CD19+复发难治淋巴瘤经CAR-T治疗获得持续缓解

橙色雨丝 · 发表于 2015-12-3 13:44:35

本帖最后由橙色雨丝于 2015-12-3 14:22 编辑

Sustained Remissions Following Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) in Patients with Relapsed or Refractory CD19+ Lymphomas

Stephen J. Schuster, MD1, Jakub Svoboda, MD1, Sunita Dwivedy Nasta, MD1, David L. Porter, MD1, Elise A. Chong, MD1, Daniel J. Landsburg, MD1, Anthony R. Mato, MD, MSCE1, Simon F. Lacey, PhD, BS2*, Jan J. Melenhorst, PhD3*, Anne Chew, PhD3*, Jens Hasskarl, MD, PhD4*, Gaurav D. Shah, MD5*, Mariusz A. Wasik, MD6*, Katherine T. Marcucci, PhD3*, Zhaohui Zheng, MS2*, Bruce L. Levine, PhD3 and Carl H. June, MD3

1Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
2Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA
3Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
4Novartis, Basel, Switzerland
5Novartis, East Hanover, NJ
6Pathology and Laboratory Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA

BACKGROUND: Autologous T cells genetically modified to express a chimeric antigen receptor consisting of an external anti-CD19 single chain antibody domain with CD3ζ and 4-1BB signaling domains (CTL019 cells) can mediate potent anti-tumor effects in patients (pts) with relapsed or refractory chronic lymphocytic and acute lymphoblastic leukemias. We are conducting a phase IIa clinical trial to evaluate the safety and efficacy of CTL019 cells in pts with relapsed or refractory CD19+ non-Hodgkin lymphomas (NHL).

METHODS: Pts with CD19+ diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), or mantle cell lymphoma (MCL) with no available curative treatment options, a limited prognosis (<2 years anticipated survival), and responsive or stable disease with most recent therapy are eligible. Pts with DLBCL have residual disease after primary and salvage therapies and are not eligible for autologous stem cell transplant (ASCT) or have relapsed or residual disease after ASCT; FL pts have progression of lymphoma <2 years after second or higher line of therapy (not including single agent monoclonal antibody therapy); MCL pts have relapsed, residual, or progressive disease after rituximab-chemotherapy combination therapy and are not appropriate for transplant or have relapsed after transplant. After steady state apheresis to collect peripheral blood leukocytes, pts receive lymphodepleting chemotherapy based on disease burden, histology, and past therapies. One to 4 days after chemotherapy, pts receive a single dose of CTL019 cells by intravenous infusion. Peripheral blood and marrow samples are collected for immunophenotypic, cytokine, and molecular studies at pre-specified times after T cell infusion. Initial tumor response assessment is performed 3 months after T cell infusion using International Working Group response criteria. Enrollment started in February 2014; data reported here are through July 26, 2015.

RESULTS: To date, 38 pts have enrolled (DLBCL 21; FL 14; MCL 3). The median age is 56 years (range: 25-77), male: female ratio is 22:16, median number of prior therapies is 4 (range: 1-10), and number of pts with prior transplant is 12 (32%; 11 ASCT, 1 allotransplant). Ann Arbor stages at enrollment are: Stage IV 23 pts (61%), Stage III 7 pts (18%), Stage II 6 pts (16%), Stage 1E 2 pts (5%); 11 pts (29%) had bone marrow involvement. LDH was increased in 28 pts (74%). ECOG PS was 0 in 16 pts (42%) and 1 in 22 pts (58%). As of July 26, 2015, 24 patients have received the protocol-specified dose of CTL019 cells (13 DLBCL; 9 FL; 2 MCL). Lymphodepleting chemotherapy regimens were bendamustine (6 pts), cyclophosphamide (11 pts), cyclophosphamide-fludarabine (1 pt), modified EPOCH (3 pts), and radiation-cyclophosphamide (3 pts). Median total CTL019 cell dose is 5.00e8 (range: 1.79e8 – 5.00e8); median CTL019 cell dose/kg is 5.84e6 (range: 3.08e6-8.87e6). Median peak CTL019 cell expansion in blood occurred 7 days after infusion (range: 2-14 days); there was no difference in peak expansion between responders and non-responders. Cytokine release syndrome (CRS) occurred in 16 pts (14 grade 2; 1 grade 3; 1 grade 4) and did not predict response. Neurologic toxicity occurred in 3 pts: 2 episodes of delirium (1 grade 2, 1 grade 3) and one possibly related grade 5 encephalitis. 22 pts are evaluable for response (DLBCL 13, FL 7, MCL 2). Overall response rate (ORR) at 3 months is 68% (15/22): DLBCL 54% (7/13); FL 100% (7/7); MCL 50% (1/2). At the median follow-up 11.7 months, progression-free survival (PFS) from CTL019 infusion is 62% (DLBCL 43%; FL 100%). For responders at median follow up, response duration is 83% for DLBCL and 100% for FL.

CONCLUSIONS: These results demonstrate that CTL019 cells can be prepared from extensively pretreated pts with active NHL and can induce durable responses with toxicity that is less than reported for chronic lymphocytic and acute lymphoblastic leukemias.

橙色雨丝 · 发表于 2015-12-3 14:21:49

本帖最后由橙色雨丝于 2015-12-3 14:24 编辑

美国血液病学会第57届年会就要开幕了，全世界与血液病相关的人士，包括研究人员，专家，医生，患者等，他们的目光都将集中到那里；
不出意外的话，CAR－T，即嵌合抗原受体T细胞疗法仍将是热点；
不会有太大的惊喜，毕竟对这项技术的期望值可能已经高出了目前的技术能力；
宾夕法尼亚大学是最早搞CAR－T的几个小组之一，他们将要做的关于其CTL019临床试验的update将吸引很多人的注意力；
根据上文，他们加工的自体T细胞用CD3z和4-1BB作为共刺激信号，显然用的仍是二代技术。其实虽然三代、四代技术现在都有了，理论上比二代更先进，但是在临床上还未能显示出更高的有效率；
简单概括一下，在入组的38例患者中，有21例弥漫大B，14例滤泡，3例套细胞；其中12例已经做过移植；CAR-T细胞回输后，有16例发生了细胞因子风暴，但是与疗效无关；3个月的总有效率为68%，其中弥漫大B是54%，滤泡是100%，套细胞是50%（这个以前报道过）；最新的情况是，经11.7个月的随访，全组的无进展生存率是62%，其中弥漫大B是43%，滤泡是100%；如果只把那些治疗有效的患者挑出来，那么在接近一年的时间里，83%的弥漫大B保持了持续的缓解，100%的滤泡保持了持续的缓解！

linjiagenga1 · 发表于 2015-12-3 14:47:38

之前出差顺便去北京咨询了宋玉琴解答car-t乃是患者不得已而为之即便缓解之后没有大化疗（比如自体移植）跟进的话也会很快复发询问了您您也表示同意
不知道这个将近一年的持续缓解结果能否更新一下目前对car-t的认识

还有有种说法是如果有些病人不能或者不愿意自体移植可以用car-t代替不知道这种说法站不站得住脚