Phase I trial of interferon gamma to potentiate cyclosporine-induced graft-versus-host disease in women undergoing autologous bone marrow transplantation for breast cancer.

Kennedy, M. J.; Vogelsang, Georgia B.; Rj, Jones; Farmer, Evan R.; Hess, A. D.; Altomonte, V; Huelskamp, A M; Davidson, Nancy E.

doi:10.1200/jco.1994.12.2.249

Cited by 79 publications

(47 citation statements)

References 16 publications

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“…12 It has been demonstrated that CsA-induced GVHD can be augmented by interferon-␥. 34 Ratanatharathorn et al 35 reported that interferon-␣ administration can both induce autologous GVHD and enhance autologous GVHD induced by CsA. In addition, interleukin-2 amplifies antitumor activity and shows synergism with CsA in induction of a potent graftversus-tumor effect.…”

Section: Discussionmentioning

confidence: 99%

Cyclosporin A-induced graft-versus-host disease following autologous bone marrow and stem cell transplantation in hematological malignancies of childhood

Gruhn

Häfer

Kosmehl³

et al. 1998

Bone Marrow Transplant

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Summary:Cyclosporin A (CsA) can induce graft-versus-host disease (GVHD) following autologous bone marrow transplantation (ABMT) and autologous peripheral blood stem cell transplantation (APBSCT) in adults. We investigated whether GVHD can be induced following ABMT and APBSCT in childhood, and which cells are involved in the pathogenesis of this syndrome. We conducted a prospective study of 20 children and adolescents with hematological malignancies receiving CsA after ABMT and APBSCT. Skin biopsies were obtained on day 21 after transplantation or in the event of a rash. Immunophenotypic analysis of peripheral blood lymphocytes was performed on days 14, 21, 28 and 60 after transplantation. Clinical GVHD of the skin, confirmed by histological criteria, occurred in five patients. Five patients had no clinical GVHD but had acute GVHD alterations on routine skin biopsy. In all 10 patients with a positive skin biopsy for GVHD, CD4 + lymphocytes were the predominant cells in the epidermis. Immunophenotypic analysis of peripheral blood lymphocytes revealed a significantly increased CD4/CD8 ratio in patients with a positive skin biopsy (P Ͻ 0.01). Our findings indicate that it is possible to induce acute GVHD following ABMT and APBSCT in childhood. In addition, CD4 + lymphocytes play an important role in the pathogenesis of CsA-induced GVHD. Keywords: cyclosporin A; graft-versus-host disease; bone marrow transplantation; hematopoietic stem cell transplantation Despite the increased morbidity and mortality in patients with graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT), GVHD is associated with a clinically significant antitumor effect. 1,2 It has been shown that mature T cells from the donor contaminating the bone marrow inoculum are responsible for the development of GVHD. 3 T cell depletion of donor marrow for allogeneic BMT leads to a markedly reduced incidence of GVHD in the marrow recipients. Unfortunately, T cell depletion is also associated with an increased incidence of marrow graft failure and an increase in relapse rate. 4 The procedure-related toxicity is lower after autologous bone marrow transplantation (ABMT) than after allogeneic BMT. In contrast, the higher relapse rates after autologous and syngeneic BMT than after allogeneic BMT are at least partly due to the absence of graft-versus-tumor effect associated with GVHD. 5,6 A syndrome that clinically resembles acute GVHD has been observed spontaneously in 8% of patients receiving autologous or syngeneic BMT. 7 This syndrome appears to involve only the skin, is generally mild, and is self-limiting. Due to the rarity of this phenomenon, it has not been possible to determine its effects on leukemic relapse rates.In ABMT, further significant dose escalation with the current conditioning protocols is limited due to unacceptable toxicity. Therefore, interest has focused on methods stimulating immunologically mediated antitumor activity. In animal models, GVHD was induced by treatment with cyclosporin A (CsA) in rats or mice un...

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Section: Discussionmentioning

confidence: 99%

Cyclosporin A-induced graft-versus-host disease following autologous bone marrow and stem cell transplantation in hematological malignancies of childhood

Gruhn

Häfer

Kosmehl³

et al. 1998

Bone Marrow Transplant

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“…Phase I and II studies were performed to evaluate the potential efficacy of post transplant immune modulation using CsA with or without IFN-g to induce auto-GVHD. 10,14,[21][22][23][24][25][26] We will review these data from a clinical and mechanistic perspective and speculate as to how auto-GVHD might be more effectively harnessed in future clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Autologous graft-versus-host disease: harnessing anti-tumor immunity through impaired self-tolerance

Kline

Subbiah

Lazarus

et al. 2007

Bone Marrow Transplant

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“…Cyclosporin A-induced syngeneic and autologous GVHD has been observed experimentally in rodents [15][16][17] and clinically in cancer patients. [18][19][20][21][22][23] The data presented in this report demonstrate that a GVT mechanism is present in mice with SGVHD. Mice in which SGVHD was induced rejected a minimal tumor challenge of a class II Ϫ B cell lymphoma after cessation of CsA therapy and the rejection coincided with histological evidence of the disease.…”

Section: Discussionmentioning

confidence: 90%

“…[15][16][17] Although the mechanism(s) by which CsA treatment of syngeneic reconstituted animals induces syngeneic GVHD (SGVHD) is not totally understood, CsA-induced autologous GVHD has been used in cancer patients post-transplant to assess the antitumor effects. [18][19][20][21][22][23][24] A low-grade cutaneous GVHD which spontaneously regressed was induced in a high percentage of the patients following autologous transplantation and CsA treatment. Isolated T cells from such patients showed the ability to lyse autologous peripheral blood lymphocytes in vitro.…”

mentioning

confidence: 99%

Rejection of an MHC class II negative tumor following induction of murine syngeneic graft-versus-host disease

Bryson

Jennings

Lowery

et al. 1999

Bone Marrow Transplant

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Summary:Cyclosporin A (CsA) has been used clinically to induce graft-versus-host disease following autologous bone marrow transplantation in an attempt to destroy residual leukemia cells and reduce relapse. To analyze the antitumor potential of murine syngeneic graft-versus-host disease (SGVHD), C3H/HeN mice were lethally irradiated, reconstituted with T cell-depleted syngeneic bone marrow (ATBM) and treated with CsA for 21 days. Graft-versus-leukemia activity was assessed by challenging groups of olive oil-treated control ATBM (OO-ATBM) and CsA-treated (CsA-ATBM) mice 1 week after CsA therapy with graded doses of the syngeneic 38C13 B cell lymphoma. Following CsA treatment, up to 70% of CsA-ATBM developed SGVHD and more than 70% of the animals injected with 500 38C13 cells exhibited long-term survival (MST Ͼ80 days). In contrast, none of the OO-ATBM control mice developed SGVHD, and more than 75% of these mice died following injection of 500 38C13 tumor cells (MST = 34 days). Long-term survivors were not resistant to tumor challenge suggesting that tumor-specific immunity did not develop. Finally, class II negative 38C13 cells cultured in IL-4 or IL-10 were not inducible for MHC class II molecules, demonstrating that class II-independent antitumor mechanisms exist in SGVHD mice. Keywords: syngeneic bone marrow transplantation; cyclosporin A; graft-versus-host disease; graft-versus-tumor Bone marrow transplantation (BMT) has been used as a first-line therapy for many patients with leukemia or lymphoma. 1,2 A major cause of morbidity and mortality following allogeneic BMT is graft-versus-host disease (GVHD), the development of which correlates with the presence of alloreactive T cells present in the donor cell inoculum. [1][2][3][4][5] Such cells initiate a multifactorial set of specific and nonspecific immune responses which result in the induction of the two forms of GVHD: acute and chronic. It has been shown in animal models 6 and in retrospective analyses of clinical studies of BMT for leukemias and lymphomas, that the development of GVHD following allogeneic BMT may be beneficial and correlate with a graftversus-leukemia (GVL) response. 7,8 Allogeneic BMT recipients who develop acute or chronic GVHD have lower relapse rates than patients transplanted with autologous or syngeneic BM. 9,10 Furthermore, when patients undergoing allogeneic transplants are given T cell-depleted BM to eliminate GVHD, increased relapse rates occur, suggesting that T cells present in the donor graft are necessary for inhibition of leukemic relapse. 11 Cytotoxic T lymphocytes (CTL), 12 lymphokine-activated killer cells, 13 and natural killer cells (NK) 14 are all thought to participate in the GVL process. Recently, much effort has been expended to discriminate beneficial GVL responses from the harmful GVHD effector mechanisms. In murine models of GVHD, it has been possible to separate GVHD immune mechanisms from GVL responses. 7 However, such findings have not yet been extrapolated to man.Interestingly, rodents treated with the immun...

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Phase I trial of interferon gamma to potentiate cyclosporine-induced graft-versus-host disease in women undergoing autologous bone marrow transplantation for breast cancer.

Abstract: CSA-induced GVHD can be safely augmented by IFN-gamma in women treated with high-dose alkylating agents and autologous bone marrow transplantation. There is little evidence of increased toxicity. Evidence of antitumor efficacy awaits further investigation.

Cited by 79 publications

References 16 publications

Cyclosporin A-induced graft-versus-host disease following autologous bone marrow and stem cell transplantation in hematological malignancies of childhood

Cyclosporin A-induced graft-versus-host disease following autologous bone marrow and stem cell transplantation in hematological malignancies of childhood

Autologous graft-versus-host disease: harnessing anti-tumor immunity through impaired self-tolerance

Rejection of an MHC class II negative tumor following induction of murine syngeneic graft-versus-host disease

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