Graft versus neuroblastoma reaction is efficiently elicited by allogeneic bone marrow transplantation through cytolytic activity in the absence of GVHD |
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Authors: | Shifra Ash Vered Gigi Nadir Askenasy Ina Fabian Jerry Stein Isaac Yaniv |
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Institution: | (1) Department of Pediatric Hematology-Oncology, Schneider Children’s Medical Center of Israel, 14 Kaplan Street, 49202 Petach Tikva, Israel;(2) Frankel Laboratory, Schneider Children’s Medical Center of Israel, 14 Kaplan Street, 49202 Petach Tikva, Israel;(3) Department of Cell Biology, Sackler School of Medicine, Tel Aviv University, 69788 Ramat Aviv, Israel; |
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Abstract: | Continuous efforts are dedicated to develop immunotherapeutic approaches to neuroblastoma (NB), a tumor that relapses at high
rates following high-dose conventional cytotoxic therapy and autologous bone marrow cell (BMC) reconstitution. This study
presents a series of transplant experiments aiming to evaluate the efficacy of allogeneic BMC transplantation. Neuro-2a cells
were found to express low levels of class I major histocompatibility complex (MHC) antigens. While radiation and syngeneic
bone marrow transplantation (BMT) reduced tumor growth (P < 0.001), allogeneic BMT further impaired subcutaneous development of Neuro-2a cells (P < 0.001). Allogeneic donor-derived T cells displayed direct cytotoxic activity against Neuro-2a in vitro, a mechanism of
immune-mediated suppression of tumor growth. The proliferation of lymphocytes from congenic mice bearing subcutaneous tumors
was inhibited by tumor lysate, suggesting that a soluble factor suppresses cytotoxic activity of syngeneic lymphocytes. However,
the growth of Neuro-2a cells was impaired when implanted into chimeric mice at various times after syngeneic and allogeneic
BMT. F1 (donor-host) splenocytes were infused attempting to foster immune reconstitution, however they engrafted transiently
and had no effect on tumor growth. Taken together, these data indicate: (1) Neuro-2a cells express MHC antigens and immunogenic
tumor associated antigens. (2) Allogeneic BMT is a significantly better platform to develop graft versus tumor (GVT) immunotherapy
to NB as compared to syngeneic (autologous) immuno-hematopoietic reconstitution. (3) An effective GVT reaction in tumor bearing
mice is primed by MHC disparity and targets tumor associated antigens. |
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