic: limited in 3 (5%), extensive in 12 (19%) Krishnamurthy, Potter et al. BBMT 2013

17 GvHD Can we dissect GvL from GvHD? GvL Immune reconstitution

18 Manipulated DLI - CD8 depleted - T-reg depleted - T-rapa

19 Probability of complete cytogenetic response and molecular remission after CD4+ DLI in patients with relapsed early-phase CML. Nineteen patients with cytogenetic or stable-phase CML relapse were evaluable for response. Alyea E P et al. Blood 1998;91: by American Society of Hematology

20 Maury et al, Sci Transl Med 2010

21 Phase 2 clinical trial design of ex vivo and in vivo Sirolimus for low-intensity allogeneic HCT. Donors underwent steady-state apheresis #1, whereby CD4+ T cells were purified by positive selection; costimulated with anti-cd3 and anti-cd28; and exposed to I... Fowler D H et al. Blood 2013;121: by American Society of Hematology

22 - Faster CD4 reconstitution - Probability of acute GVHD 20% and 40% at days 100 and No TRM - 45% in sustained complete remission (42-84 months).

23 Tumour antigens Tumour-specific antigens: Virus encoded proteins Idiotypes of B and T cell tumours Mutated cellular proteins

24 Chronic myeloid leukaemia and the Philadelphia (Ph) chromosome 9 9q q- (Ph) bcr abl abl-bcr bcr-abl expresses a fusion oncoprotein with tyrosine kinase activity p210

25 MHC class I processing limits the display of peptides containing mutated sequences ER Intracellular protein Class I Mutated sequence

26 CML: The irony of efficient peptide binding

27 Tumour antigens Tumour-specific antigens: Virus encoded proteins Idiotypes of B and T cell tumours Mutated cellular proteins Tumour-associated antigens: Over-expressed cellular proteins Tissue-specific differentiation antigens Expression of silent genes

28 Disease Melanoma Renal cell cancer Patients Percentage % 96 2 Patient characteristics (NIH Trials) Ovarian cancer 4 1 Colorectal cancer 3 1 Breast cancer 1 0 Prior Treatment Surgery Chemotherapy Radiotherapy Hormonal Immunotherapy Any 2 or more Any 3 or more Response Total 440 patients received 541 different vaccines. CR, complete response; PR partial response; NR, no response. Performance status, Eastern Cooperative Oncology Group performance status. CR 4 1 Nature medicine Vol. 10 / No. 9 / Sept 2004 PR 9 2 NR

29 Can GVHD and GVL be dissected? Tumour-specific antigens Selection of haemopoietic-restricted polymorphism

30 Molecules involved in the immune responses after allogeneic SCT Genetic disparities between donor and recipient determine specificity MHC-mismatched: Major Histocompatibility Complex MHC-matched: Minor Histocompatibility Antigens Most SCT patients are MHC matched

31 Minor H antigens can be haemopoietic specific HA1-specific TCL Skin explant assay HY-specific TCL Dickinson et al, Nat Med (2002)

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33 CD19-specific CARs are impacting on management of B-cell malignancy NCI MSKCC CoH BCM UPenn scfv FMC63 SJ25C1 FMC63 FMC63 FMC63 Hinge CD28 CD28 IgG4 IgG1 CD8α Transmembrane Co-stimulatory domain CD28 CD28 Nil Nil v CD28 4-1BB Signalling domain CD3ζ CD3ζ CD3ζ CD3ζ CD3ζ From Maher J (2014) Current Gene Therapy Pooled response data ALL (adults and children) 80% CR (UPenn & MSKCC) CLL 22% CR (UPenn)

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