CAR T-cell therapy is effective for CD19-dim B-lymphoblastic leukemia but is impacted by prior blinatumomab therapy

Pillai, Vinodh; Muralidharan, Kavitha; Meng, Wenzhao; Bagashev, Asen; Oldridge, Derek A.; Rosenthal, Jaclyn; Arnam, John Van; Melenhorst, J. Joseph; Mohan, Diwakar; DiNofia, Amanda M.; Luo, Minjie; Cherian, Sindhu; Fromm, Jonathan R.; Wertheim, Gerald; Thomas-Tikhonenko, Andrei; Paessler, Michele; June, Carl H.; Prak, Eline T. Luning; Bhoj, Vijay; Grupp, Stephan A.; Maude, Shannon L.; Rheingold, Susan R.

doi:10.1182/bloodadvances.2019000692

Cited by 163 publications

(128 citation statements)

References 39 publications

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“…The loss of CD19 is a major problem in relapsed patients with persisting CAR-T cells, or patients with prior CD19-directed therapy ( 26 ). Current models of using two (or more) CARs transduced on a single cell (by various methods) ( 27 ) show some success in preclinical models, but clinical results have not yet matured.…”

Section: Discussionmentioning

confidence: 99%

Gamma-Delta CAR-T Cells Show CAR-Directed and Independent Activity Against Leukemia

et al. 2020

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Autologous T cells engineered to express a chimeric antigen receptor (CAR) against the CD19 antigen are in the frontline of contemporary hemato-oncology therapies, leading to high remission rates in B-cell malignancies. Although effective, major obstacles involve the complex and costly individualized manufacturing process, and CD19 target antigen loss or modulation leading to resistant and relapse following CAR therapy. A potential solution for these limitations is the use of donor-derived γδT cells as a CAR backbone. γδT cells lack allogenecity and are safely used in haploidentical transplants. Moreover, γδT cells are known to mediate natural anti-tumor responses. Here, we describe a 14-day production process initiated from peripheral-blood mononuclear cells, leading to a median 185-fold expansion of γδ T cells with high purity (>98% CD3+ and >99% γδTCR+). CAR transduction efficacy of γδ T cells was equally high when compared to standard CART cells (60.5 ± 13.2 and 65.3 ± 18.3%, respectively). CD19-directed γδCAR-T cells were effective against CD19+ cell lines in vitro and in vivo, showing cytokine production, direct target killing, and clearance of bone marrow leukemic cells in an NSG model. Multiple injections of γδCAR-T cells and priming of mice with zoledronate lead to enhanced tumor reduction in vivo. Unlike standard CD19 CART cells, γδCAR-T cells were able to target CD19 antigen negative leukemia cells, an effect that was enhanced after priming the cells with zoledronate. In conclusion, γδCAR-T cell production is feasible and leads to highly pure and efficient effector cells. γδCAR-T cell may provide a promising platform in the allogeneic setting, and may target leukemic cells also after antigen loss.

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Section: Discussionmentioning

confidence: 99%

Gamma-Delta CAR-T Cells Show CAR-Directed and Independent Activity Against Leukemia

et al. 2020

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“…Emergence of or selection for tumor cells that do not express the target antigen, a concept called "antigen loss, " can also negatively impact CAR T and CAR NK cell antitumor activity. For example, relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) patients who were previously administered blinatumomab, a bispecific antibody that targets CD3 on T cells and CD19 on B cells, were less likely to achieve minimal residual disease deep remission and were more likely to experience relapse due to antigen loss after treatment with anti-CD19 CAR T cells (125). Use of dual CAR concepts to target two tumor-associated antigens can lead to improved tumor control.…”

Section: Discussion/outlookmentioning

confidence: 99%

Use of Cell and Genome Modification Technologies to Generate Improved “Off-the-Shelf” CAR T and CAR NK Cells

et al. 2020

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The broad success of adoptive immunotherapy to treat human cancer has resulted in a paradigm shift in modern medicine. Modification of autologous and allogenic immune cells with chimeric antigen receptors (CAR) designed to target specific antigens on tumor cells has led to production of CAR T and CAR NK cell therapies, which are ever more commonly introduced into cancer patient treatment protocols. While allogenic T cells may offer advantages such as improved anti-tumor activity, they also carry the risk of adverse reactions like graft-versus-host disease. This risk can be mitigated by use of autologous immune cells, however, the time needed for T and/or NK cell isolation, modification and expansion may be too long for some patients. Thus, there is an urgent need for strategies to robustly produce "off-the-shelf" CAR T and CAR NK cells, which could be used as a bridging therapy between cancer diagnosis or relapse and allogeneic transplantation. Advances in genome modification technologies have accelerated the generation of designer cell therapy products, including development of "off-the-shelf" CAR T cells for cancer immunotherapy. The feasibility and safety of such approaches is currently tested in clinical trials. This review will describe cell sources for CAR-based therapies, provide background of current genome editing techniques and the applicability of these approaches for generation of universal "off-the-shelf" CAR T and NK cell therapeutics.

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“…In the setting of B-ALL, a recent expert opinion from the EBMT and the ASTCT (278) has addressed the possible drawbacks of new treatment options, such as blinatumomab and inotuzumab ozogamicin, and their place in the context of novel cellular therapies. For instance, blinatumomab, which represents an important option for relapsed and MRD positive patients, should be avoided as a bridging therapy before CAR T-cell infusion to minimize the risk of antigen loss (278,279) , although some conflicting data on this issue have been reported (31). The role of allogeneic HSCT after CAR T-cell therapy is being actively debated as well, since some patients (i.e., those with prolonged CAR T-cell persistence and confirmed MRD negative remission) might not need it.…”

Section: Discussionmentioning

confidence: 99%

The Advent of CAR T-Cell Therapy for Lymphoproliferative Neoplasms: Integrating Research Into Clinical Practice

et al. 2020

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Research on CAR T cells has achieved enormous progress in recent years. After the impressive results obtained in relapsed and refractory B-cell acute lymphoblastic leukemia and aggressive B-cell lymphomas, two constructs, tisagenlecleucel and axicabtagene ciloleucel, were approved by FDA. The role of CAR T cells in the treatment of B-cell disorders, however, is rapidly evolving. Ongoing clinical trials aim at comparing CAR T cells with standard treatment options and at evaluating their efficacy earlier in the disease course. The use of CAR T cells is still limited by the risk of relevant toxicities, most commonly cytokine release syndrome and neurotoxicity, whose management has nonetheless significantly improved. Some patients do not respond or relapse after treatment, either because of poor CAR T-cell expansion, lack of anti-tumor effects or after the loss of the target antigen on tumor cells. Investigators are trying to overcome these hurdles in many ways: by testing constructs which target different and/or multiple antigens or by improving CAR T-cell structure with additional functions and synergistic molecules. Alternative cell sources including allogeneic products (off-the-shelf CAR T cells), NK cells, and T cells obtained from induced pluripotent stem cells are also considered. Several trials are exploring the curative potential of CAR T cells in other malignancies, and recent data on multiple myeloma and chronic lymphocytic leukemia are encouraging. Given the likely expansion of CAR T-cell indications and their wider availability over time, more and more highly specialized clinical centers, with dedicated clinical units, will be required. Overall, the costs of these cell therapies will also play a role in the sustainability of many health care systems. This review will focus on the major clinical trials of CAR T cells in B-cell malignancies, including those leading to the first Cerrano et al. CART Research and Clinical Practice FDA approvals, and on the new settings in which these constructs are being tested. Besides, the most promising approaches to improve CAR T-cell efficacy and early data on alternative cell sources will be reviewed. Finally, we will discuss the challenges and the opportunities that are emerging with the advent of CAR T cells into clinical routine.

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CAR T-cell therapy is effective for CD19-dim B-lymphoblastic leukemia but is impacted by prior blinatumomab therapy

Abstract: Key Points Preinfusion dim CD19 expression and rare CD19– events in B-ALL do not affect relapses or responses to CD19-directed CAR T-cells. Prior blinatumomab treatment increases the rate of failure to achieve MRD– remission and CD19– MRD and relapse.

Cited by 163 publications

References 39 publications

Gamma-Delta CAR-T Cells Show CAR-Directed and Independent Activity Against Leukemia

Gamma-Delta CAR-T Cells Show CAR-Directed and Independent Activity Against Leukemia

Use of Cell and Genome Modification Technologies to Generate Improved “Off-the-Shelf” CAR T and CAR NK Cells

The Advent of CAR T-Cell Therapy for Lymphoproliferative Neoplasms: Integrating Research Into Clinical Practice

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