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CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia.

ABSTRACT: Adults with relapsed B cell acute lymphoblastic leukemia (B-ALL) have a dismal prognosis. Only those patients able to achieve a second remission with no minimal residual disease (MRD) have a hope for long-term survival in the context of a subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have treated five relapsed B-ALL subjects with autologous T cells expressing a CD19-specific CD28/CD3? second-generation dual-signaling chimeric antigen receptor (CAR) termed 19-28z. All patients with persistent morphological disease or MRD(+) disease upon T cell infusion demonstrated rapid tumor eradication and achieved MRD(-) complete remissions as assessed by deep sequencing polymerase chain reaction. Therapy was well tolerated, although significant cytokine elevations, specifically observed in those patients with morphologic evidence of disease at the time of treatment, required lymphotoxic steroid therapy to ameliorate cytokine-mediated toxicities. Indeed, cytokine elevations directly correlated to tumor burden at the time of CAR-modified T cell infusions. Tumor cells from one patient with relapsed disease after CAR-modified T cell therapy, who was ineligible for additional allo-HSCT or T cell therapy, exhibited persistent expression of CD19 and sensitivity to autologous 19-28z T cell-mediated cytotoxicity, which suggests potential clinical benefit of additional CAR-modified T cell infusions. These results demonstrate the marked antitumor efficacy of 19-28z CAR-modified T cells in patients with relapsed/refractory B-ALL and the reliability of this therapy to induce profound molecular remissions, forming a highly effective bridge to potentially curative therapy with subsequent allo-HSCT.

SUBMITTER: Brentjens RJ

PROVIDER: S-EPMC3742551 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia.

Brentjens Renier J RJ Davila Marco L ML Riviere Isabelle I Park Jae J Wang Xiuyan X Cowell Lindsay G LG Bartido Shirley S Stefanski Jolanta J Taylor Clare C Olszewska Malgorzata M Borquez-Ojeda Oriana O Qu Jinrong J Wasielewska Teresa T He Qing Q Bernal Yvette Y Rijo Ivelise V IV Hedvat Cyrus C Kobos Rachel R Curran Kevin K Steinherz Peter P Jurcic Joseph J Rosenblat Todd T Maslak Peter P Frattini Mark M Sadelain Michel M

Science translational medicine 20130301 177

Adults with relapsed B cell acute lymphoblastic leukemia (B-ALL) have a dismal prognosis. Only those patients able to achieve a second remission with no minimal residual disease (MRD) have a hope for long-term survival in the context of a subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have treated five relapsed B-ALL subjects with autologous T cells expressing a CD19-specific CD28/CD3ζ second-generation dual-signaling chimeric antigen receptor (CAR) termed 19-28z. ...[more]

PMID: 23515080

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Project description:Chimeric antigen receptor (CAR) T cells achieve response and durable remission in patients with relapsed/refractory (R/R) B cell malignancies. Following collection of patient T cells, chemotherapy ("bridging chemotherapy") is utilized during the manufacture of CAR T cells. However, the optimal bridging chemotherapy has yet to be defined. Our objective in this study was to report clinical outcomes following bridging chemotherapy in a cohort of pediatric/young adult patients with R/R B cell acute lymphoblastic leukemia (B-ALL) treated with CAR T cell therapy. This retrospective study included patients enrolled on clinical trial NCT01860937 or referred to Memorial Sloan Kettering Cancer Center for commercial CAR T cell therapy (tisagenlecleucel). Bridging chemotherapy (given after T cell collection and before CAR T cell infusion) was defined as high intensity if myelosuppression was expected for >7 days. Outcome comparison analyses were performed in high-intensity versus low-intensity bridging chemotherapy, 1 cycle versus ≥2 cycles of bridging chemotherapy, disease burden at the start of bridging chemotherapy, disease burden at the start of bridging chemotherapy with chemotherapy intensity, tumor debulking by bridging chemotherapy, and disease burden pre-lymphodepleting chemotherapy (LDC) for CAR T cell treatment. The outcomes of this analysis showed that the incidence of grade ≥3 infection was significantly higher (94% versus 56%; P = .019) and overall survival (OS) was significantly lower (hazard ratio, 3.73; 95% confidence interval, 1.39 to 9.97; P = .006) in patients who received ≥2 cycles versus 1 cycle of bridging chemotherapy. No difference in incidence was found for cytokine release syndrome (P > .99) or neurotoxicity/immune effector cell-associated neurotoxicity syndrome (P = .70). Disease burden at the start of bridging chemotherapy, disease burden prior to LDC, and tumor debulking by bridging chemotherapy also did not significantly affect outcomes after CAR T cell therapy in this cohort. In this study, patients receiving ≥2 cycles of bridging chemotherapy had higher rates of infection and lower OS but no difference in CAR-specific toxicity. Clinicians should carefully consider the use of additional cycles of chemotherapy during the bridging period as it delays treatment with CAR T cells and increases the risk of infectious complications. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Project description:BackgroundRecent evidence suggests that resistance to CD19 chimeric antigen receptor (CAR)-modified T cell therapy may be due to the presence of CD19 isoforms that lose binding to the single-chain variable fragment (scFv) in current use. As such, further investigation of CARs recognize different epitopes of CD19 antigen may be necessary.MethodsWe generated a new CD19 CAR T (HI19α-4-1BB-ζ CAR T, or CNCT19) that includes an scFv that interacts with an epitope of the human CD19 antigen that can be distinguished from that recognized by the current FMC63 clone. A pilot study was undertaken to assess the safety and feasibility of CNCT19-based therapy in both pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia (R/R B-ALL).ResultsData from our study suggested that 90% of the 20 patients treated with infusions of CNCT19 cells reached complete remission or complete remission with incomplete count recovery (CR/CRi) within 28 days. The CR/CRi rate was 82% when we took into account the fully enrolled 22 patients in an intention-to-treat analysis. Of note, extramedullary leukemia disease of two relapsed patients disappeared completely after CNCT19 cell infusion. After a median follow-up of 10.09 months (range, 0.49-24.02 months), the median overall survival and relapse-free survival for the 20 patients treated with CNCT19 cells was 12.91 months (95% confidence interval [CI], 7.74-18.08 months) and 6.93 months (95% CI, 3.13-10.73 months), respectively. Differences with respect to immune profiles associated with a long-term response following CAR T cell therapy were also addressed. Our results revealed that a relatively low percentage of CD8+ naïve T cells was an independent factor associated with a shorter period of relapse-free survival (p = 0.012, 95% CI, 0.017-0.601).ConclusionsThe results presented in this study indicate that CNCT19 cells have potent anti-leukemic activities in patients with R/R B-ALL. Furthermore, our findings suggest that the percentage of CD8+ naïve T cells may be a useful biomarker to predict the long-term prognosis for patients undergoing CAR T cell therapy.Trial registrationClinicalTrials.gov : NCT02975687; registered 29 November, 2016. https://clinicaltrials.gov/ct2/keydates/NCT02975687.

Dataset Information

CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia.

Publications

CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia.

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