Brudno Jennifer N, Somerville Robert P T, Shi Victoria, Rose Jeremy J, Halverson David C, Fowler Daniel H, Gea-Banacloche Juan C, Pavletic Steven Z, Hickstein Dennis D, Lu Tangying L, Feldman Steven A, Iwamoto Alexander T, Kurlander Roger, Maric Irina, Goy Andre, Hansen Brenna G, Wilder Jennifer S, Blacklock-Schuver Bazetta, Hakim Frances T, Rosenberg Steven A, Gress Ronald E, Kochenderfer James N
Jennifer N. Brudno, Robert P.T. Somerville, Victoria Shi, Jeremy J. Rose, David C. Halverson, Daniel H. Fowler, Juan C. Gea-Banacloche, Steven Z. Pavletic, Dennis D. Hickstein, Tangying L. Lu, Steven A. Feldman, Alexander T. Iwamoto, Brenna G. Hansen, Bazetta Blacklock-Schuver, Frances T. Hakim, Steven A. Rosenberg, Ronald E. Gress, and James N. Kochenderfer, National Cancer Institute; Roger Kurlander and Irina Maric, National Institutes of Health, Bethesda; Jennifer S. Wilder, Frederick National Laboratory for Cancer Research, Frederick, MD; and Andre Goy, John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ.
J Clin Oncol. 2016 Apr 1;34(10):1112-21. doi: 10.1200/JCO.2015.64.5929. Epub 2016 Jan 25.
Progressive malignancy is the leading cause of death after allogeneic hematopoietic stem-cell transplantation (alloHSCT). After alloHSCT, B-cell malignancies often are treated with unmanipulated donor lymphocyte infusions (DLIs) from the transplant donor. DLIs frequently are not effective at eradicating malignancy and often cause graft-versus-host disease, a potentially lethal immune response against normal recipient tissues.
We conducted a clinical trial of allogeneic T cells genetically engineered to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. Patients with B-cell malignancies that had progressed after alloHSCT received a single infusion of CAR T cells. No chemotherapy or other therapies were administered. The T cells were obtained from each recipient's alloHSCT donor.
Eight of 20 treated patients obtained remission, which included six complete remissions (CRs) and two partial remissions. The response rate was highest for acute lymphoblastic leukemia, with four of five patients obtaining minimal residual disease-negative CR. Responses also occurred in chronic lymphocytic leukemia and lymphoma. The longest ongoing CR was more than 30 months in a patient with chronic lymphocytic leukemia. New-onset acute graft-versus-host disease after CAR T-cell infusion developed in none of the patients. Toxicities included fever, tachycardia, and hypotension. Peak blood CAR T-cell levels were higher in patients who obtained remissions than in those who did not. Programmed cell death protein-1 expression was significantly elevated on CAR T cells after infusion. Presence of blood B cells before CAR T-cell infusion was associated with higher postinfusion CAR T-cell levels.
Allogeneic anti-CD19 CAR T cells can effectively treat B-cell malignancies that progress after alloHSCT. The findings point toward a future when antigen-specific T-cell therapies will play a central role in alloHSCT.
进行性恶性肿瘤是异基因造血干细胞移植（alloHSCT）后主要的死亡原因。alloHSCT后，B细胞恶性肿瘤通常采用来自移植供体的未处理供体淋巴细胞输注（DLI）进行治疗。DLI常常无法有效根除恶性肿瘤，且常引发移植物抗宿主病，这是一种针对正常受者组织的潜在致命性免疫反应。
我们开展了一项关于基因工程改造的异基因T细胞的临床试验，这些T细胞表达靶向B细胞抗原CD19的嵌合抗原受体（CAR）。alloHSCT后病情进展的B细胞恶性肿瘤患者接受了单次CAR T细胞输注。未给予化疗或其他治疗。T细胞取自每位受者的alloHSCT供体。
20例接受治疗的患者中有8例获得缓解，其中包括6例完全缓解（CR）和2例部分缓解。急性淋巴细胞白血病的缓解率最高，5例患者中有4例获得微小残留病阴性CR。慢性淋巴细胞白血病和淋巴瘤患者也出现了缓解。一名慢性淋巴细胞白血病患者持续最长的CR超过30个月。所有患者在CAR T细胞输注后均未出现新发急性移植物抗宿主病。毒性反应包括发热、心动过速和低血压。获得缓解的患者血液中CAR T细胞的峰值水平高于未缓解的患者。输注后CAR T细胞上程序性细胞死亡蛋白-1的表达显著升高。CAR T细胞输注前血液中B细胞的存在与输注后较高的CAR T细胞水平相关。
异基因抗CD19 CAR T细胞可有效治疗alloHSCT后进展的B细胞恶性肿瘤。这些发现预示着抗原特异性T细胞疗法在alloHSCT中将发挥核心作用的未来。
