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Graft versus neuroblastoma reaction is efficiently elicited by allogeneic bone marrow transplantation through cytolytic activity in the absence of GVHD

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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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Acknowledgments

This work was supported by grants from the Israel Cancer Research Fund, Israel Ministry of Health, Israel Cancer Research Association, and the Frankel Trust for Experimental Bone Marrow Transplantation. The excellent technical assistance of Mrs. Natalia Binkovsy, Mrs. Ela Zuzovsky, and Mrs. Ana Zemlianski is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Pediatric Hematology-Oncology, Schneider Children’s Medical Center of Israel, 14 Kaplan Street, 49202, Petach Tikva, Israel

    Shifra Ash, Jerry Stein & Isaac Yaniv

  2. Frankel Laboratory, Schneider Children’s Medical Center of Israel, 14 Kaplan Street, 49202, Petach Tikva, Israel

    Shifra Ash, Vered Gigi & Nadir Askenasy

  3. Department of Cell Biology, Sackler School of Medicine, Tel Aviv University, 69788, Ramat Aviv, Israel

    Vered Gigi & Ina Fabian

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  1. Shifra Ash
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  2. Vered Gigi
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  3. Nadir Askenasy
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  5. Jerry Stein
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Correspondence to Nadir Askenasy.

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Ash, S., Gigi, V., Askenasy, N. et al. Graft versus neuroblastoma reaction is efficiently elicited by allogeneic bone marrow transplantation through cytolytic activity in the absence of GVHD. Cancer Immunol Immunother 58, 2073–2084 (2009). https://doi.org/10.1007/s00262-009-0715-6

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