Success of Adoptive Immunotherapy Followed by Stem Cell Transplantation in the Management of Epstein Barr Virus (EBV)-Driven Primary Central Nervous System Lymphoma (PCNSL) in Immunodeficient Child.
Authors: Gharib Maged I. , Haque Tanzina , Nicholson James A. , Wilkie Gwen , Morton-Jones Marie , Carr Trevor F. , Arkwright Peter D. , Turner Andrew J.L. , Kelsey Anna M. , Crawford Dorothy H. , Wynn Robert F. 
Published: October 2019

Abstract
EBV-driven PCNSL is a rare form of B-cell non-Hodgkin’s lymphoma (NHL) seen in immuno-compromised (particularly AIDs) patients. The prognosis is gloomy and most patients die of their disease as radiotherapy and chemotherapy are usually ineffective in inducing durable remission. We report successful treatment of an 8 years old girl who presented with multifocal EBV-driven B-cell PCNSL with adoptive immunotherapy. Due to rarity of the disease particularly in children, she was investigated for and found to have an underlying primary immunodeficiency associated with defective immunity to herpes viruses. Her underlying immune defect did not fit with any of the currently well characterized congenital immune deficiency syndromes, but as also demonstrated in one of her two brothers, it seemed to have been inherited in an autosomal recessive fashion. Both were persistently lymphopenic (0.3–1.1 X 109/L), with proportionate reduction of T, B, and NK cells. Immunoglobulin classes were normal, as were specific antibody responses to tetanus. Mitogen responses to PHA, serum IgG2 levels and post-vaccination responses to Hib and Pneumococcus were low in both children. Antibody response to EBV was abnormal in both children with development of IgG antibodies to the capsular antigen (VCA) but not the nuclear antigen (EBNA). She was initially treated with conventional chemotherapy (intrathecal as well as systemic high dose Cytarabine and Methrotrexate), Rituximab, anti-virals and immunoglobulins. Neurological deterioration gradually progressed despite four weeks of such treatment. She eventually became bed ridden with quadreparesis and significant bulbar palsy requiring intubation for airway protection. In view of conventional treatment failure, immunotherapy with ex-vivo expanded EBV-specific cytotoxic T-lymphocytes (CTL) from a partially HLA matched donor was initiated. These were given weekly for seven consecutive weeks. There were no untoward effects. She made a remarkable neurological recovery within few weeks and became fully mobile in four months when she received non-myeloablative stem cell transplantation. Post transplant peripheral EBV reactivation (presenting as infectious mononucleosis-like disease without neurological manifestations) was promptly controlled with Rituximab and further doses of allogeneic EBV-CTLs. The child is now well five months post transplantation with evidence of immune reconstitution and remains in complete remission. GVHD prophylaxis has now been totally withdrawn. This is the first report of the successful use of EBV-specific cytotoxic T-lymphocytes in the treatment of primary CNS lymphoma in an immunocompromised patient. It offers new hope in a condition, which until now has been associated with a bleak outlook. The clinical response to immunotherapy is a clear demonstration that although the migration of resting blood lymphocytes across the inter-endothelial tight junctions forming the blood-brain-barrier may be largely restricted in physiological conditions, the migration of activated T lymphocytes into the brain in this clinical setting is unimpeded.