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Title: The immune anti-tumor effects of allogeneic bone marrow transplantation and adoptive cell therapy with donor and recipient leukocyte infusions in mice carrying neuroblastoma
Other Titles: De immuun anti-tumor effecten van allogene beenmergtransplantatie en adoptieve cel therapie met donor en gastheer leukocyten infusies in muizen met neuroblastoma
Authors: Willems, Leen
Issue Date: 1-Jul-2013
Abstract: <p class="MsoNormal" style="margin-bottom:0cm;margin-bottom:.0001pt;text-align:justify;text-justify:inter-ideograph;line-height:150%">Allogeneic hematopoietic stem cell transplantation(HSCT) and posttransplant adoptive cell therapy with donor leukocyte infusions(DLI) are known to exert potent graft-versus-leukemia effects and convincingevidence is emerging that this approach can also elicit responses against solidtumors. Graft-versus-leukemia effects – specifically after DLI – largely relyon lymphohematopoietic graft-versus-host T cell alloreactivity which can resultin graft-versus-host disease when it extends to epithelial tissues. Not onlyfor hematological but also for solid tumors the association of anti-tumoreffects with graft-versus-host disease represents the major obstacle to thesuccessful application of allogeneic HSCT and adoptive DLI therapy as animmunotherapeutic strategy. Recent data in mice have shown that challenge withrecipient-type rather than donor-type leukocytes (recipient leukocyte infusion,RLI) can equally provide antitumor effects in hematological malignancies. <span style="mso-bidi-font-family:Calibri;mso-bidi-theme-font:minor-latin;mso-ansi-language:EN-US" lang="EN-US">RLI provokes lymphohematopoietic host-versus-graft Tcell reactivity with rejection of the graft and associated anti-leukemicresponses and does not carry the risk of graft-versus-host disease. Thisstrategy is currently being explored clinically in patients with hematologicalmalignancies. In experimental mouse models, it was demonstrated that NK cells, activated in vivo inthe course of RLI-induced T cell alloreactivity, contribute to the survivaladvantage produced by RLI<span style="mso-bidi-font-family:Calibri;mso-bidi-theme-font:minor-latin;mso-ansi-language:EN-US" lang="EN-US">.<p class="MsoNormal" style="margin-bottom:6.0pt;text-align:justify;text-justify:inter-ideograph;line-height:150%"><span style="mso-bidi-font-family:Calibri;mso-bidi-theme-font:minor-latin;mso-ansi-language:EN-US" lang="EN-US">Allogeneichematopoietic stem cell transplantation may also hold potential for thetreatment of high-risk neuroblastoma, a common extracranial solid tumor inchildhood that carries a bleak prognosis. Despite aggressive treatmentincluding high-dose chemotherapy and lymphohematopoietic rescue with autologoushematopoietic stem cells, relapse is very frequent. This spurs research intopost-transplant immunotherapeutic interventions to enhance antitumor immunity.Neuroblastoma cells are known to be sensitive to NK cell cytotoxicity and strategiestargeting NK cells are therefore particularly of interest. Alternatively, casereports suggest that allogeneic HSCT in high-risk neuroblastoma patients mayprolong survival and thus confers a graft-versus-neuroblastoma effect. This hasbeen experimentally demonstrated in mice. A phase I/II trial is currentlyinvestigating the anti-tumoreffect of haplo-identical HSCT in children withneuroblastoma. <p class="MsoNormal" style="margin-bottom:6.0pt;text-align:justify;text-justify:inter-ideograph;line-height:150%"><span style="mso-ansi-language:EN-US" lang="EN-US">The overall aim of this study was to investigate the potential combinedeffect of allogeneic HSCT and the novel RLI strategy on the growth ofexperimentally induced neuroblastoma tumors. Given the efficacy of RLI inenhancing graft-versus-leukemia effects in mice, the evidence that such effectsinvolve not only T cells but also NK cells, and the knowledge thatneuroblastoma cells are generally sensitive to NK cell cytotoxicity, we hypothesized that RLI may be aneffective and safe alternative to DLI to enhance the immune-mediated graft-versus-neuroblastomaeffect. Immune interventions after standard therapy with autologous HSCT forneuroblastoma can –to some extent– enhance endogenous anti-neuroblastoma immunity.In mice it has been shown that T cells devoid of anti-host alloreactivity mayfoster anti-neuroblastoma effects of allogeneic bone marrow transplantation(BMT) in mice. This supported our hypothesis that challenge with syngeneicmature effector cells may –in addition to causing alloreactive T cellresponses– foster direct anti-tumor reactions. <p class="MsoNormal" style="margin-bottom:6.0pt;text-align:justify;text-justify:inter-ideograph;line-height:150%"><span style="mso-bidi-font-family:Calibri;mso-bidi-theme-font:minor-latin;mso-ansi-language:EN-US" lang="EN-US">The specific aimof this work was to study the effects of RLI adoptive therapy on the local andmetastatic growth of neuroblastoma tumors in allogeneic bone marrow chimeras.We studied RLI in comparison with DLI since this is the standard approach usedin hematological malignancies ánd the approach currently studied in clinicaltrial for high-risk neuroblastoma. We used mouse models of focal and systemicposttransplant neuroblastoma relapse in a setting of MHC-mismatched allogeneicBMT: we chose to inoculate mice after the transplant to study immune anti-tumoreffects independently of direct effects of recent radiation therapy on thetumor. We used three different models. First, a focal model in which tumorcells are injected subcutaneously and give rise to a local and clinicallymeasurable tumor (subcutaneous model).Second, a systemic model where tumor cells are inoculated intravenously andthus cause direct metastatic spread (intravenousmodel). Third, a more physiological and preclinical model of metastaticspread where tumor cells are inoculated under the kidney capsule and where thelocal tumor is removed in toto after 7 days by a nephrectomy (kidney model). For the systemic andkidney models, we generated a luciferase-expressing tumor cell line anddeveloped a bioluminescence imaging protocol to non-invasively followmetastasis-free survival in vivo.<p class="MsoNormal" style="margin-bottom:6.0pt;text-align:justify;text-justify:inter-ideograph;line-height:150%"><span style="mso-ansi-language:EN-US" lang="EN-US">In part I of this work we used the subcutaneous model to study theeffects of allogeneic BMT and adoptive cell therapy on local neuroblastomagrowth. <span style="mso-bidi-font-size:10.0pt;line-height:150%;mso-ansi-language:EN-US" lang="EN-US">We confirmed that allogeneic BMT in mice providesa baseline graft-versus-neuroblastoma effect. We next demonstrated that bothDLI ánd RLI, when given to mixed bone marrow chimeras, further slow the localgrowth of subcutaneous implanted neuroblastoma tumors. DLI provoked a rapidconversion to full donor chimerism but mice developed severe GvHD, whereas RLIproduced complete graft-rejection but left mice healthy. The chimerism ofintratumoral leukocytes evolved in parallel with peripheral blood chimerism andwas -both after DLI and RLI- associated with increased intra-tumor CD8/CD4ratios, CD8+ T-cell IFN-<span style="mso-bidi-font-size:10.0pt;line-height:150%;mso-bidi-font-family:Calibri;mso-bidi-theme-font:minor-latin">gamma<span style="mso-bidi-font-size:10.0pt;line-height:150%;mso-ansi-language:EN-US" lang="EN-US">-expression and NK-cell Granzyme B-expression. The effect of RLI wasweaker than that of DLI but co-transfer of naïve recipient-type NK cells couldelicit a growth-limiting effect on neuroblastoma tumors in RLI chimeras. <p class="MsoNormal" style="margin-bottom:6.0pt;text-align:justify;text-justify:inter-ideograph;line-height:150%"><span style="mso-bidi-font-size:10.0pt;line-height:150%;mso-ansi-language:EN-US" lang="EN-US">In part II we investigated theeffects of posttransplant adoptive cell therapy on the systemic spread ofneuroblastoma. The final prognosis for patients with solid tumors, andespecially for neuroblastoma, is determined by the presence of distant therapynon-responsive metastases. <span style="mso-bidi-font-family:Calibri;mso-bidi-theme-font:minor-latin;mso-ansi-language:EN-US" lang="EN-US">Novel forms ofimmunotherapy therefore only hold clinical potential if they are efficacious onboth local and systemic spread of the tumor.Using the intravenous tumor model we documented that allogeneic BMT provides asignificant overall survival benefit relative to syngeneic BMT. Moreover, usingluciferase-expressing tumor cells and bioluminescence imaging we showed thatboth <span style="mso-bidi-font-family:Calibri;mso-bidi-theme-font:minor-latin;mso-ansi-language:EN-US" lang="EN-US">DLI and RLI produce a significant delay inmetastatic spread. The bioluminescence imaging studies in the kidney model -although preliminary - were consistent with those of the intravenous model andsupport the notion that both DLI and RLI have the potential to limit metastaticspread of neuroblastoma. <p class="MsoNormal" style="margin-bottom:6.0pt;text-align:justify;text-justify:inter-ideograph;line-height:150%"><span style="mso-bidi-font-size:10.0pt;line-height:150%;mso-ansi-language:EN-US" lang="EN-US">In part III we addressed thequestion whether syngeneic BMT by itself can provide an immuneanti-neuroblastoma effect. The current standard treatment of high-riskneuroblastoma includes high-dose chemotherapy and autologous HSCT which servesmerely as a lymphohematopoietic rescue. However, the potential intrinsic immuneeffects of this procedure have so far not been investigated. <span style="mso-bidi-font-family:Calibri;mso-bidi-theme-font:minor-latin;mso-ansi-language:EN-US" lang="EN-US">Our data are preliminary but show that, relative tonaïve mice, syngeneic BMT facilitates tumorigenesis of subcutaneouslyinoculated tumor cells while on the other hand it delays the growth ofestablished tumors. CD8+ T and NK cells synergistically regulatedtumor growth. Direct evidence of CD8+ T cells could not be found.However, the role of NK cells is supported by the evidence of increased Fas-L expressionand by the fact that adoptively transferred syngeneic NK cells could reinforcethe reduction in tumor growth.<p class="MsoNormal" style="margin-bottom:6.0pt;text-align:justify;text-justify:inter-ideograph;line-height:150%"><span style="mso-bidi-font-family:Calibri;mso-bidi-theme-font:minor-latin;mso-ansi-language:EN-US" lang="EN-US">In conclusion,the data support the potential value of DLI in mediating graft-versus-solidtumor effects. Importantly, they also deliver the first experimental evidencethat RLI is able to target a solid tumor and that it thus may represent a safealternative to DLI for this purpose. We document that lymphohematopoieticalloreactivity extends to the environment of the tumor itself, indicating thatalso for solid tumors it is closely related with the antitumor effect. Studieson the leukocytes contained within the focal neuroblastoma tumors providedevidence strongly suggesting that the antitumor effect of both DLI and RLIinvolves not only CD8+ T cells but also cytotoxic NK cells. Whereasin the DLI setting, the antitumor effect may rely predominantly on alloreactiveCD8+ T and NK cells, we provided evidence that the T cellalloreactivity provoked by an RLI challenge suffices to provide syngeneic naïveNK cells with the potential to attack syngeneic neuroblastoma cells in vivo. Weconclude therefore that RLI and DLI in allogeneic chimeras can provoke an in vivo lymphokine-activated killerphenomenon leading to cytotoxically active NK cells, even in the syngeneicsetting. The alloreactive T cell response produced by RLI and DLI may alsofacilitate the activation and expansion of tumor-specific donor or host CD8+T cells. Consistent with prior studies in leukemia models the RLI effect wasweaker than the DLI effect but this could be compensated by the additionalinfusion of syngeneic NK cells, a procedure that does not compromise the safetyprofile of RLI. Lastly, although to some extent preliminary, the data indicatethat the effects of both DLI and RLI are not limited to the local growth of atissue-localized tumor but can also limit the metastatic spread of a solidtumor. This is a critical requirement for a novel form of immunotherapy to beclinically relevant. <p class="MsoNormal" style="margin-top:6.0pt;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;margin-bottom:.0001pt;text-align:justify;text-justify:inter-ideograph;line-height:150%"><span style="mso-bidi-font-family:Calibri;mso-bidi-theme-font:minor-latin;mso-ansi-language:EN-US" lang="EN-US">The data may beparticularly helpful to understand the value of allogeneic HSCT and adoptivecell therapy for neuroblastoma. We demonstrate that this approach may provide asynergistic T cell and NK cell interaction resulting in an effective antitumorresponse against neuroblastoma, even in the setting where RLI is used. This isparticularly interesting since neuroblastoma is well known to be sensitive toNK cell cytotoxicity. With this respect, the data also suggest that NK cells equallycontribute to the baseline antitumor effect of allogeneic HSCT inneuroblastoma. Last, our preliminary observations in the syngeneic BMT modelshow that the effects of conditioning and autologous lymphohematopoieticreconstitution on neuroblastoma growth are complex and may include paradoxicaleffects on tumorigenesis and tumor progression. 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Publication status: published
KU Leuven publication type: TH
Appears in Collections:Laboratory of Experimental Transplantation
Department of Human Genetics - miscellaneous

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