Humanized CD19-Targeted Chimeric Antigen Receptor (CAR) T Cells in CAR-Naive and CAR-Exposed Children and Young Adults With Relapsed or Refractory Acute Lymphoblastic Leukemia

Myers, Regina M.; Li, Yimei; Leahy, Allison Barz; Barrett, David M.; Teachey, David T.; Callahan, Colleen; Fasano, Christina; Rheingold, Susan R.; DiNofia, Amanda M.; Wray, Lisa; Aplenc, Richard; Baniewicz, Diane; Liu, Hongyan; Shaw, Pamela A.; Pequignot, Edward; Getz, Kelly; Brogdon, Jennifer L.; Fesnak, Andrew D.; Siegel, Donald L.; Davis, Megan M.; Bartoszek, Chelsie; Lacey, Simon F.; Hexner, Elizabeth O.; Chew, Anne; Wertheim, Gerald; Levine, Bruce L.; June, Carl H.; Grupp, Stephan A.; Maude, Shannon L.

doi:10.1200/jco.20.03458

Cited by 117 publications

(64 citation statements)

References 25 publications

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“…34 Treatment with investigational humanized CD19-specific CAR T cells is an option for relapsed patients but is not widely available. 35 Reinfusion of tisagenlecleucel when additional doses are manufactured is under clinical investigation (NCT04225676) but the utility of this approach may be ineffective if the patient has already established an anti-CAR immunologic response. 36 In summary, CD19-specific CAR T cells for R/R EM disease offers a beneficial, effective option with similar toxicity and OS rates when compared to patients with BM only disease.…”

Section: Discussionmentioning

confidence: 99%

Tisagenlecleucel outcomes in relapsed/refractory extramedullary ALL: a Pediatric Real World CAR Consortium Report

et al. 2022

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Chimeric antigen receptor (CAR) T-cells have transformed the therapeutic options for relapsed/refractory (R/R) B-cell ALL. Data for CAR therapy in extramedullary (EM) involvement is limited. Retrospective data was abstracted from the Pediatric Real World CAR Consortium (PRWCC) of 184 infused patients from 15 US institutions. Response (CR) rate, overall survival (OS), relapse-free survival (RFS), and duration of B-cell aplasia (BCA) in patients referred for tisagenlecleucel with EM disease (both CNS3 and non-CNS EM) were compared to bone marrow (BM) only. Patients with CNS disease were further stratified for comparison. Outcomes are reported on 55 patients with EM disease prior to CAR (n=40 CNS3; n=15 non-CNS EM). The median age at infusion in CNS cohort was 10 years (range <1-25) and the non-CNS EM cohort was 13 years (2-26). In patients with CNS disease, 88% (35/40) achieved a CR, versus only 66% (10/15) with non-CNS EM disease. Patients with CNS disease (both with and without marrow involvement) had comparable 24-month OS outcomes to non-CNS EM or BM only (p=0.41). There was no difference in 12-month RFS between CNS, non-CNS EM, or BM only patients (p=0.92). No increased toxicity was seen with CNS or non-CNS EM disease (p=0.3). Active CNS disease at time of infusion did not impact outcomes. Isolated (iCNS) disease trended towards improved OS when compared to combined CNS and BM (p=0.12). R/R EM disease can be effectively treated with tisagenlecleucel with toxicity, relapse rates and survival rates comparable to patients with BM only. Outcomes for iCNS relapse are encouraging.

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Section: Discussionmentioning

confidence: 99%

Tisagenlecleucel outcomes in relapsed/refractory extramedullary ALL: a Pediatric Real World CAR Consortium Report

et al. 2022

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“…Although this CR rate was lower than those obtained in patients firstly accepted mCD19 CAR-T in which CR rates reached 81–90% [ 1 – 4 ], the therapeutic efficiency of hCD19 CAR-T cells for these heavily treated patients who had no more treatment options was encouraging. A recent study also reported that the humanized CD19 CAR-T produced initial responses in 64% of patients treated for CD19+ relapse, early B-cell recovery, or nonresponse after prior murine CAR-T cells [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that one patient relapsing after mCD19 CAR-T did not respond to a secondary infusion of mCD19 CAR-T cells but obtained CR following hCD19 CAR-T [ 8 ]; and 4 of 5 patients who had received previous mCD19 CAR-T and relapsed with CD19 + B lymphoblastic cells achieved CR by treatment with humanized selective CD19 CAR-T [ 9 ]. Very recently, while this paper was in preparation, a new study showed that, in 33 childhood and young adult B-ALL patients with prior mCD19 CAR exposure (CD19+ relapse, n = 15; B-cell recovery, n = 16; no response to prior CAR-T cells, n = 2), the overall response rate at 1 month after humanized CD19 CAR-T cell infusion was 64% [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Humanized CD19 CAR-T cells in relapsed/refractory B-ALL patients who relapsed after or failed murine CD19 CAR-T therapy

An¹,

Lin²,

Deng

et al. 2022

BMC Cancer

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Background For CD19-positive relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) after treatment with murine CD19 (mCD19) CAR-T, the reinfusion of mCD19 CAR-T cells may be ineffective due to anti-mouse single-chain variable fragment (scFv) antibody caused by mCD19 CAR. To overcome this immunogenicity, we applied humanized CD19 (hCD19) CAR-T cells to treat r/r B-ALL patients with prior mCD19 CAR-T therapy. Methods Nineteen pediatric and adult patients were included, 16 relapsed after and 3 were primarily resistant to mCD19 CAR-T. All patients presented with more than 5% blasts in bone marrow and/or extramedullary disease, and still showed CD19 antigen expression. Humanized CD19-CARs were lentiviral vectors carrying a second generation CAR with 4–1-BB co-stimulatory and CD3ζ signaling domains. Patient-derived cells were collected for producing CAR-T cells, the median dose of infused hCD19 CAR-T cells was 2.4 × 105/kg (range, 1.0–18.0 × 105/kg). Results hCD19 CAR-T resulted in a complete remission (CR) rate of 68% (13/19). Among 13 remission patients, 11 underwent allogeneic hematopoietic cell transplantation (allo-HCT) (3 were second HCT) and 10 remained in CR; the event-free survival rates at 12–18 months were 91% in 11 patients received following allo-HCT and 69% in all CR patients. Six cases had no response to hCD19 CAR-T, 3 died of disease progression; another 3 received salvage second transplantation, of them, 2 relapsed again (one died). Cytokine release syndrome (CRS) occurred in 95% (18/19) of patients, most CRS events were grade 1 and grade 2 (n = 17), there was only one grade 4 CRS. Two cases experienced grade 1 neurotoxicity. Conclusions Humanized CD19 CAR-T cell therapy could be a treatment option for CD19-positive B-ALL patients who relapsed after or resisted prior murine CD19 CAR-T, hCD19 CAR-T followed by allo-HCT provided a longer remission in CR patients. Nevertheless, the prognosis of non-responders to hCD19 CAR-T remained dismal. Trial registration Chinese Clinical Trial Registry/WHO International Clinical Trial Registry (ChiCTR1900024456, URL: www.chictr.org.cn); registered on July 12, 2019.

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“…To reduce ICANS and CRS and to diminish T-cell exhaustion, Ghorashian et al ( 25 ) designed and investigated a low-affinity CD19.scFv (CAT CD19 CAR-T, Figure 1A ), as discussed above. Lastly, the strategy of humanised scFvs is being pursued to avoid the activation of the patient's immune system against murine parts of the CAR and subsequent rejection of the cells and short-term persistence ( 109 ).…”

Section: Factors Influencing Long-term Efficacymentioning

confidence: 99%

“…Another approach reported from the same group at the CHOP/University of Pennsylvania ( 109 ) is the infusion of a humanised CAR construct (huCART19 or CTL119) in attempt to overcome the possibility of an anti-murine immune response. In a pilot trial (NCT02374333), 33 R/R BCP-ALL patients with either partial or no response to prior tisagenlecleucel, CD19 + relapse or early B-cell recovery (defined as occurring within 6 months of prior CAR T-cell infusion), were infused with huCART19 ( 109 ). The ORR 1 month after infusion was 64% in the re-treatment cohort.…”

Section: Strategies For Preventing Leukaemic Relapse Post Car-tmentioning

confidence: 99%

Chimeric Antigen Receptor T-Cell Therapy in Paediatric B-Cell Precursor Acute Lymphoblastic Leukaemia: Curative Treatment Option or Bridge to Transplant?

et al. 2022

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Chimeric antigen receptor T-cell therapy (CAR-T) targeting CD19 has been associated with remarkable responses in paediatric patients and adolescents and young adults (AYA) with relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). Tisagenlecleucel, the first approved CD19 CAR-T, has become a viable treatment option for paediatric patients and AYAs with BCP-ALL relapsing repeatedly or after haematopoietic stem cell transplantation (HSCT). Based on the chimeric antigen receptor molecular design and the presence of a 4-1BB costimulatory domain, tisagenlecleucel can persist for a long time and thereby provide sustained leukaemia control. “Real-world” experience with tisagenlecleucel confirms the safety and efficacy profile observed in the pivotal registration trial. Recent guidelines for the recognition, management and prevention of the two most common adverse events related to CAR-T — cytokine release syndrome and immune-cell–associated neurotoxicity syndrome — have helped to further decrease treatment toxicity. Consequently, the questions of how and for whom CD19 CAR-T could substitute HSCT in BCP-ALL are inevitable. Currently, 40–50% of R/R BCP-ALL patients relapse post CD19 CAR-T with either CD19− or CD19+ disease, and consolidative HSCT has been proposed to avoid disease recurrence. Contrarily, CD19 CAR-T is currently being investigated in the upfront treatment of high-risk BCP-ALL with an aim to avoid allogeneic HSCT and associated treatment-related morbidity, mortality and late effects. To improve survival and decrease long-term side effects in children with BCP-ALL, it is important to define parameters predicting the success or failure of CAR-T, allowing the careful selection of candidates in need of HSCT consolidation. In this review, we describe the current clinical evidence on CAR-T in BCP-ALL and discuss factors associated with response to or failure of this therapy: product specifications, patient- and disease-related factors and the impact of additional therapies given before (e.g., blinatumomab and inotuzumab ozogamicin) or after infusion (e.g., CAR-T re-infusion and/or checkpoint inhibition). We discuss where to position CAR-T in the treatment of BCP-ALL and present considerations for the design of supportive trials for the different phases of disease. Finally, we elaborate on clinical settings in which CAR-T might indeed replace HSCT.

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Humanized CD19-Targeted Chimeric Antigen Receptor (CAR) T Cells in CAR-Naive and CAR-Exposed Children and Young Adults With Relapsed or Refractory Acute Lymphoblastic Leukemia

Cited by 117 publications

References 25 publications

Tisagenlecleucel outcomes in relapsed/refractory extramedullary ALL: a Pediatric Real World CAR Consortium Report

Tisagenlecleucel outcomes in relapsed/refractory extramedullary ALL: a Pediatric Real World CAR Consortium Report

Humanized CD19 CAR-T cells in relapsed/refractory B-ALL patients who relapsed after or failed murine CD19 CAR-T therapy

Chimeric Antigen Receptor T-Cell Therapy in Paediatric B-Cell Precursor Acute Lymphoblastic Leukaemia: Curative Treatment Option or Bridge to Transplant?

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