HLA半相合淋巴细胞输注治疗59例难治性实体瘤的临床分析
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摘要
目的:观察HLA半相合淋巴细胞输注治疗难治性实体瘤的近期疗效、毒副反应及对生活质量的影响,探讨其临床应用价值。
资料与方法:经多次治疗后出现复发或病情进展的Ⅳ期实体瘤患者,理解并愿意接受HLA半相合淋巴细胞输注,签署知情同意书。所有患者在进行供者淋巴细胞输注(DLI)治疗前4～8周或同时接受常规治疗。胃癌患者在进行DLI治疗前4～8周接受常规剂量的“紫杉类+奥沙利铂”或“卡培他滨”化疗,肾癌患者在DLI治疗期间同时口服“沙利度胺”,肝癌患者在进行DLI治疗前4～8周接受“顺铂+表阿霉素”肝动脉栓塞化疗,其余患者在进行DLI治疗前均接受不同方式的常规剂量的放疗或化疗。供受者间需测定HLA-A、HLA-B、HLA-DR共6个位点,选定合适的供者后对其进行ABO血型、乙肝表面抗原、艾滋病病毒抗体、丙肝病毒抗体及梅毒抗体的检测。符合条件的供者在CS-3000Plus血细胞分离机上按“淋巴细胞采集程序”采集单个核细胞,循环血量为8000ml,采集的供者单个核细胞约55ml,加145 ml的生理盐水稀释到200 ml;经稀释、混匀后的采集血送我院放射治疗中心接受60Go照射(DT 25 Gy)后输注给患者,每4～8周重复一次,治疗前后监测患者CD3/HLA-DR、CD25值的变化,同时观察是否发生GVHD。aGVHD临床分级按Glucksberg标准分为Ⅰ～Ⅳ级,cGVHD按NIH共识标准分为轻、中、重度;每次输注后4周对患者进行常规评价,按RECIST标准分为完全缓解(CR)、部分缓解(PR)、疾病稳定(SD)、疾病进展(PD),以CR+PR+SD所占的比率作为疾病控制率(DCR),同时按卡氏体力状况评分标准对患者进行生活质量的评价。
结果:①2004年2月至2008年8月,我院59例Ⅳ期难治性实体瘤患者接受含有(0.983±0.425)×108 CD3+细胞/Kg体重的DLI,全部病例均可评价疗效。胃癌16例,CR 1例,SD 8例,PD 7例,DCR为56.25%,中位总生存期为15.7个月(8.5～52.1个月);肾癌13例,CR 1例,SD 5例,PD 7例,DCR为46.15%,中位总生存期为28.3个月(8.9～46.4个月);肝癌11例,SD 6例,PD 5例,DCR为54.55%,中位总生存期为9.6个月(3.6～51.2个月);其他恶性实体瘤共19例,PR 1例,SD 6例,PD 12例,DCR为36.84%,中位总生存期16.3个月(7.4～54.8个月)。②接受2～7次DLI组的DCR高于仅接受1次DLI组(P <0.05);接受>1.0×108 CD3+细胞/Kg组的DCR高于<1.0×108 CD3+细胞/Kg组(P <0.005);46例患者在DLI治疗前后进行CD3/HLA-DR和CD25的检测,CD3/HLA-DR升高组的DCR高于降低组(P <0.005),CD25升高组的DCR高于降低组(P <0.05)。不同病种、供受者不同性别组合、不相合位点数不同组别间DCR的差异无统计学意义(P >0.50)。③全部病例均可评价毒副反应,其中有10例(16.95%)发生了Ⅰ～Ⅱ级的aGVHD,未发现Ⅲ～Ⅳ级aGVHD或cGVHD者。④29例患者在DLI治疗前后KPS评分提高10分及以上。
结论:①HLA半相合淋巴细胞输注治疗复发性或难治性实体瘤具有一定的效果。②HLA半相合淋巴细胞输注治疗复发性或难治性实体瘤无明显毒副反应。③HLA半相合淋巴细胞输注治疗复发性或难治性实体瘤是否可延长总生存期有待于进一步的观察。
Objective:Observe the short-term efficacy,the toxicity,and the quality of life about HLA-haploidentical lymphocyte infusions for refractory solid tumors,and explore its clinical value.
Data and Methods:Patients with phase IV solid tumors who were failed by conventional therapy,understand and are willing to accept HLA haploidentical lymphocyte infusions,then sign the informed consent. All patients received routine therapy 4 to 8 weeks before DLI or simultaneously. Patients with gastric cancer received conventional doses of“Taxane+ Oxaliplatin”or“Capecitabine”4 to 8 weeks before DLI;patients with RCC take“Thalidomide”orally during DLI;patients with HCC undergo a TACE with“Cisplatin+Epirubicin”4 to 8 weeks before DLI;the other acceptted common radiotherapy or chemotherapy before DLI. Donor/recipient’s loci determination for six sites among HLA-A,HLA-B,HLA-DR,is needed for the pairs. We must detect ABO blood type,HBsAg,anti-HIV,anti-HCV and syphilis antibody for the suitable donors. The eligible donors have a collection of MNCs on the CS-3000Plus blood cell separator,according to the“lymphocyte collection procedures”,and the circulating blood volume is 8000ml. The MNCs is about 55ml,diluted into 200ml by 145ml of normal saline. The mixture above will accept 60Go irradiation (DT 25Gy),then infuse into the patients. Repeat the infusion every 4～8 weeks,detect the value of CD3/HLA-DR and CD25 pre-DLI and post-DLI,observe the occurrence of GVHD. Acute GVHD is clinically graded asⅠ～Ⅳbased on Glucksberg criteria,and chronic GVHD is classified as mild,moderate and severe according to National Institutes of Health consensus development project on standards for cGVHD. 4 weeks after each infusion,there is a conventional evaluation,which is classified into CR,PR,SD and PD on the basis of RECIST,the percentage of CR and PR plus SD is regarded as the disease control rate. Meanwhile,we evaluate the quality of life in terms of Karnofsky Performance Status standards.
Results:①From February 2004 to August 2008,59 patients with refractory solid tumors accepted (0.983±0.425)×108 CD3+cells/Kg weight of DLIs,all can be evaluated. 1 of 16 cases with gastric cancer achieved CR,8 SD,and 7 PD,the DCR is 56.25%,and the median OS is 15.7 months (8.5 to 52.1 months);the DCR of 13 patients with RCC is 46.15%,including 1 CR and 5 SD,and the median OS is 28.3 months (8.9 to 46.4 months);in 11 cases of HCC,6 had SD and 5 PD,the DCR is 54.55%,and the median OS is 9.6 months (3.6 to 51.2 months). The other malignants were 19 cases,one achieved PR,6 SD,and 12 PD,the DCR is 36.84%,and the median OS is 16.3months (7.4 to 54.8 months).②The DCR with 2～7 times of DLIs is higher than only once(P <0.05);the DCR of the group with >1.0×108CD3+ cells/Kg is higher than the other one with <1.0×108CD3+cells/Kg(P <0.005);46 patients had a detection of CD3/HLA-DR and CD25 before and after DLI,the DCR of the group with CD3/HLA-DR rising is higher than the decline one(P <0.005),and the change of CD25 is similar(P<0.05);the difference of DCR between different diseases,combinations of donor/recipient and loci-mismatched numbers are no signi- ficant(P>0.50).③The toxicities can be assessed in all patients,and 10 cases (16.95%) occurred in gradeⅠ～Ⅱof aGVHD,not gradeⅢ～ⅣaGVHD or cGVHD.④The KPS score has a improvement with 10 points or more in 29 patients after DLI.
Conclusion:①HLA haploidentical lymphocyte infusions may have some effects for patients with relapsed or refractory solid tumors.②The toxicities is not significant in HLA haploidentical lymphocyte infusions for relapsed or refractory solid tumors.③Whether HLA haploidentical lymphocyte infusions for relapsed or refractory solid tumors can improve the overall survival or not remains to be seen.
资料与方法:经多次治疗后出现复发或病情进展的Ⅳ期实体瘤患者,理解并愿意接受HLA半相合淋巴细胞输注,签署知情同意书。所有患者在进行供者淋巴细胞输注(DLI)治疗前4～8周或同时接受常规治疗。胃癌患者在进行DLI治疗前4～8周接受常规剂量的“紫杉类+奥沙利铂”或“卡培他滨”化疗,肾癌患者在DLI治疗期间同时口服“沙利度胺”,肝癌患者在进行DLI治疗前4～8周接受“顺铂+表阿霉素”肝动脉栓塞化疗,其余患者在进行DLI治疗前均接受不同方式的常规剂量的放疗或化疗。供受者间需测定HLA-A、HLA-B、HLA-DR共6个位点,选定合适的供者后对其进行ABO血型、乙肝表面抗原、艾滋病病毒抗体、丙肝病毒抗体及梅毒抗体的检测。符合条件的供者在CS-3000Plus血细胞分离机上按“淋巴细胞采集程序”采集单个核细胞,循环血量为8000ml,采集的供者单个核细胞约55ml,加145 ml的生理盐水稀释到200 ml;经稀释、混匀后的采集血送我院放射治疗中心接受60Go照射(DT 25 Gy)后输注给患者,每4～8周重复一次,治疗前后监测患者CD3/HLA-DR、CD25值的变化,同时观察是否发生GVHD。aGVHD临床分级按Glucksberg标准分为Ⅰ～Ⅳ级,cGVHD按NIH共识标准分为轻、中、重度;每次输注后4周对患者进行常规评价,按RECIST标准分为完全缓解(CR)、部分缓解(PR)、疾病稳定(SD)、疾病进展(PD),以CR+PR+SD所占的比率作为疾病控制率(DCR),同时按卡氏体力状况评分标准对患者进行生活质量的评价。
结果:①2004年2月至2008年8月,我院59例Ⅳ期难治性实体瘤患者接受含有(0.983±0.425)×108 CD3+细胞/Kg体重的DLI,全部病例均可评价疗效。胃癌16例,CR 1例,SD 8例,PD 7例,DCR为56.25%,中位总生存期为15.7个月(8.5～52.1个月);肾癌13例,CR 1例,SD 5例,PD 7例,DCR为46.15%,中位总生存期为28.3个月(8.9～46.4个月);肝癌11例,SD 6例,PD 5例,DCR为54.55%,中位总生存期为9.6个月(3.6～51.2个月);其他恶性实体瘤共19例,PR 1例,SD 6例,PD 12例,DCR为36.84%,中位总生存期16.3个月(7.4～54.8个月)。②接受2～7次DLI组的DCR高于仅接受1次DLI组(P <0.05);接受>1.0×108 CD3+细胞/Kg组的DCR高于<1.0×108 CD3+细胞/Kg组(P <0.005);46例患者在DLI治疗前后进行CD3/HLA-DR和CD25的检测,CD3/HLA-DR升高组的DCR高于降低组(P <0.005),CD25升高组的DCR高于降低组(P <0.05)。不同病种、供受者不同性别组合、不相合位点数不同组别间DCR的差异无统计学意义(P >0.50)。③全部病例均可评价毒副反应,其中有10例(16.95%)发生了Ⅰ～Ⅱ级的aGVHD,未发现Ⅲ～Ⅳ级aGVHD或cGVHD者。④29例患者在DLI治疗前后KPS评分提高10分及以上。
结论:①HLA半相合淋巴细胞输注治疗复发性或难治性实体瘤具有一定的效果。②HLA半相合淋巴细胞输注治疗复发性或难治性实体瘤无明显毒副反应。③HLA半相合淋巴细胞输注治疗复发性或难治性实体瘤是否可延长总生存期有待于进一步的观察。
Objective:Observe the short-term efficacy,the toxicity,and the quality of life about HLA-haploidentical lymphocyte infusions for refractory solid tumors,and explore its clinical value.
Data and Methods:Patients with phase IV solid tumors who were failed by conventional therapy,understand and are willing to accept HLA haploidentical lymphocyte infusions,then sign the informed consent. All patients received routine therapy 4 to 8 weeks before DLI or simultaneously. Patients with gastric cancer received conventional doses of“Taxane+ Oxaliplatin”or“Capecitabine”4 to 8 weeks before DLI;patients with RCC take“Thalidomide”orally during DLI;patients with HCC undergo a TACE with“Cisplatin+Epirubicin”4 to 8 weeks before DLI;the other acceptted common radiotherapy or chemotherapy before DLI. Donor/recipient’s loci determination for six sites among HLA-A,HLA-B,HLA-DR,is needed for the pairs. We must detect ABO blood type,HBsAg,anti-HIV,anti-HCV and syphilis antibody for the suitable donors. The eligible donors have a collection of MNCs on the CS-3000Plus blood cell separator,according to the“lymphocyte collection procedures”,and the circulating blood volume is 8000ml. The MNCs is about 55ml,diluted into 200ml by 145ml of normal saline. The mixture above will accept 60Go irradiation (DT 25Gy),then infuse into the patients. Repeat the infusion every 4～8 weeks,detect the value of CD3/HLA-DR and CD25 pre-DLI and post-DLI,observe the occurrence of GVHD. Acute GVHD is clinically graded asⅠ～Ⅳbased on Glucksberg criteria,and chronic GVHD is classified as mild,moderate and severe according to National Institutes of Health consensus development project on standards for cGVHD. 4 weeks after each infusion,there is a conventional evaluation,which is classified into CR,PR,SD and PD on the basis of RECIST,the percentage of CR and PR plus SD is regarded as the disease control rate. Meanwhile,we evaluate the quality of life in terms of Karnofsky Performance Status standards.
Results:①From February 2004 to August 2008,59 patients with refractory solid tumors accepted (0.983±0.425)×108 CD3+cells/Kg weight of DLIs,all can be evaluated. 1 of 16 cases with gastric cancer achieved CR,8 SD,and 7 PD,the DCR is 56.25%,and the median OS is 15.7 months (8.5 to 52.1 months);the DCR of 13 patients with RCC is 46.15%,including 1 CR and 5 SD,and the median OS is 28.3 months (8.9 to 46.4 months);in 11 cases of HCC,6 had SD and 5 PD,the DCR is 54.55%,and the median OS is 9.6 months (3.6 to 51.2 months). The other malignants were 19 cases,one achieved PR,6 SD,and 12 PD,the DCR is 36.84%,and the median OS is 16.3months (7.4 to 54.8 months).②The DCR with 2～7 times of DLIs is higher than only once(P <0.05);the DCR of the group with >1.0×108CD3+ cells/Kg is higher than the other one with <1.0×108CD3+cells/Kg(P <0.005);46 patients had a detection of CD3/HLA-DR and CD25 before and after DLI,the DCR of the group with CD3/HLA-DR rising is higher than the decline one(P <0.005),and the change of CD25 is similar(P<0.05);the difference of DCR between different diseases,combinations of donor/recipient and loci-mismatched numbers are no signi- ficant(P>0.50).③The toxicities can be assessed in all patients,and 10 cases (16.95%) occurred in gradeⅠ～Ⅱof aGVHD,not gradeⅢ～ⅣaGVHD or cGVHD.④The KPS score has a improvement with 10 points or more in 29 patients after DLI.
Conclusion:①HLA haploidentical lymphocyte infusions may have some effects for patients with relapsed or refractory solid tumors.②The toxicities is not significant in HLA haploidentical lymphocyte infusions for relapsed or refractory solid tumors.③Whether HLA haploidentical lymphocyte infusions for relapsed or refractory solid tumors can improve the overall survival or not remains to be seen.
引文
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[40]张立成,郭坤元,董波等.γ射线照射单倍型供者淋巴细胞输注抗白血病作用的实验研究[J].中华血液学杂志. 2000,21(2):81-83.
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[43]Kim JG,Sohn SK,Kim DH,et al. Impact of ABO incompatibility on outcome after allogeneic peripheral blood stem cell transplantation[J]. Bone Marrow Transplant. 2005,35(5):489-495.
[44]Canals C,Mu?iz-Díaz E,Martínez C,et al. Impact of ABO incompatibility on allogeneic peripheral blood progenitor cell transplantation after reduced intensity conditioning [J].Transfusion,2004,44(11):1603-1611.
[45]Worel N,Greinix HT,Keil F,et al. Severe immune hemolysis after minor ABO-mismatched allogeneic peripheral blood progenitor cell transplantation occurs more frequently after nonmyeloablative than myeloablative conditioning[J]. Transfusion. 2002,42(10):1293-1301.
[46]Nicolas Blin,Richard Traineau,Régis de Latour,et al. Impact of donor/recipient major ABO mismatch on allogeneic transplantation outcome according to stem cell source:results from an 809-patient retrospective study[J]. Blood (ASH Annual Meeting Abstracts). 2008,112: Abstract 2157.
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[5]吴秉毅,宋朝阳,郭坤元等.自体外周血干细胞移植联合单倍体淋巴细胞输注治疗恶性血液病[J].中国实验血液学杂志.2003,11(3):287-291.
[6]朱家斌等.输注淋巴细胞防治造血干细胞移植后白血病复发的观察[J].右江医学. 2007,35(6):699-700.
[7]艾辉胜,余长林,王丹红等.非清髓异基因外周血造血干细胞移植治疗血液病的临床观察[J].中华血液学杂志. 2003,24(2):86-89.
[8]李庆山,毛平,王顺清等.非清髓性移植后供者淋巴细胞输注治疗血液病的疗效观察[J].中山大学学报(医学科学版). 2004,25(6):573-576.
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[1] Kolb HJ,Mittermueller J,Clemm C,et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients[J]. Blood. 1990,76(12):2462-2465.
[2]董陆佳,叶根耀主编.现代干细胞移植治疗学.北京:人民军医出版社,2001,5.
[3]Childs RW,Clave E,Tisdale J,et al. Successful treatment of metastatic renal cell carcinoma with a nonmyeloablative allogeneic peripheral-blood progenitor-cell transplant:evidence for a graft-versus-tumor effect[J]. J Clin Oncol. 1999,17(7):2044-2049.
[4]Ballester OF,Fang T,Raptis A,et al. Adoptive immunotherapy with donor lymphocyte infusions and interleukin-2 after high-dose therapy and autologous stem cell rescue for multiple myeloma[J]. Bone Marrow Transplant. 2004,34(5):419-423.
[5]吴秉毅,宋朝阳,郭坤元等.自体外周血干细胞移植联合单倍体淋巴细胞输注治疗恶性血液病[J].中国实验血液学杂志.2003,11(3):287-291.
[6]朱家斌等.输注淋巴细胞防治造血干细胞移植后白血病复发的观察[J].右江医学. 2007,35(6):699-700.
[7]艾辉胜,余长林,王丹红等.非清髓异基因外周血造血干细胞移植治疗血液病的临床观察[J].中华血液学杂志. 2003,24(2):86-89.
[8]李庆山,毛平,王顺清等.非清髓性移植后供者淋巴细胞输注治疗血液病的疗效观察[J].中山大学学报(医学科学版). 2004,25(6):573-576.
[9]丁邦和,李玉峰,钱芳.非清髓性异基因造血干细胞移植联合供者淋巴细胞输注治疗恶性血液病[J].临床肿瘤学杂志. 2008,13(6):545-548.
[10]Mapara MY,Kim YM,Marx J,et al. Donor lymphocyte infusion mediated graft- versus-leukemia effects in mixed chimeras established with a non- myeloablative conditioning regimen:extinction of graft-versus-leukemia effects after conversion to full donor chimerism [J]. Transplantation. 2003,76(2):297-305.
[11]Peggs KS,Thomson K,Hart DP,et al.Dose-escalated donor lymphocyte infusions following reduced intensity transplantation:toxicity,chimerism,and disease responses[J]. Blood. 2004,103(4):1548-1556.
[12] Marks DI,Lush R,Cavenagh J,et al. The toxicity and efficacy of donor lymphocyte infusions given after reduced-intensity conditioning allogeneic stem cell transplantation[J]. Blood. 2002,100(9):3108-3114.
[13] Russell NH,Byrne JL,Faulkner RD, et al .Donor lymphocyte infusions can result in sustained remissions in patients with residual or relapsed lymphoid malignancy following allogeneic haemopoietic stem cell transplantation[J]. Bone Marrow Transplant. 2005,36(5):437-441.
[14]Bloor AJ,Thomson K,Chowdhry N,et al. High response rate to donor lymphocyte infusion after allogeneic stem cell transplantation for indolent non-Hodgkin lymphoma[J].Biol Blood Marrow Transplant. 2008,14(1):50-58.
[15]Shimoni A,Gajewski JA,Donato M,et al. Long-term follow-up of recipients of CD8-depleted donor lymphocyte infusions for the treatment of chronic myelogenous leukemia relapsing after allogeneic progenitor cell transplantation[J]. Biol Blood Marrow Transplant. 2001,7(10):568-575.
[16]Zetterquist H,Hentschke P,Thorne A,et al. A graft-versus-colonic cancer effect after allogeneic stem-cell transplantation[J]. Bone Marrow Transplant. 2001,28(12):1161-1166.
[17]Bay JO,Fleury J,Choufi B,et al.Allogeneic hematopoietic stem cell transplantation in ovarian carcinoma:results of five patients[J]. Bone Marrow Transplant. 2002,30(2):95-102.
[18] Barkholt L,Bregni M,Remberger M,et al. Allogeneic haematopoietic stem cell transplantation for metastatic renal carcinoma in Europe[J]. Ann Oncol. 2006,17(7):1134-1140.
[19] Bregni M,Dodero A,Peccatori J,et al. Nonmyeloablative conditioning followed by hematopoietic cell allografting and donor lymphocyte infusions for patients with metastatic renal and breast cancer[J]. Blood. 2002,99(11):4234-4236.
[20]陈强,李晓峰,叶韵斌等. MHC半相合脾加骨髓细胞诱发H22荷瘤小鼠的抗肿瘤效应[J].中国肿瘤生物治疗杂志.2006,13(2):107-111.
[21] Porter DL,Connors JM,Deerlin J,et al.Graft-versus-tumor induction with donor leukocyte infusions as primary therapy for patients with malignancies[J]. J Clini Onco. 1999,17(4):1234-1243.
[22]Strair RK,Schaar D,Medina D,et al. Antineoplastic effects of partially HLA-matched irradiated blood mononuclear cells in patients with renal cell carcinoma [J].J Clini Onco. 2003,21(20):3785-3791.