© 2004 Foundation for Promotion of Cancer Research
Review Article |
Reduced-intensity Hematopoietic Stem Cell Transplantation (RIST) for Solid Malignancies
Department of Medical Oncology, Hematopoietic Stem Cell Transplantation Unit, The National Cancer Center Hospital, Tokyo, Japan
For reprints and all correspondence: Masahiro Kami, Department of Medical Oncology, Hematopoietic Stem Cell Transplantation Unit, the National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. E-mail: mkami{at}ncc.go.jp
Received June 18, 2004; accepted October 6, 2004
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Abstract |
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 TOP Abstract ALLOGENEIC HEMATOPOIETIC STEM...REDUCED-INTENSITY STEM CELL...PRECLINICAL MODEL OF NON...RATIONALE OF ALLO-SCT FOR...CLINICAL TRIALS FOR SOLID...MECHANISMFUTURE DIRECTIONSReferences |
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Reduced intensity stem cell transplantation (RIST) is a new approach of stem cell transplantation, which has shown promising features as reported in multiple phase I and II studies. Elderly patients, who are not eligible for conventional myeloablative hematopoietic stem cell transplantation (HSCT), are now treatable with RIST. It has also reduced regimen-related toxicity and provided better prognosis in short-term follow-up than conventional HSCT. Among solid tumors, metastatic renal cell carcinoma was found to respond well to RIST. Clinical studies are currently being conducted to evaluate the efficacy of RIST in other types of solid tumors. However, the mechanism of graft-versus-host disease (GVHD) and graft-versus-tumor (GVT) effects remains unclear. More knowledge on the mechanism is crucial to enhance the antitumor effect and to improve the prognosis further.
Key Words: graft-versus-tumor effects • graft-versus-host disease • renal cell carcinoma • allogeneic hematopoietic stem cell transplantation • breast cancer
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ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION AS AN IMMUNE THERAPY |
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TOPAbstractALLOGENEIC HEMATOPOIETIC STEM...REDUCED-INTENSITY STEM CELL...PRECLINICAL MODEL OF NON...RATIONALE OF ALLO-SCT FOR...CLINICAL TRIALS FOR SOLID...MECHANISMFUTURE DIRECTIONSReferences |
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Allogeneic hematopoietic stem cell transplantation (allo-SCT) for the treatment of hematological malignancies was originally based upon the effect of a myeloablative preparative regimen. A preparative regimen using high-dose chemoradiotherapy would suppress the host's immune response and eradicate the residual tumor cells. Marrow was infused to restore hematopoiesis (1). In combination with preceding induction and consolidation cytotoxic chemotherapy, myeloablative preparative regimens followed by allo-SCT were supposed to eradicate the residual underlying diseases.
However, it was found that allogeneic cells were responsible for immunological responses against tumor cells. This is called a graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) effect (2). Evidence supporting this hypothesis includes (i) lower incidences of relapse in patients receiving allo-SCT than in those receiving autologous SCT (3); (ii) higher risk of relapse in patients receiving syngeneic SCT (4); and (iii) lower risk of relapse in patients with acute and/or chronic graft-versus-host disease (GVHD) than those without these conditions (5). Furthermore, GVL or GVT effects were found to be mediated by lymphocytes, especially T cells, based on the clinical findings of (i) higher risk of relapse after T-cell depletion than non-depleted SCT (6); and (ii) therapeutic effects of donor lymphocyte infusion (DLI) (7). In particular, chronic myeloid leukemia (CML) responds well to DLI, and most patients with CML who relapse following allo-SCT can achieve remission with DLI (8). Based on these findings, allo-SCT is now regarded as one of the available immune therapies.
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REDUCED-INTENSITY STEM CELL TRANSPLANTATION (RIST) |
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TOPAbstractALLOGENEIC HEMATOPOIETIC STEM...REDUCED-INTENSITY STEM CELL...PRECLINICAL MODEL OF NON...RATIONALE OF ALLO-SCT FOR...CLINICAL TRIALS FOR SOLID...MECHANISMFUTURE DIRECTIONSReferences |
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The high-dose chemotherapy and radiation used as preparative regimen for allo-SCT are associated with a considerable morbidity and mortality (9). This approach has therefore been restricted to young patients without co-morbidities. The majority of patients with hematological malignancies are ineligible for high-dose chemotherapy or radiotherapy because of their old age and co-morbidities. Although allo-SCT is the most powerful treatment for refractory hematological malignancies, only a small proportion of these patients have the opportunity to undergo this treatment.
Recently, a new strategy for transplantation using a reduced-intensity or non-myeloablative preparative regimen has been developed to reduce regimen-related toxicity (RRT) while preserving adequate antitumor effects (10–14). Various regimens with different intensity can be categorized roughly into two intensity groups: (i) reduced-intensity regimens which retain a certain degree of RRT and require hospitalization; and (ii) minimally myelosuppressive regimens which rely on post-grafting immunosuppression to permit engraftment (15,16). The aim of post-grafting immunosuppression is to control GVHD and to suppress residual host-versus-graft (HVG) effects that would impede engraftment.
These reduced-toxicity regimens are frequently termed ‘non-myeloablative’ and ‘reduced-intensity’ regimens. At present, a variety of preparative regimens have been developed. Both myelosuppression and immunosuppression vary widely among them. According to a working definition, a truly non-myeloablative regimen should allow prompt hematopoietic recovery (within 28 days of transplantation) without stem cell rescue, and mixed chimerism usually occurs upon engraftment (15,16). These regimens do not ablate host immunity and depend on the activity of donor T cells to achieve engraftment. The regimen of 2 Gy total body irradiation (TBI) with or without fludarabine reported by the Seattle Transplantation Team (12) is classified as a truly non-myeloablative regimen. In contrast, autologous hematopoietic recovery does not occur without stem cell support after the other regimens such as fludarabine/busulfan and fludarabine/cyclophosphamide, and they are termed reduced-intensity preparative regimens.
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PRECLINICAL MODEL OF NON-MYELOABLATIVE SCT |
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TOPAbstractALLOGENEIC HEMATOPOIETIC STEM...REDUCED-INTENSITY STEM CELL...PRECLINICAL MODEL OF NON...RATIONALE OF ALLO-SCT FOR...CLINICAL TRIALS FOR SOLID...MECHANISMFUTURE DIRECTIONSReferences |
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The Seattle Transplantation Team reported the results of preclinical canine studies on non-myeloablative SCT. The researchers considered that two immunological barriers must be overcome in the setting of allo-SCT (17). One is the GVHD, and the other is the rejection or HVG reaction. Both reactions are mediated by T lymphocytes, suggesting that immunosuppressive agents given after allo-SCT to control GVHD might modulate HVG reactions. The latter feature would allow minimization of the high-dose chemotherapy given before allo-SCT for host suppression.
Animal models demonstrated a dose–response relationship between TBI and engraftment (18). In random-bred dogs, a single fraction of 920 cGy TBI, corresponding to 1500 cGy fractionated TBI, resulted in engraftment of dog leukocyte antigen (DLA)-identical littermate marrow in all cases. When the dose was decreased by 50%, the majority of dogs rejected their grafts. At the reduced dose, the addition of post-grafting prednisone did not enhance engraftment, while cyclosporin given for 5 weeks led to engraftment in all of the animals. When the TBI dose was decreased further to 200 cGy, cyclosporin only allowed engraftment for 3–4 months, after which the grafts were rejected. The combination of methotrexate and cyclosporin resulted in engraftment in two out of five animals, but the rest rejected. A combination of mycophenolate mofetil (MMF) and cyclosporin given for 4 and 5 weeks after transplantation was evaluated for its effect on engraftment. The regimen was capable of both controlling GVHD and preventing graft rejection by suppressing a GVH reaction, with 11 of 12 dogs demonstrating stable engraftment of marrow from DLA-identical littermates (19).
They further investigated whether the major role of TBI is to create marrow space or to provide host immunosuppression (20). They irradiated the central lymph node chain from the neck to the upper abdomen with 450 cGy before allo-SCT, and administered MMF and cyclosporin after allo-SCT. At 6 weeks post-transplant, donor cells were present in non-irradiated marrow spaces, suggesting that radiation was not essential to create marrow space for engraftment. After 1 year, DLI was given to the animals and recipient cells disappeared within 9 weeks. These findings indicate that engraftment might be accomplished by blocking HVG reactions and inducing the GVH reaction, and that high-dose cytotoxic chemotherapy and radiotherapy could be eliminated from the preparative regimens.
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RATIONALE OF ALLO-SCT FOR SOLID TUMORS |
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TOPAbstractALLOGENEIC HEMATOPOIETIC STEM...REDUCED-INTENSITY STEM CELL...PRECLINICAL MODEL OF NON...RATIONALE OF ALLO-SCT FOR...CLINICAL TRIALS FOR SOLID...MECHANISMFUTURE DIRECTIONSReferences |
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Several findings justify allo-SCT for solid tumors: (i) GVT effects can target tissue-specific polymorphic antigens which are not derived from hematopoietic lineages; (ii) some solid tumors are sensitive to immunotherapy, such as renal cell carcinoma (RCC), melanoma and ovarian cancer; (iii) antigens restricted to the tumor could stimulate tumor-specific alloimmunity in contrast to defective T cells in the tumor-bearing host; and (iv) in theory, all carcinomas arising from epithelial tissues such as keratinocytes, fibroblasts, exocrine glands, hepatobiliary trees and the gastrointestinal tract, which are targets of acute and chronic GVHD, should be susceptible to a GVT effect.
Before clinical trials were initiated, murine models have provided some evidence for a GVT effect (21,22). Among animals inoculated with mammary adenocarcinoma cells, the recipients of allo-SCT showed better survival than did those of syngeneic SCT (21). Further studies provided evidence that murine mammary adenocarcinoma cells expressed minor histocompatibility antigens (mHas) that could be targeted by alloreactive donor T cells in the setting of allogeneic but not autologous bone marrow transplantation (23). Prigozhina et al. demonstrated in animal models that effective eradication of tumor cells as well as leukemic cells can be achieved following allo-SCT using non-myeloablative preparative regimens (24).
The earliest clinical evidence supporting the existence of a GVT effect in a solid tumor was observed in a patient with metastatic breast carcinoma undergoing fully myeloablative SCT for relapsed acute myeloid leukemia. The incidental regression of a metastatic lesion of breast carcinoma raised the possibility of a responsible GVT effect (25). Regression of liver metastasis in association with severe acute GVHD was reported in a woman transplanted for metastatic breast carcinoma. The researchers demonstrated that allogeneic T cells collected during GVHD and cultivated were able to mediate a cytotoxic effect against breast cancer cell lines (26), suggesting that disease regression resulted from donor T cells targeting broadly expressed mHas. Since then, similar anecdotal reports have been published concerning a possible GVT effect in lung cancer (27), ovarian cancer (28), colon cancer (29), neuroblastoma (30), pancreas cancer (31,32) and ependymoma (33). Porter et al. conducted a phase I clinical trial to determine whether a GVT effect could be observed after primary DLI without stem cell support in patients with primary cancers (34). Three of four patients with acute GVHD and late chimerism responded to primary DLI. These findings indicate that the GVT effect does occur in the setting of allo-SCT for solid tumors.
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CLINICAL TRIALS FOR SOLID TUMORS |
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TOPAbstractALLOGENEIC HEMATOPOIETIC STEM...REDUCED-INTENSITY STEM CELL...PRECLINICAL MODEL OF NON...RATIONALE OF ALLO-SCT FOR...CLINICAL TRIALS FOR SOLID...MECHANISMFUTURE DIRECTIONSReferences |
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METASTATIC RENAL CELL CANCER (RCC)
In 1997, Childs et al. initiated a clinical trial to evaluate GVT effects in metastatic RCC (35). Chemotherapy is ineffective in the majority of cases and does not prolong survival. However, RCC has a distinct nature from that of other solid tumors. There is increasing evidence that they may be susceptible to T-cell immune responses. Biopsy of spontaneously regressing lesions has shown tumor-infiltrating lymphocytes with predominant CD8+ T cells exhibiting major histocompatibilty complex (MHC) class I restricted cytotoxicity against autologous tumor targets (36). Furthermore, unlike most solid tumors, RCC is susceptible to cytokines such as interleukin-2 (IL-2) and interferon-
(37), suggesting that T cells represent the principle effector.
Childs' group treated 19 patients with metastatic RCC (35). The preparative regimen consisted of fludarabine 25 mg/m2 for 5 days and cyclophosphamide 60 mg/kg for 2 days. Cyclosporin, used to prevent GVHD, was withdrawn early in patients with mixed T-cell chimerism and/or disease progression. Patients without response received up to three courses of DLI. At the time of the last follow-up, nine of the 19 patients were alive 287–831 days after transplantation (median follow-up, 402 days). Two died of transplantation-related causes, and eight from progressive disease. In 10 patients, metastatic disease regressed: three had a complete response, and seven had a partial response. The patients who had a complete response remained in remission 27, 25 and 16 months after transplantation. Results of this clinical trial were updated in 2002 (38). Clinical response is significantly associated with the development of GVHD. There is a 4–6 month interval between transplantation and development of a GVT effect, and patients with rapidly progressive diseases are unlikely to benefit from RIST. Disease response was observed most commonly in patients with pulmonary metastases of clear-cell histology without other organ involvement. Some patients who had failed to respond to interferon- prior to transplantation achieved responses following administration of a low dose of this agent after transplantation.
After the first report on RIST for RCC, several phase I/II studies have been reported (Table 1) (39–44). Response rates varied widely from 0 to 57%, but it should be noted that some responses were reported in seven of the nine studies. While long-term prognosis remains unknown, response to allo-SCT has been confirmed in some independent studies. Rini et al. described regression of primary kidney tumors, a rare event among responders to cytokine-based therapy (39). According to a European retrospective survey (45), allo-SCT was used in <20 cases of solid tumors until 1997; since then it increased to 159 in 2002, mainly for RCC.
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We also initiated a phase I clinical trial on RIST for metastatic RCC (46). From June 2000 to April 2002, nine patients received peripheral blood stem cell transplantation from a human leukocyte antigen (HLA)-identical sibling donor. The conditioning regimen consisted of fludarabine 180 mg/m2 or cladribine 0.66 mg/kg, plus busulfan 8 mg/kg and rabbit anti-thymocyte globulin (ATG). GVHD prophylaxis consisted of cyclosporin 3 mg/kg alone. All of the patients achieved engraftment, with no grade III–IV non-hematological RRT, and complete donor cell type chimerism was achieved without additional DLI by day 60. Acute and chronic GVHD was seen in four patients each. One patient achieved partial remission (response rate 11%) and, as of July 2003, six patients are alive with a median follow-up of 22.5 months. The actuarial overall survival rate was 74% at 2 years. We followed all the 26 patients who were referred to our institute for RIST and were subject to HLA typing. Transplanted patients (n = 9) showed significantly higher overall survival rate than those who had not received RIST (n = 17) (Fig. 1A, P = 0.016). We compared the overall survival rates between 12 patients with matched donors and the other 14 patients without them (Fig. 1B). The 1-year actuarial survival rates were 74 and 48% in patients with donors and those without them, respectively (P = 0.088). This study confirmed the feasibility of allo-SCT for metastatic RCC, and suggests that it might improve prognosis of patients with metastatic RCC. Further phase II or III studies are warranted.
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BREAST CANCER
After the first case report by Eibl et al. (26), Ueno et al. reported the results of a feasibility study on conventional myeloablative allo-SCT for metastatic breast cancer in 16 patients (47,48). This study included patients without progressive disease. The preparative regimen consisted of cyclophosphamide, carmustine and thiotepa. GVHD prophylaxis was mainly tacrolimus and methotrexate. The responses were complete response (n = 1), partial response (n = 5) and stable disease (n = 8) in the 15 evaluable patients. Two patients responded during acute GVHD following the withdrawal of immunosuppression.
Ueno et al. further investigated the feasibility of RIST for metastatic breast cancer (43). A total of eight patients received allo-SCT following fludarabine and melphalan. Three patients showed some clinical responses (complete response two, minor response one). Metastatic lesions resolved 3 months after development of chronic GVHD in one patient, and the other two patients demonstrated tumor response at 13 and 17 months after transplantation. The delayed response was comparable with that in RIST for RCC. Since fludarabine and melphalan produce little cytoreduction in metastatic breast cancer and the underlying disease progressed immediately after transplantation in more than half of the patients, it is reasonable to assume that the disease response was attributable to a GVT effect.
Since their reports, GVT effects against breast cancer have been confirmed by other researchers (40–42,49) (Table 2).
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MELANOMA
Childs and Srinivasan treated 11 patients with metastatic melanoma (50). This study highlights some of the potential problems in applying RIST for some solid tumors. Death from rapid disease progression occurred before day 100 in five patients. Although three patients achieved partial regression, their responses occurred early in the courses of RIST with a short duration, suggesting that these responses were attributable to chemotherapy effects related to preparative regimens rather than GVT effects. One patient had delayed regression of several subcutaneous metastatic nodules. The investigators speculated that RIST should be limited to a minority of melanoma patients who have slow-growing diseases.
OTHER CANCERS
There is little information on the efficacy of allo-SCT for most solid tumors. Some anecdotal reports have been published on allo-SCT for a variety of cancers (28,31,44,51–54). A case report and a small case series of RIST for metastatic ovarian cancer and colorectal cancer have been published recently (28,42,44,53,54). These tumors may be promising candidates for allo-SCT; however, it should be noted that both ovarian and colorectal cancer are susceptible to chemotherapy, making it difficult to conclude that disease regression was attributable to a GVT effect.
We evaluated a total of 14 patients with refractory non-renal solid tumors (four rhabdomyosarcoma, two melanoma, two neuroblastoma, two cholangiocarcinoma, two other sarcomas and two other carcinomas) who underwent RIST according to our institutional phase I protocol (52,55). The conditioning regimen and GVHD prophylaxis were the same as those for metastatic RCC. All patients but one with melanoma achieved complete donor chimerism without DLI. Only three patients showed grade II–IV acute GVHD and two showed chronic GVHD. Four patients died before day 100 after RIST and another four after day 100. Seven out of the eight patients died of disease progression. Although comprehensive evaluation of the GVT effect is impossible due to the diversity of the diseases, it is remarkable that there are two patients with disease-free survival longer than 11 months after RIST. One is a 7-year-old female with metastatic neuroblastoma which recurred after autologous bone marrow transplantation. The other is a 16-year-old female with metastatic alveolar type rhabdomyosarcoma. Both were transplanted when they had a small volume of residual disease compared with other patients with sarcoma. Among patients with carcinomas, a 56-year-old male with cholangiocarcinoma showed objective tumor regression which did not satisfy the criteria for partial regression (Fig. 2). There was no apparent correlation between GVHD and a GVT effect.
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MECHANISM |
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TOPAbstractALLOGENEIC HEMATOPOIETIC STEM...REDUCED-INTENSITY STEM CELL...PRECLINICAL MODEL OF NON...RATIONALE OF ALLO-SCT FOR...CLINICAL TRIALS FOR SOLID...MECHANISMFUTURE DIRECTIONSReferences |
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The precise mechanism of the GVT effect remains unknown. The lack of information on tumor target antigens and immune mediators for GVT effects does not allow us to predict which diseases will respond to RIST.
Disease regression associated with cyclosporin withdrawal, complete donor chimerism and GVHD provides evidence that cytotoxic donor T cells play an important role in this response. RCC cells express a broad range of mHas that could render them susceptible to a GVT effect (56). These findings suggest that both broadly expressed mHas and antigens restricted to RCC cells may be a target of a GVT effect. Recent studies have demonstrated that distinct T-cell populations recognizing tumor-specific antigens and/or mHas are involved in the GVT effect (57). T-cell clones attacking both RCC cells and hematopoietic cells of the recipients were isolated from responding patients (58). Retrospective clinical studies and in vitro studies using clinical samples demonstrated that cytotoxic T cells against leukemia-specific antigens or hematopoiesis-restricted mHas can induce remission in allo-SCT for acute leukemia (59–61). In animal models, adoptive transfer of HA-1- and HA-2-specific cytotoxic T lymphocytes generated in vitro can be used as immunotherapy to treat hematological malignancies relapsing after allo-SCT (62,63). Using these cytotoxic T cells, GVT effects can be separated from GVHD (64). In contrast to allo-SCT for hematological malignancies, little information is available concerning target antigens and cytotoxic T cells in allo-SCT for solid malignancies, and further studies are warranted.
Some investigators suggested that innate immunity plays an important role in the development of a GVT effect. Natural killer (NK) cells have been studied intensively, since they are capable of mediating a GVL effect in acute myeloid leukemia without causing GVHD (65). Igarashi et al. reported that allogeneic NK cells with killer immunoglobulin-like receptor ligand incompatibility play an important role in cytotoxicity against melanoma and renal cell carcinoma cells (66). Furthermore, Teshima et al. reported that the local cytokine storm associated with the early phase of allogeneic transplantation plays an important role in GVHD (67). The tumor progression and regression in concordance with corticosteroid use and discontinuation observed in our study (46,68) are compatible with their suggestion, since the cytokine production is readily suppressed by corticosteroid.
Stelljes et al. recently reported an interesting animal study using allogeneic parent-into-F(1) murine transplantation models [BALB/c or C57BL/6
[C57BL/6 x BALB/c]F(1)] with different tumors derived from either parental strain (69). They provided experimental proof of a donor CD8+ T cell-mediated tumor-associated antigen-specific anti-tumor response in vivo that is driven by GVHD. GVHD was identified as a driving force for GVT effects in RIST for solid tumors. It may represent one of the mechanisms contributing to GVT effects observed in allogeneic transplant recipients.
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FUTURE DIRECTIONS |
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TOPAbstractALLOGENEIC HEMATOPOIETIC STEM...REDUCED-INTENSITY STEM CELL...PRECLINICAL MODEL OF NON...RATIONALE OF ALLO-SCT FOR...CLINICAL TRIALS FOR SOLID...MECHANISMFUTURE DIRECTIONSReferences |
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CONTROL OF NEGATIVE ASPECTS OF RIST
Despite progressive improvement of transplant safety, the risk of significant transplant-related malignancy (TRM) limits the widespread application of allo-SCT for solid tumors. TRM remains 10–25% even in RIST. Without evidence of efficacy, most physicians considered this risk too high to justify studies of allo-SCT in patients with solid malignancies. The risk/benefit ratio is an important factor to decide the treatment plan in individual cases.
GVHD is the most significant concern in RIST as well as conventional allo-SCT (70). Approximately two-thirds of RIST recipients develop grade II–IV acute GVHD, and 10% of patients who receive RIST from an HLA-identical sibling died of GVHD in the National Cancer Center Hospital (70). Intensification of GVHD prophylaxis using potent immunosuppressive agents such as MMF, infliximab, ATG and CAMPATH-1H has contributed to improve GVHD-related outcomes (50,71,72); however, use of these agents might diminish GVT effects (50,68), and could increase the rate of serious infections (73). T-cell depletion can significantly reduce the risk of GVHD; however, it does not provide definite evidence of improving the outcomes of allo-SCT for solid or hematological malignancies. They might increase the risk of graft rejection and life-threatening infections (74). Several new strategies of T-cell depletion are currently under investigation, such as delayed T-cell add-back (75), the use of a suicide gene system (76), and selective CD8+ depletion (77). Enhancement of the recovery of tissue damaged by GVHD is another promising approach. Some researchers showed that keratinocyte growth factor (KGF) administration is beneficial for the treatment and prevention of chemotherapy-induced gastrointestinal damage (78,79). It might ameliorate the organ damage caused by GVHD, leading to separation of GVHD from the beneficial GVL effects after allo-SCT (80). Since KGF has a possible risk of oncogenesis and cancer progression, further studies are required to investigate its safety in the setting of allo-SCT for solid tumors.
Another common immunological complication is the progression of the primary disease during immunosuppression. Preparative regimens of RIST have intense immunosuppressive effects to ensure the engraftment of donor cells. The half-life of antibodies such as ATG and CAMPATH-1H is so long as to maintain their immunosuppressive effects after RIST. Although these agents are effective in GVHD prophylaxis, they may deteriorate GVT effects and induce disease progression during immunosuppression (35). This phenomenon needs to be recognized as toxicity associated with conditioning regimens in RIST for solid tumors. However, when the primary disease is in progression at transplant, the possible association of conditioning regimens with early post-transplant progression cannot be distinguished from the natural course of the disease. This issue is troublesome in phase I or II clinical trials, particularly in solid tumors, as they are in progression at transplant. When the primary disease is in complete or partial remission, or stable disease at transplant, early post-transplant progression is more likely to be associated with conditioning regimens, requiring the clinician to be alert to this.
ENHANCEMENT OF A GVT REACTION
Future studies should focus on directing the immune responses specifically to the tumors. In hematological malignancies, leukemia-specific cytotoxic T lymphocytes (CTLs) are frequently generated after allo-SCT, and are important in maintaining remission (81). Falkenburg et al. reported that treatment with ex vivo-generated leukemia-reactive T cells achieved remission in a patient with CML who relapsed after allo-SCT and was resistant to DLI (82). These results support the possibility of using DLI ex vivo primed against solid tumor cells. Several antigens targeted by alloreactive lymphocytes have been identified in allo-SCT for solid tumors. However, the expression of tumor-specific antigens varies considerably within the same tumor and at different stages of diseases. It is therefore difficult to produce antigen-specific CTLs in the treatment of solid tumors.
There are some possibilities to enhance tumor-specific allogeneic immunity prior to transplantation. One is to utilize donor cells activated against tumor alloantigens. While GVHD is a significant concern associated with pre-transplant immunization of allogeneic marrow donors with recipient-derived tumor cells (83), some animal studies have shown that immunization of allo-SCT recipients with tumor cells can enhance GVT activities without exacerbating GVHD (84,85). It has been shown that CTLs can be generated using the whole tumor cells, which allows epitopes to be selected that are immunogeneic in the context of individual CTL repertoires (86). This approach can be applicable in allo-SCT for solid tumors with unknown target antigens. Morecki et al. reported that pre-immunization with mHa-mismatched tumor or spleen cells was capable of activating effector cells to induce GVT effects (87).
Post-transplant vaccination against tumor-specific or mHas or ex vivo generation of tumor-specific T cells followed by their adoptive transfer is another promising approach. Luznik et al. reported an animal model, showing a cooperation between host and donor T cells in the response to a tumor cell vaccine given after an RIST protocol that achieves stable mixed chimerism (88). GVT effects may be enhanced by the use of cytokines such as granulocyte–macrophage colony-stimulating factor (GM-CSF), which may improve antigen presentation, and interferons, which may increase tumor antigen presentation by upregulating MHC class I and class II HLA molecules. Animal studies demonstrate that other cytokines such as IL-1 (89), IL-11 (90), and procedures capable of interfering with immunoregulatory mechanisms (91,92) are effective for inhibiting GVHD while preserving GVT effects.
Besides immunological approaches, it is critical to clarify the best timing and patient conditions for allo-SCT against solid tumors. Disease progression kinetic and immune status of the hosts are major factors influencing the sensitivity to allogeneic immunity (42). The efficacy of tumor cell eradication by alloreactive lymphocytes depends on the initial ratio between the number of tumor-specific immunocompetent cells in the graft and tumor cell burden of the recipient. Tumor debulking by the preparative regimen or surgical procedures before transplant might be important to enhance GVT effects. Preclinical evidence suggests that a lymphopenic host may represent a favorable clinical setting for immunotherapy (93). Dudley et al. provided evidence of cancer regression by the adoptive transfer of autologous tumor-reactive T cells directed against melanoma antigens in patients receiving a non-myeloablative, highly immunosuppressive preparative regimen (94). This approach may be helpful in allo-SCT for solid tumors.
EVALUATION OF TUMOR RESPONSES
Evaluation methods of tumor response to RIST have not been established. Even in the article of RIST for RCC by Childs et al. (35), their method of tumor response evaluation was not clearly described. It is critical to develop a global method to evaluate tumor response to RIST to share RIST results worldwide (95). Although the RECIST (Response Evaluation Criteria in Solid Tumors) system has been used as a gold standard to evaluate the response of solid tumors to treatment mainly in the field of cancer chemotherapy (96), it has not been fully validated in the area of allo-SCT for solid tumors. Compared with hematological malignancies, solid tumors are generally more resistant to the cytotoxic agents used in conditioning regimens administered before transplantation. Consequently, there may be some important differences in evaluating the response of solid tumors between RIST and conventional chemotherapy.
First, the feasibility of applying RECIST should be critically validated before its extensive application in transplantation (97). Tumor regression occurs several months after transplantation, and most tumors continue their natural growth until the manifestation of effective alloimmunity to restrain tumor growth. If the original RECIST criteria (96) are applied to patients undergoing RIST for solid tumors, most of the GVT effect would be evaluated as progressive disease, which would preclude subsequent evaluation (Fig. 3). Therefore, RECIST may underestimate the efficacy of RIST. Secondly, the proper time to measure the tumor size as a baseline for evaluating a subsequent tumor response has not been defined. In contrast to the results with chemotherapy, the tumor often temporarily increases in size following RIST. Accordingly, when the size at transplantation is used as a baseline, as in chemotherapy, a therapeutic effect following the initial progression could be overlooked or underestimated (Fig. 3). On the other hand, evaluating regression from the largest size after transplant certainly overestimates the effect of treatment (Fig. 3), and gives an unacceptable bias. Thirdly, the tumor size after RIST often fluctuates in response to a de novo GVT effect, post-transplant immunotherapy including DLI, and adjustment of immunosuppressive agents (Fig. 4). In this situation, it is clear that any evaluation of the response duration, such as progression-free survival and the overall response duration, is essentially impossible using the current RECIST criteria. Improved overall survival will ultimately be evaluated in phase III trials. To reach this point, a global standard evaluation system, that enables the effective screening of a therapeutic effect in an earlier phase II study, will need to be established. We hope that this review will inspire a productive discussion.
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USE OF ALTERNATIVE STEM CELL SOURCES
Only 30–40% of patients in Japan have an HLA-identical sibling to serve as an allo-SCT donor. Unrelated bone marrow or umbilical cord blood may serve as an effective source of stem cells, thereby broadening the scope of patients who may benefit from allo-SCT. RIST using these stem cells is a promising alternative option. Some pilot studies have demonstrated the feasibility of allo-SCT from MUD (98,99) or using umbilical cord blood (100,101). Trials evaluating RIST using alternative stem cell sources have been started in many transplantation centers.
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References |
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TOPAbstractALLOGENEIC HEMATOPOIETIC STEM...REDUCED-INTENSITY STEM CELL...PRECLINICAL MODEL OF NON...RATIONALE OF ALLO-SCT FOR...CLINICAL TRIALS FOR SOLID...MECHANISMFUTURE DIRECTIONSReferences |
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