Potent Graft-Versus-Renal Cell Carcinoma (RCC) Effects in a Murine Minor Histocompatibility Antigen (mHa)-Mismatched Allogeneic Transplant Model.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4982-4982
Author(s):  
Andreas Lundqvist ◽  
Ramaprasad Srinivasan ◽  
Dante Suffredini ◽  
Yoshiyuki Takahashi ◽  
Jason Wynberg ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Metastatic Disease ◽  
Graft Versus Host Disease ◽  
Hematopoietic Cell Transplantation ◽  
Bone Marrow Cells ◽  
Host Disease ◽  
Minor Histocompatibility Antigens ◽  
Graft Versus Host ◽  
Total Body ◽  
Improvement In Survival

Abstract Donor immune-mediated anti-neoplastic effects make the greatest contribution to the durable disease remissions obtained in hematological malignancies following allogeneic hematopoietic cell transplantation (a-HCT). Recent studies have demonstrated that clinically meaningful graft-versus-tumor (GVT) effects can also be induced against select solid tumors following a-HCT. GVT effects have been most extensively documented in RCC, where response rates in the range of 20%–50% have been reported. Unfortunately, death from eventual disease progression and morbidity from graft-versus-host disease (GVHD) limit a broader application of a-HCT to manage this tumor. In order to explore mechanisms underlying GVT effects against RCC, and to optimize outcome following transplantation, we sought to establish a murine MHC-compatible, but mHA-disparate a-HCT model in mice with metastatic RCC. Recipient Balb/C (H-2d) mice were conditioned with a myeloablative regimen consisting of 950cGy total body irradiation and transplanted with bone marrow cells and splenocytes from either syngeneic (Balb/C) or allogeneic, mHA mismatched B10.d2 (H-2d) mice. Murine RCC cells (RENCA, 1x105 cells/mouse) were injected into the tail veins of both Balb/C recipient groups 3 days after transplantation and were followed for survival and the establishment of metastatic pulmonary lesions. Recipients of allo-HCT had improved survival (mean 54±2 days) compared to those receiving syngeneic transplants (mean 31±0 days: p<0.001). At death, 4/4 mice receiving syngeneic transplants demonstrated widespread pulmonary metastatic disease while none of the allo-HCT recipients (n=4) developed metastatic disease (Figure 1A). A slight improvement in survival for allo-HCT recipients was also noted when Balb/C mice were injected subcutaneously with RENCA (1x105 cells) three days following transplantation (31±0 for syngeneic and 40±7 for allogeneic recipients; p=0.04). Serial measurements of subcutaneous tumor nodules (Figure 1B) revealed significantly slower tumor growth in allo-HCT recipients (mean volume = 272mm3, day 31) compared to recipients of syngeneic grafts (mean volume = 11mm3, day 31). Graft-versus-host disease (GVHD) characterized by alopecia, weight loss and diarrhea occurred at a median 28±3 days after transplantation and was the primary cause of death in a-HCT recipients. Unlike previously reported murine a-HCT models for solid tumors, pre-transplant priming of donor mice with recipient splenocytes or tumor cells was not required for the generation of GVT effects. These data suggest donor immune responses against minor histocompatibility antigens can mediate potent GVT effects against RCC following allo-HCT. This murine model will serve as a platform for the development of tumor- targeted a-HCT strategies aimed at refining and enhancing GVT effects while mitigating GVHD. Figure Figure

scholarly journals Three resected cases of esophageal carcinoma considered as being secondary solid tumors after bone marrow transplantation

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yamato Ninomiya ◽  
Soji Ozawa ◽  
Kazuo Koyanagi ◽  
Miho Yamamoto ◽  
Tadashi Higuchi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Esophageal Carcinoma ◽  
Solid Tumors ◽  
Graft Versus Host Disease ◽  
Total Body Irradiation ◽  
Marrow Transplantation ◽  
Host Disease ◽  
Graft Versus Host ◽  
Total Body

Abstract Background Bone marrow transplantation is now an established treatment for some hematopoietic disorders and hematopoietic malignancies, and secondary solid tumors that develop after bone marrow transplantation have begun to attract attention. Case presentation Herein, we report 3 cases of esophageal carcinoma that developed after bone marrow transplantation. Case 1: 40-year-old female received cyclophosphamide and total body irradiation at 12 Gy for acute myeloid leukemia, followed by related bone marrow transplantation. She developed chronic graft-versus-host disease manifesting as pulmonary complications and was administered cyclosporine. Nine years after the transplantation, she was diagnosed as having esophageal carcinoma Stage II and underwent radical surgery. She died of the primary disease 17 months after the surgery. Case 2: A 45-year-old male patient received cyclophosphamide, VP-16 and total body irradiation at 13.2 Gy for acute lymphocytic leukemia, followed by related bone marrow transplantation. He developed chronic graft-versus-host disease manifesting as liver dysfunction. Fifteen years after the transplantation, he was diagnosed as having esophageal carcinoma Stage II and underwent radical surgery. Seven months after the surgery, he died of the primary disease. Case 3: A 30-year-old female patient received cyclophosphamide and total body irradiation at 3 Gy for Fanconi anemia, followed by unrelated bone marrow transplantation. She developed chronic graft-versus-host disease manifesting as a rash and was administered tacrolimus and methotrexate. Fifteen years after the transplantation, she was diagnosed as having esophageal carcinoma Stage III and underwent radical surgery. She died of sepsis 7 months after the surgery. Conclusion The esophageal carcinomas developing after bone marrow transplantation had the characteristics of secondary solid tumors in all 3 patients, such as early onset, after total body irradiation, association with chronic graft-versus-host disease, and history of use of immunosuppressive drugs. Patients undergoing bone marrow transplantation require long-term follow-up after the transplantation, considering the possible development of secondary solid tumors, and in regard to secondary solid tumors developing in the gastrointestinal tract, it must be borne in mind that the risk of esophageal carcinoma is particularly high.

Synthetic Retinoid Am80 Ameliorates Chronic Graft-Versus-Host Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4487-4487
Author(s):  
Hisakazu Nishimori ◽  
Haruko Sugiyama ◽  
Koichiro Kobayashi ◽  
Yoshiko Yamasuji ◽  
Eisei Kondo ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Graft Versus Host Disease ◽  
Hematopoietic Cell Transplantation ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Histopathological Examination ◽  
Host Disease ◽  
Graft Versus Host ◽  
Synthetic Retinoid ◽  
Ifn Γ

Abstract Abstract 4487 Chronic graft-versus-host disease (cGVHD) remains a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation, and the treatment of cGVHD remains challenging. All-trans retinoic acid (ATRA), a potent vitamin A derivative, can regulate immune responses. Synthetic retinoid Am80, which shows biological activity approximately 10 times more potent than that of ATRA by binding to RARα and RARβ, but not RARγ, also reduces the severity and progression of immune disease models, including those for contact dermatitis, collagen-induced arthritis, allergic encephalomyelitis, and atherosclerosis. We hypothesized that the administration of ATRA or Am80 could modulate cGVHD. BALB/c (H-2d) mice were subjected to sublethal irradiation and injected with 8 × 106 T-cell-depleted bone marrow cells and 8 × 106 spleen cells from major histocompatibility complex-matched, multiple minor histocompatibility antigen-mismatched B10.D2 (H-2d) mice. Then, the mice were given oral ATRA (200 μg/body), Am80 (1.0 mg/kg body weight), or vehicle daily, beginning from day 0. ATRA slightly decreased the clinical cGVHD score, whereas Am80 significantly reduced the score (Table). When administered daily, Am80 decreased the clinical score beginning from day 21, as in a treatment setting (data not shown). Histopathological examination of the skin showed significantly reduced GVHD pathology in recipients of Am80 (Table). Flow cytometry analysis of the peripheral draining lymph nodes on day 16 showed significant reductions in IFN-γ+, IL-17+, and Foxp3+ cells in Am80-treated recipients compared to controls (Table), whereas no reduction in IL-13+ cells was observed. Cytometric bead arrays and enzyme-linked immunosorbent assays (ELISA) revealed decreased levels of the cytokines IFN-γ, IL-17, TNF-α, and IL-6 in the supernatant of peripheral lymph nodes from Am80-administered recipients (data not shown). Real-time RT-PCR of ears from these recipients on day 21 showed that the administration of Am80 reduced the expression of Foxp3 and TGF-β (Table and data not shown). Therefore, the administration of retinoids ameliorates cGVHD by reducing Th1 and Th17 inflammatory cytokines and the fibrosis factor TGF-β. Thus, treatment with retinoids may be effective for prophylaxis and treatment of cGVHD. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Synergism Between Mycophenolate Mofetil and Cyclosporine in Preventing Graft-Versus-Host Disease Among Lethally Irradiated Dogs Given DLA-Nonidentical Unrelated Marrow Grafts

Blood ◽  
1998 ◽  
Vol 91 (7) ◽  
pp. 2581-2587 ◽  
Author(s):  
Cong Yu ◽  
Kristy Seidel ◽  
Richard A. Nash ◽  
H. Joachim Deeg ◽  
Brenda M. Sandmaier ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Group 4 ◽  
Group 2 ◽  
Total Body ◽  
Host Tolerance ◽  
Long Term Survivors

Abstract Mycophenolate mofetil (MMF) was evaluated either alone or combined with cyclosporine (CSP) for preventing graft-versus-host disease (GVHD) in dogs given 9.2 Gy total body irradiation and DLA-nonidentical unrelated marrow grafts. Marrow autograft studies showed gut toxicity as limiting MMF side effects. Four groups were studied for GVHD prevention: six dogs in group 1 received MMF 10 mg/kg twice daily subcutaneously (SC) on days 0 to 27. They died between 8 to 28 days from infection or GVHD; survival was better than that of 72 controls given no immunosuppression (P = .04), but not different from 19 dogs given CSP. Four dogs in group 2 received MMF as described, along with CSP at 10 to 15 mg/kg twice daily on days 0 to 27. They died at 6 to 98 days from CSP-associated toxicity, weight loss, or infection. Nine dogs in group 3 received MMF SC twice daily 6 mg/kg/d for 3 days, followed by 10 mg/kg twice daily until day 27, along with CSP as described; four died between 7 to 106 days with intussusception, infection, or GVHD, and five became long-term survivors. Six dogs in group 4 received shortened MMF (21 days) and reduced doses of CSP given through day 100. Three died with GVHD or infection between days 38 to 119, and three became long-term survivors. Results support the notion of synergism between MMF and CSP, as evidenced by stable graft-host tolerance in greater than 50% of dogs.

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