Multicenter Study of Third-Party Virus-Specific T
cells to Treat Adenovirus, Epstein-Barr Virus or
Cytomegalovirus Infecti...
The Center for Cell and Gene Therapy has a
Research Collaboration with Celgene and Bluebird Bio
Many investigators at the ...
Viral infections post-transplant
• 40% deaths after alternative donor
transplant due to viral infections
• Antiviral drugs...
1
Infusion
Blood draw
T cells
T-cell product
generation
Antigen
Specificity
2
3
4
SCT
donor
SCT
recipientImmunotherapy for...
Immunotherapy for viral infections
• Virus-specific T cells as prophylaxis
and treatment
–EBV
–Adv/EBV (bivirus)
–Adv/EBV/...
Generation of trivirus-specific T cell
lines using Ad5f35 vectors
6 wk
PBMC EBV LCL
B95-8 EBV virus
Trivirus
CTL
Restimula...
• In vitro expanded donor-derived virus-
specific T cells targeting Adv, EBV, CMV
–Safe
–Reconstituted antiviral immunity ...
The problem
- Individualized products
- impractical for widespread/urgent use
Assess whether banked virus-
specific T cells (VSTs) produced
clinical benefit in partially HLA-
matched 3rd party recipie...
3rd party VST therapy
Blood
donor
A1, A24;
B8, 18;
DR1, 15
EBV activity – B8, DR1
CMV activity – A24
Adv activity – A1, A2...
3rd party VST therapy
Blood
donor
A1, A24;
B8, 18;
DR1, 15
EBV activity – B8, DR1
CMV activity – A24
Adv activity – A1, A2...
3rd party VST therapy
Blood
donor
A1, A24;
B8, 18;
DR1, 15
Trivirus
VST
EBV activity – B8, DR1
CMV activity – A24
Adv acti...
VST Product
• Most closely HLA-matched trivirus-specific
VSTs
–Some VST lines already made for
previous studies
–New VST l...
Phenotype of VSTs
0
20
40
60
80
100
0 1 2 3 4 5 6
%Positivecells
CD3 CD4 CD8 Effector Central
memory memory
Trivirus specificity of VSTs
1
10
100
1000
10000
0 0.5 1 1.5 2 2.5 3 3.5
SFC/1x105
Adv CMV EBV
Clinical protocol
• Treatment of refractory EBV, CMV, or Adv
• Patients receive 2 x 107 VSTs/m2
• If partial response may ...
Screening
• 82 patients screened
– 23 - Bone marrow
– 33 - Peripheral blood stem cells
– 12 - Single cord
– 13 - Double co...
Screening
• 24 patients with line not on study
–subsequently not eligible due to
other infections
–improved
–progressed an...
Patients Treated on Study
• 50 patients infused – 45 evaluable
– 19 received VSTs for CMV
– 17 received VSTs for Adv
– 9 r...
Are the VSTs safe?
• Acute GVHD within 45 days first infusion
– 8 patients developed GVHD (6 prior history)
• 6 Grade I; 1...
Pre VSTs
Viral Inclusion
Immunostain for CMV
Ulcers on
endoscopy
Post-VSTs
No Viral Inclusions
Normal endoscopy
CMV Coliti...
Clinical response correlates with
increase in VSTs
0
200
400
600
800
1000
1200
1400
1600
Pre wk1 wk2 wk4 3 mo
SFC/2x105
CM...
Overall CMV responses
•19 patients treated for CMV
•17/19 responded to VSTs
•9 CR
•8 PR
Clinical benefit - Adv
0.E+00
5.E+05
1.E+06
2.E+06
Pre wk1
Stool
Copies/ml
Blood
0
10
20
30
40
0
500
1000
1500
2000
Pre wk...
Clinical benefit - Adv
0
10
20
30
40
0
500
1000
1500
2000
Pre wk2 wk4 wk6
SFC/2x105
Blood
Adv T cells
0.E+00
5.E+05
1.E+06...
Overall Adv responses
•17 patients treated for Adv
•14/17 responded to VSTs
•7 CR
•7 PR
Clinical Responses –EBV (pt37)
Pre VSTs 1 month post VSTs
Immune Responses –EBV (pt37)
0
20
40
60
80
Pre wk2 wk4
SFC/2x105
EBV T cells
Overall EBV responses
•9 patients treated for EBV
•6/9 responded to VSTs
•2 CR
•4 PR
Do VSTs Persist?
•Deep sequencing
TCRs
•Detect specificities
in both donor and
recipient
VSTline
PT37
Pre infusion PBMCswk...
Probability
0.0
0.2
0.4
0.6
0.8
1.0
Days Post VST Infusion
0 7 14 21 28 35 42
Cumulative Incidence of First CR/PR by Infec...
What happened to patients without
a line?
•Line identified for 74/82
•8 patients without a suitable line
•6 died of progre...
What happened to patients without
a line?
•Line identified for 74/82
•8 patients without a suitable line
•6 died of progre...
Summary of 3rd Party VST Trial
• Low attributable toxicity
• VSTs effective in clearing EBV/Adv/CMV
disease
• T cell expan...
Solutions
- Individualized products
Administration of “off the shelf” T cells
Ongoing studies
- Individualized products
Administration of “off the shelf” T cells
- Simplify manufacture
- Cost
- Comple...
TRL Lab PIs
Helen Heslop
Cliona Rooney
Malcolm Brenner
Catherine Bollard
Juan Vera
GMP/QC Laboratory
Adrian Gee
Debbie Lyo...
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Multicenter Study of Third-Party Virus-Specific T cells to Treat Adenovirus, Epstein-Barr Virus or Cytomegalovirus Infections after Hematopoietic Stem Cell Transplantation

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Multicenter Study of Third-Party Virus-Specific T cells to Treat Adenovirus, Epstein-Barr Virus or Cytomegalovirus Infections after Hematopoietic Stem Cell Transplantation

  1. 1. Multicenter Study of Third-Party Virus-Specific T cells to Treat Adenovirus, Epstein-Barr Virus or Cytomegalovirus Infections after Hematopoietic Stem Cell Transplantation
  2. 2. The Center for Cell and Gene Therapy has a Research Collaboration with Celgene and Bluebird Bio Many investigators at the Center (including the presenter) have patent applications in the fields of T cell and gene-modified T cell therapy for cancer Disclosure
  3. 3. Viral infections post-transplant • 40% deaths after alternative donor transplant due to viral infections • Antiviral drugs –Costly –Significant side effects –Often ineffective • Alternative - Adoptive T cell transfer
  4. 4. 1 Infusion Blood draw T cells T-cell product generation Antigen Specificity 2 3 4 SCT donor SCT recipientImmunotherapy for viral infections
  5. 5. Immunotherapy for viral infections • Virus-specific T cells as prophylaxis and treatment –EBV –Adv/EBV (bivirus) –Adv/EBV/CMV (trivirus)
  6. 6. Generation of trivirus-specific T cell lines using Ad5f35 vectors 6 wk PBMC EBV LCL B95-8 EBV virus Trivirus CTL Restimulation +IL2 6 wk Ad5f35pp65 transduced EBV LCL Ad5f35pp65 vector Ad5f35pp65 vector PBMC
  7. 7. • In vitro expanded donor-derived virus- specific T cells targeting Adv, EBV, CMV –Safe –Reconstituted antiviral immunity for EBV, CMV and Adv –Effective in clearing disease –Considerable expansion in vivo Clinical Outcome Summary – Donor-specific setting Leen et al, Nat Med. 2006 Leen et al, Blood. 2009
  8. 8. The problem - Individualized products - impractical for widespread/urgent use
  9. 9. Assess whether banked virus- specific T cells (VSTs) produced clinical benefit in partially HLA- matched 3rd party recipients
  10. 10. 3rd party VST therapy Blood donor A1, A24; B8, 18; DR1, 15 EBV activity – B8, DR1 CMV activity – A24 Adv activity – A1, A24, DR15 Trivirus VST EBV – A1, 11; B8, 35; DR8 MDACC
  11. 11. 3rd party VST therapy Blood donor A1, A24; B8, 18; DR1, 15 EBV activity – B8, DR1 CMV activity – A24 Adv activity – A1, A24, DR15 Trivirus VST EBV – A1, 11; B8, 35; DR8 MDACC
  12. 12. 3rd party VST therapy Blood donor A1, A24; B8, 18; DR1, 15 Trivirus VST EBV activity – B8, DR1 CMV activity – A24 Adv activity – A1, A24, DR15 CMV – A2, 24; B7, 27; DR1, 15 Adv – A1, 11; B7, 8; DR3, 11 EBV – A1, 11; B8, 35; DR8 CHLA Boston MDACC
  13. 13. VST Product • Most closely HLA-matched trivirus-specific VSTs –Some VST lines already made for previous studies –New VST lines made from donors with common alleles (PACT) • 32 lines • Multicenter study (TCH, TMH, MDACC, Duke, Dana Farber, CHLA, Hackensack, Mass General, Uni. Of Miami, Boston Children’s Hospital)
  14. 14. Phenotype of VSTs 0 20 40 60 80 100 0 1 2 3 4 5 6 %Positivecells CD3 CD4 CD8 Effector Central memory memory
  15. 15. Trivirus specificity of VSTs 1 10 100 1000 10000 0 0.5 1 1.5 2 2.5 3 3.5 SFC/1x105 Adv CMV EBV
  16. 16. Clinical protocol • Treatment of refractory EBV, CMV, or Adv • Patients receive 2 x 107 VSTs/m2 • If partial response may receive additional doses at 2+ weekly intervals
  17. 17. Screening • 82 patients screened – 23 - Bone marrow – 33 - Peripheral blood stem cells – 12 - Single cord – 13 - Double cord • Line identified for 74/82 – Suitable line if matched at least one antigen with activity against infecting virus
  18. 18. Screening • 24 patients with line not on study –subsequently not eligible due to other infections –improved –progressed and died prior to infusion –declined
  19. 19. Patients Treated on Study • 50 patients infused – 45 evaluable – 19 received VSTs for CMV – 17 received VSTs for Adv – 9 received VSTs for EBV
  20. 20. Are the VSTs safe? • Acute GVHD within 45 days first infusion – 8 patients developed GVHD (6 prior history) • 6 Grade I; 1 Grade II; 1 Grade III – 1 chronic GVHD flare (discontinued immunosuppression) • 2 developed transplant-associated microangiopathy (both on sirolimus)
  21. 21. Pre VSTs Viral Inclusion Immunostain for CMV Ulcers on endoscopy Post-VSTs No Viral Inclusions Normal endoscopy CMV Colitis Responds to VSTs – pt69 Do the VST produce clinical benefit?
  22. 22. Clinical response correlates with increase in VSTs 0 200 400 600 800 1000 1200 1400 1600 Pre wk1 wk2 wk4 3 mo SFC/2x105 CMV T cells Control
  23. 23. Overall CMV responses •19 patients treated for CMV •17/19 responded to VSTs •9 CR •8 PR
  24. 24. Clinical benefit - Adv 0.E+00 5.E+05 1.E+06 2.E+06 Pre wk1 Stool Copies/ml Blood 0 10 20 30 40 0 500 1000 1500 2000 Pre wk2 wk4 wk6
  25. 25. Clinical benefit - Adv 0 10 20 30 40 0 500 1000 1500 2000 Pre wk2 wk4 wk6 SFC/2x105 Blood Adv T cells 0.E+00 5.E+05 1.E+06 2.E+06 Pre wk1 Stool Copies/ml
  26. 26. Overall Adv responses •17 patients treated for Adv •14/17 responded to VSTs •7 CR •7 PR
  27. 27. Clinical Responses –EBV (pt37) Pre VSTs 1 month post VSTs
  28. 28. Immune Responses –EBV (pt37) 0 20 40 60 80 Pre wk2 wk4 SFC/2x105 EBV T cells
  29. 29. Overall EBV responses •9 patients treated for EBV •6/9 responded to VSTs •2 CR •4 PR
  30. 30. Do VSTs Persist? •Deep sequencing TCRs •Detect specificities in both donor and recipient VSTline PT37 Pre infusion PBMCswk2wk4
  31. 31. Probability 0.0 0.2 0.4 0.6 0.8 1.0 Days Post VST Infusion 0 7 14 21 28 35 42 Cumulative Incidence of First CR/PR by Infection CMV (N=23) EBV (N=9) Adenovirus (N=18) Overall response rate • Overall 74% 74% - CMV 67% - EBV 79% - Adv • Durable 4 subsequent progression/recurrence CR/PR based on infection Days post-VST
  32. 32. What happened to patients without a line? •Line identified for 74/82 •8 patients without a suitable line •6 died of progressive infection •1 failed multiple antivirals but eventually cleared post-DLI •1 PR by day 42
  33. 33. What happened to patients without a line? •Line identified for 74/82 •8 patients without a suitable line •6 died of progressive infection •1 failed multiple antivirals but eventually cleared post-DLI •1 PR by day 42 •Response rate 13% vs 74% VST group Leen et al, Blood, in press
  34. 34. Summary of 3rd Party VST Trial • Low attributable toxicity • VSTs effective in clearing EBV/Adv/CMV disease • T cell expansion seen in approx. 50% of responders • May require several infusions to sustain benefit • Persistence for 12 weeks in a recipient of a 4/6 matched line
  35. 35. Solutions - Individualized products Administration of “off the shelf” T cells
  36. 36. Ongoing studies - Individualized products Administration of “off the shelf” T cells - Simplify manufacture - Cost - Complexity - Increase breadth of specificity
  37. 37. TRL Lab PIs Helen Heslop Cliona Rooney Malcolm Brenner Catherine Bollard Juan Vera GMP/QC Laboratory Adrian Gee Debbie Lyon Zhuyong Mei Suzanne Poole CTL Laboratory Oumar Diouf Joyce Ku Pallavi Mohpatra Huimin Zhang Weili Liu TRL Laboratory Ulrike Gerdemann Usha Katari Anastasia Papadopolou Jacqueline Kiernan Joey Tong Lisa Rollins Clinical Research Bambi Grilley Bridget Medina Alician Brown Yu-Feng Lin Transplant Service Bob Krance Kathy Leung Caridad Martinez George Carrum Ram Kamble CHALLAH J. Antin B. Dey D. Avigan P. Szabolcs E.J. Shpall P Kebriaei, N. Kapoor S-Y Pai, S.D. Rowley, BR Dey, Acknowledgements Funding: NCI Program Project Grant, NHLBI Somatic Cell Therapy Center, Lymphoma SPORE, Leukemia and Lymphoma Society Specialized Center of Research, Doris Duke Distinguished Clinical Scientist Award, PACT EMMES Adam Mendizabal Katherine Christensen NMDP Dennis Confer NHLBI John Thomas

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