The ABCs of Immunotherapy for Adult Patients With B-Cell Acute Lymphoblastic Leukemia

2017 ◽  
Vol 52 (3) ◽  
pp. 268-276 ◽  
Author(s):  
Troy Z. Horvat ◽  
Amanda N. Seddon ◽  
Adebayo Ogunniyi ◽  
Amber C. King ◽  
Larry W. Buie ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Data Extraction ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
Efficacy And Safety ◽  
Car T Cells ◽  
Car T ◽  
American Society

Objective: To review the pharmacology, efficacy, and safety of Food and Drug Administration approved and promising immunotherapy agents used in the treatment of acute lymphoblastic leukemia (ALL). Data Sources: A literature search was performed of PubMed and MEDLINE databases (1950 to July 2017) and of abstracts from the American Society of Hematology and the American Society of Clinical Oncology. Searches were performed utilizing the following key terms: rituximab, blinatumomab, inotuzumab, ofatumumab, obinutuzumab, Blincyto, Rituxan, Gazyva, Arzerra, CAR T-cell, and chimeric antigen receptor (CAR). Study Selection/Data Extraction: Studies of pharmacology, clinical efficacy, and safety of rituximab, ofatumumab, obinutuzumab, inotuzumab, blinatumomab, and CAR T-cells in the treatment of adult patients with ALL were identified. Data Synthesis: Conventional chemotherapy has been the mainstay in the treatment of ALL, producing cure rates of approximately 90% in pediatrics, but it remains suboptimal in adult patients. As such, more effective consolidative modalities and novel therapies for relapsed/refractory disease are needed for adult patients with ALL. In recent years, anti-CD20 antibodies, blinatumomab, inotuzumab, and CD19-targeted CAR T-cells have drastically changed the treatment landscape of B-cell ALL. Conclusion: Outcomes of patients with relapsed disease are improving thanks to new therapies such as blinatumomab, inotuzumab, and CAR T-cells. Although the efficacy of these therapies is impressive, they are not without toxicity, both physical and financial. The optimal sequencing of these therapies still remains a question.

scholarly journals Efficacy and Safety of CD28- or 4-1BB-Based CD19 CAR-T Cells in B Cell Acute Lymphoblastic Leukemia

2020 ◽  
Vol 18 ◽  
pp. 272-281 ◽  
Author(s):  
Xiangyu Zhao ◽  
Junfang Yang ◽  
Xian Zhang ◽  
Xin-An Lu ◽  
Min Xiong ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Efficacy And Safety ◽  
Car T Cells ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals CAR-T Cell Therapies: An Overview of Clinical Studies Supporting Their Approved Use against Acute Lymphoblastic Leukemia and Large B-Cell Lymphomas

2020 ◽  
Vol 21 (11) ◽  
pp. 3906 ◽  
Author(s):  
Aamir Ahmad ◽  
Shahab Uddin ◽  
Martin Steinhoff
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
Clinical Studies ◽  
Lymphoblastic Leukemia ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Large B Cell

Chimeric Antigen Receptor (CAR)-T cell therapy is an exciting development in the field of cancer immunology, wherein immune T-cells from patients are collected, engineered to create ‘CAR’-T cells, and infused back into the same patient. Currently, two CAR-T-cell-based therapies, Tisagenlecleucel and Axicabtagene ciloleucel, are approved by FDA for the treatment of hematological malignancies, acute lymphoblastic leukemia and large B-cell lymphomas. Their approval has been a culmination of several phase I and II clinical studies, which are the subject of discussion in this review article. Over the years, CAR-T cells have evolved to be significantly more persistent in patients’ blood, resulting in a much-improved clinical response and disease remission. This is particularly significant given that the target patient populations of these therapies are those with relapsed and refractory disease who have often progressed on multiple therapies. Despite the promising clinical results, there are still several challenges that need to be addressed. Of particular note are the associated toxicities exemplified by cytokine release syndrome (CRS) and the neurotoxicity. CRS has been addressed by an FDA-approved therapy of its own—tocilizumab. This article focuses on the progress related to CAR-T therapy: the pertinent clinical studies and their major findings, their associated adverse effects, and future perspective.

scholarly journals Donor-Derived CAR T Cells Engineered with Sleeping Beauty in Pediatric and Adult Patients with Acute Lymphoblastic Leukemia Relapsed Post-HSCT

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 472-472
Author(s):  
Chiara F Magnani ◽  
Giuseppe Gaipa ◽  
Federico Lussana ◽  
Giuseppe Gritti ◽  
Daniela Belotti ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
Dose Level ◽  
Dose Escalation ◽  
Lymphoblastic Leukemia ◽  
Sleeping Beauty ◽  
Advisory Board ◽  
Adult Patients ◽  
Car T Cells ◽  
Car T

Abstract Introduction Allogeneic Chimeric Antigen Receptor (CAR) T cells engineered with non-viral methods offer a modality to reduce costs and logistical complexity of the viral process and allow lymphodepleted patients to access CAR T cell treatment. We recently proposed the use of Sleeping Beauty (SB) transposon to engineer donor-derived T cells differentiated according to the cytokine-induced killer (CIK) cell protocol (Magnani CF et al. J Clin Invest. 2021). We report here outcomes on B-cell acute lymphoblastic leukemia (B-ALL) patients, relapsing after transplantation, treated with donor-derived anti-CD19 CAR T cells (CARCIK-CD19). Methods We conducted an academic, multi-center, phase I/II dose-escalation trial in patients relapsed after allogeneic hematopoietic stem cell transplantation (HSCT). The infusion product was manufactured in-house starting from 50 mL of peripheral blood from the HSCT donor by electroporation with GMP-grade plasmids. All patients underwent lymphodepletion with Fludarabine (30 mg/m 2/day x 4 days) and Cyclophosphamide (500 mg/m 2/day x 2 days), before proceeding to CARCIK-CD19 infusion. We used the Bayesian Optimal Interval (BOIN) design to define a four-dose escalation scheme. Primary objectives were to define the Maximum Tolerated Dose (MTD), safety, and feasibility. Secondary objectives included the assessment of complete hematologic response (CR), duration of response (DOR), progression-free (PFS), event-free (EFS), and overall survival (OS). This study was registered at ClinicalTrials.gov, NCT03389035. Results From January 2018 to June 2021, a total of 32 patients were screened, 26 enrolled (6 children and 20 adults) and 21 infused (4 children and 17 adults). Reasons for not receiving infusion included consent withdrawal (N=1), disease progression not controlled by bridging therapy (N=3), acquisition of myeloid phenotype (N=1). The median number of prior therapies was 4 (range, 1-7) with a median time interval from HSCT to relapse of 9 months. The median BM blasts was 60% (range, 5-100%) at enrollment and 7% (range, 0-96%) post lymphodepletion. Of the 21 patients infused, CARCIK-CD19 were obtained by HLA-identical sibling (n=6, 29%), matched unrelated (n= 7, 33%), and haploidentical donors (n=8, 38%). Three patients (14%) received the first dose level of 1x10 6 CARCIK-CD19 cells/Kg, three (14%) the second of 3x10 6, and three (14%) the third of 7.5x10 6 whereas 12 patients (57%) received the fourth and last planned dose level of 15x10 6 cells/Kg, as no dose limiting toxicity (DLT) was observed. CRS was observed in six patients (three grade I and three grade II) and immune effector cell-associated neurotoxicity in two patients at the highest dose. Although 9 out of 21 had experienced acute or chronic graft-versus-host disease (GvHD) after the previous HSCT, secondary GvHD was never induced by CARCIK-CD19. Complete response was achieved by 13 out of 21 patients (61.9%, 95%CI=38-82%) and by 11 out of 15 patients treated with the 2 highest doses (73.3%, 95%CI=45-92%). Eleven of these responders were MRD-negative. Notably, the type of donor did not influence the achievement of CR 28 days post-infusion. At a median follow up of 21.6 months (range, 1.0-38.4 months), 10 patients (47.6%) are alive in CR (9 in the 2 highest dose levels). Overall, the median OS and EFS were 9.7 and 3.2 months, respectively, with a median DOR of 4.0 months (range, 1.0-23.5 months). Patients in CR at 28-days had a 6-months relapse-free survival of 48.4% (SE=14.9). EFS at 6 months was 26.5% (SE=9.9) and OS was 67.6% (SE=11.1). Among the 13 patients who achieved CR, two children underwent consolidation with a second allo-HSCT in complete remission. Adult patients did not receive any additional anti-leukemic therapies unless a relapse occurred, and four of them remained in remission and alive (+24, +9, +6, and +4 months). Robust CARCIK-CD19 cell expansion was achieved in most patients and CARCIK-CD19 cells were measurable for up to 22 months. Conclusions SB-engineered CAR T cells induce sustained responses in B-ALL patients relapsed after HSCT irrespective of the donor type and without severe toxicities. Disclosures Lussana: Incyte: Honoraria; Pfizer: Honoraria; Astellas Pharma: Honoraria; Amgen: Honoraria. Gritti: Takeda: Consultancy; Roche: Consultancy; Kite Gilead: Consultancy; IQvia: Consultancy; Italfarmaco: Consultancy; Clinigen: Consultancy. Biondi: Incyte: Consultancy, Other: Advisory Board; Bluebird: Other: Advisory Board; Novartis: Honoraria; Amgen: Honoraria; Colmmune: Honoraria.

The Evolution and Future of CAR T Cells for B‐Cell Acute Lymphoblastic Leukemia

2017 ◽  
Vol 103 (4) ◽  
pp. 591-598 ◽  
Author(s):  
Colleen E. Annesley ◽  
Corinne Summers ◽  
Francesco Ceppi ◽  
Rebecca A. Gardner
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Car T Cells ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia

Lineage Switch As a Relapse Mechanism of Pre-B Acute Lymphoblastic Leukemia Following CD19 CAR

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2524-2524 ◽  
Author(s):  
Elad Jacoby ◽  
Sang Minh Nguyen ◽  
Kathryn M Welp ◽  
Haiying Qin ◽  
Yinmeng Yang ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Late Relapse ◽  
Car T Cells ◽  
Lineage Switch ◽  
Car T ◽  
Cd19 Expression

Abstract Resistance or relapse following adoptive immunotherapy can occur as a result of antigen loss. T cells armed with chimeric antigen receptors (CARs) targeting CD19 have shown remission rates of over 70% in early clinical trials, although reports of relapse in the presence of persistent CAR T cells are emerging. To further investigate potential resistance mechanisms to CAR T cell therapy, we used 2 syngeneic murine pre-B acute lymphoblastic leukemia (ALL) cell models driven by E2a:PBX1 and Eu-RET. Transplantable cell lines generated from both models have high expression of CD19, CD22, B220, CD43 and CD127, with absence of surface immunoglobulins consistent with a pre-B cell phenotype and result in lethality within 21 days. Treatment with CD19 CAR T cells induced long-term remission with persistence of CAR T cells beyond 100 days. However, mice bearing E2a:PBX1-driven leukemia experienced relapses occurring in the majority of CAR treated animals within 1 year, all with loss of CD19 expression. Relatively early post-CAR relapses retained a pre-B phenotype with isolated loss of CD19 extracellular expression by flow cytometry, loss in CD19 exon 1 and 2 mRNA but intact mRNA for all other CD19 exons. In contrast, late post-CAR relapses demonstrated complete loss of CD19 protein and mRNA expression with concomitant loss of the major B cell transcription factors PAX5 and EBF1 suggesting loss of the B-cell developmental program. Furthermore, late post CD19 CAR relapses typically gained myeloid, stem cell or T cell phenotypic markers, consistent with a lineage switch, which was confirmed at the genomic level by RNA-seq of multiple late relapse samples. We could not identify cells in leukemia culture lacking pre-B phenotype either by single cell cloning following depletion of CD19+ cells indicating that cells with the late relapse phenotype do not exist as a rare population. Finally, we could also demonstrate intermediate phenotypes of post-CD19 CAR relapse in vivo with co-expression of both myeloid (Gr1, CD11b) and B cell markers (B220, CD22) on the same cells, suggesting a differentiation rather than a selection process. We next undertook serial in vivo passaging experiments, and confirmed leukemic-initiating potential of all CD19-loss relapses irrespective of relapse phenotype. Interestingly, leukemic relapse with CD19 expression loss that retain a B-cell program rapidly regain CD19 upon in vivo passage in the absence of CD19 CAR pressure. However, relapses due to lineage reprogramming retained a stable myeloid phenotype upon serial passage without regain of CD19 or other B cell markers. Knock-out of CD19 from leukemic cells using the CRISPR/CAS system did not alter proliferative capability or phenotype during prolonged (30 day) culture and did not diminish engraftment capacity and lethality in vivo, confirming that loss of CD19 alone is insufficient to drive lineage switch. Overall, we demonstrate a novel mechanism of resistance to immunotherapy via lineage switch and demonstrate reprograming potential of ALL under lineage-selective pressure. This observation was repeatedly seen in one murine model (E2a:PBX1) but not in another (Eu-RET), suggesting that the potential for this to occur may depend on the genetic subtype and at what stage the initiating mutation occurred. These results have important clinical implications for the development of antigen-targeting therapies for ALL and, potentially, other cancers. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document