Adoptive Treatment Of EBV-Associated Leiomyosarcoma In Immunodeficient Patients With EBV Specific Cytotoxic T Cells

Epstein-Barr virus (EBV)-associated smooth muscle tumors or leiomyosarcomas (EBV LMS) are extremely rare. These tumors develop in patients with acquired or underlying immune deficiency including those after solid organ transplant (SOT) and exhibit a latency type II phenotype. EBV LMSs are typically aggressive and respond poorly to conventional therapy. As part of an on-going trial of EBV specific cytotoxic T lymphocytes for the treatment of EBV related malignancies we have treated 5 patients with EBV LMS with cytotoxic T cell lines generated from normal donors. Five patients, three after SOT (kidney N=1, small bowel N=2), one after solid organ (kidney) and hematopoetic stem cell transplant, and one with a poorly defined underlying immune deficiency syndrome developed EBV LMS. Two patients were successfully treated for EBV lymphoproliferative disease prior to developing EBV LMS. EBV LMS was diagnosed 18 – 46 months after SOT in 4 patients, at 9 years old in the fifth and were multifocal at diagnosis in all 5 patients. All four patients who had undergone SOT failed to respond to decreased immune suppression, one had failed treatment with autologous EBV CTLs and two had failed cytotoxic chemotherapy. The EBV LMS was of host origin in 4/5 patients and of mixed donor and host origin in one. Lines of EBV CTLs were generated as previously described by co-culture of donor peripheral blood T lymphocytes with autologous EBV transformed BLCLs. Lines are tested for EBV specific cytotoxicity, sterility and absence of alloreactivity. Patients with EBV LMS were treated with cell lines generated from unrelated as well as related donors. Three patients received EBV CTLs generated from related haplo-identical parent donors including one whose parental donor was also the donor of her transplanted kidney. One patient received EBV CTLs from an HLA identical related donor. All other lines were generated from 3^rd parties. Lines from unrelated third party donors were matched at 2 – 4/8 HLA alleles. In all instances EBV directed cytotoxicity of infused lines was restricted by HLA alleles shared by the patient and the EBV LMS. Three patients achieved partial remissions (PR) lasting 18 – 122 months and one patient has had stable disease for >80 months. One patient had stable disease for 14 months before progression. Expansion of EBV CTLp was demonstrated in all patients after infusion of EBV CTLs lasting from 0.5 to 4 months. Based on the prediction that 3^rd party partially matched EBV CTLs are unlikely to persist long term in vivo four of the patients have received multiple cycles of EBV CTLs in an effort to maintain these responses. EBV directed cytotoxic T cell therapy is a novel treatment strategy for EBV LMS, a malignancy that is typically associated with a very poor prognosis. EBV CTLs from immunologically normal, partially HLA-matched third party donors, appropriately specific and HLA restricted can induce significant and durable responses to EBV LMS. Approaches designed to selectively expand T-cells specific for EBV antigens expressed by these malignancies may further improve responses.