Cytomegalovirus promotes expansion of pre-existing T-cell immunity following allogeneic transplantation significantly modulating chimerism status

Rob S. Sellar, Frederick Arce Vargas, Jake Y. Henry, Stephanie Verfuerth, Sarah Charrot, Sergio A. Quezada, Stephen Mackinnon, Kirsty J. Thomson,

and Karl S. Peggs*

University College London Cancer Institute

The Dogma

• CMV reactivations are increased if you T-deplete• Highest risk population R+/D-• New therapeutic strategies are needed

What if it is wrong?

What if it is wrong?

CMV reactivations

What if it is wrong?

CMV reactivations Days of treatment

Problematic CMV reactivations are associated with low levels of recipient chimerism

CMV reactivations

Problematic CMV reactivations are associated with low levels of recipient chimerism

CMV reactivations Days of treatment

Problematic CMV reactivations are restricted to patients with significant GvHD

CMV reactivations

Problematic CMV reactivations are restricted to patients with significant GvHD

CMV reactivations Days of treatment

Patients with significant GvHD had lower absolute lymphocyte counts

CMV appears to influence levels of recipient chimerism

CMV appears to influence levels of recipient chimerism

CMV appears to influence levels of recipient chimerism

CMV influences chimerism even in the absence of GvHD

Streptamer positive cells are exclusively of recipient origin

Streptamer positive cells are exclusively of recipient origin

Donor

Recipient

CD4+

CD8+ Strep-

CD8+ Strep+

Patient 1 Patient 2 Patient 3

DLI can be followed by a primary immune response to CMV

Donor

Recipient

Pre-DLI

4 weeks

8 weeks

12 weeks

18 weeks

CD8+ Strep- CD8+ Strep+ CD4+

Conclusions

• recipient-derived virus-specific T cells that have escaped deletion during non-myeloablative conditioning can protect against recurrent CMV infection

• expansion of these cells post transplant has a significant influence on levels of recipient chimerism

• “Campath Paradox” - T cell-depletion in the R+D- setting may paradoxically foster more rapid reconstitution of protective antiviral immunity by reducing graft-versus-host directed alloreactivity and the associated elimination of the recipient T cell compartment

Acknowledgements

• UCL Cancer Institute• Tumour Immunogy Group– Dr Karl S Peggs

– Dr Sergio A Quesada

– Dr Frederick Arce Vargas

– Jake Y Henry

• Royal Free Hospital – Professor Stephen Mackinnon

– Stephanie Verfuerth

• UCLH – Dr Kirsty Thomson

– Dr Sarah Charrot