Combining CAR T cells and the Bcl-2 family apoptosis inhibitor ABT-737 for treating B-cell malignancy

Karlsson, Susann; Lindqvist, Anna-Karin; Fransson, Moa; Paul-Wetterberg, Gabriella; Nilsson, Berith; Essand, Magnus; Nilsson, Kenneth; Frisk, Per; Jernberg-Wiklund, Helena; Loskog, S I A

doi:10.1038/cgt.2013.35

Cited by 51 publications

(48 citation statements)

References 25 publications

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“…Clinical safety data from the performed trial showed that ABT-199 had modest impact on myelosuppression, except for grade 3–4 neutropenia in 41% of patients [42]. ABT-199 is an agent currently being investigated for the treatment of AML [27], and it would be interesting to use targeted therapy sequentially with CAR T-cells, in order to exert a synergistic effect on resistant leukemia clones [43]. We also added, at a similar concentration, the pan-BCL inhibitor ABT-737 which resulted in a potent lymphotoxic effect as well [29].…”

Section: Discussionmentioning

confidence: 99%

In Vitro Pre-Clinical Validation of Suicide Gene Modified Anti-CD33 Redirected Chimeric Antigen Receptor T-Cells for Acute Myeloid Leukemia

Minagawa¹,

Jamil²,

Al‐Obaidi³

et al. 2016

PLoS ONE

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BackgroundApproximately fifty percent of patients with acute myeloid leukemia can be cured with current therapeutic strategies which include, standard dose chemotherapy for patients at standard risk of relapse as assessed by cytogenetic and molecular analysis, or high-dose chemotherapy with allogeneic hematopoietic stem cell transplant for high-risk patients. Despite allogeneic hematopoietic stem cell transplant about 25% of patients still succumb to disease relapse, therefore, novel strategies are needed to improve the outcome of patients with acute myeloid leukemia.Methods and findingsWe developed an immunotherapeutic strategy targeting the CD33 myeloid antigen, expressed in ~ 85–90% of patients with acute myeloid leukemia, using chimeric antigen receptor redirected T-cells. Considering that administration of CAR T-cells has been associated with cytokine release syndrome and other potential off-tumor effects in patients, safety measures were here investigated and reported. We genetically modified human activated T-cells from healthy donors or patients with acute myeloid leukemia with retroviral supernatant encoding the inducible Caspase9 suicide gene, a ΔCD19 selectable marker, and a humanized third generation chimeric antigen receptor recognizing human CD33. ΔCD19 selected inducible Caspase9-CAR.CD33 T-cells had a 75±3.8% (average ± standard error of the mean) chimeric antigen receptor expression, were able to specifically lyse CD33+ targets in vitro, including freshly isolated leukemic blasts from patients, produce significant amount of tumor-necrosis-factor-alpha and interferon-gamma, express the CD107a degranulation marker, and proliferate upon antigen specific stimulation. Challenging ΔCD19 selected inducible Caspase9-CAR.CD33 T-cells with programmed-death-ligand-1 enriched leukemia blasts resulted in significant killing like observed for the programmed-death-ligand-1 negative leukemic blasts fraction. Since the administration of 10 nanomolar of a non-therapeutic dimerizer to activate the suicide gene resulted in the elimination of only 76.4±2.0% gene modified cells in vitro, we found that co-administration of the dimerizer with either the BCL-2 inhibitor ABT-199, the pan-BCL inhibitor ABT-737, or mafosfamide, resulted in an additive effect up to complete cell elimination.ConclusionsThis strategy could be investigated for the safety of CAR T-cell applications, and targeting CD33 could be used as a ‘bridge” therapy for patients coming to allogeneic hematopoietic stem cell transplant, as anti-leukemia activity from infusing CAR.CD33 T-cells has been demonstrated in an ongoing clinical trial. Albeit never performed in the clinical setting, our future plan is to investigate the utility of iC9-CAR.CD33 T-cells as part of the conditioning therapy for an allogeneic hematopoietic stem cell transplant for acute myeloid leukemia, together with other myelosuppressive agents, whilst the activation of the inducible Caspase9 suicide gene would grant elimination of the infused gene modified T-cells prior to stem cell inf...

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Section: Discussionmentioning

confidence: 99%

In Vitro Pre-Clinical Validation of Suicide Gene Modified Anti-CD33 Redirected Chimeric Antigen Receptor T-Cells for Acute Myeloid Leukemia

Minagawa¹,

Jamil²,

Al‐Obaidi³

et al. 2016

PLoS ONE

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“…CAR T-cell therapy was efficient in all lines tested, whereas ABT-737 only had a direct effect in some of them. However, when combined, the apoptosis level was greatly enhanced demonstrating that ABT-737 could sensitize the apoptosis machinery to extrinsic signalling from T-cells [62]. It should, however, be noted that resting T-cells are type I cells [30] and could be sensitive to ABT-737 themselves.…”

Section: Adjuvants For Car T-cell Therapymentioning

confidence: 96%

“…We therefore also investigated ABT-737 as a pre-sensitizer to CAR T-cell therapy. Although the strongest effect was seen with concomitant addition of ABT-737 and CAR T-cells, the effect of combination treatment was still enhanced when tumour cells were pre-sensitized with ABT-737 prior to addition of CAR T-cells [62]. Another approach of apoptosis inhibitor blockade is the use of IAP inhibitors.…”

Section: Adjuvants For Car T-cell Therapymentioning

confidence: 97%

Approaches to augment CAR T-cell therapy by targeting the apoptotic machinery

Karlsson

2016

Biochemical Society Transactions

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Chimaeric antigen receptor (CAR) T-cells have shown impressive results in patients with B-cell leukaemia. Yet, in patients with lymphoma durable responses are still rare and heavy preconditioning required. Apoptosis resistance is considered a hallmark of cancer, often conveyed by a halted apoptosis signalling. Tumours regularly skew the balance of the components of the apoptotic machinery either through up-regulating anti-apoptotic proteins or silencing pro-apoptotic ones. Malignant B-cells frequently up-regulate anti-apoptotic B-cell lymphoma 2 (Bcl-2) family proteins leading to therapy resistance. CAR T-cells kill tumour cells via apoptosis induction and their efficacy may be affected by the level of Bcl-2 family proteins. Hence, there is an interesting possibility to increase the effect of CAR T-cell therapy by combining it with apoptosis inhibitor blockade agents. Compounds that inhibit Bcl-2, B-cell lymphoma extra large (Bcl-xL) and Bcl-2-like protein 2 (Bcl-w), can restore execution of apoptosis in tumour cells or sensitize them to other apoptosis-dependent treatments. Hence, there is a great interest to combine such agents with CAR T-cell therapy to potentiate the effect of CAR T-cell killing. This review will focus on the potential of targeting the apoptotic machinery to sensitize tumour cells to CAR T-cell killing.

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“…Finally, incorporating chemokine or cytokine expression into the CAR-T-cell construct might improve delivery and trafficking of the cells to the tumour 42,43,82,83 . Combination treatment with small-molecule inhibitors, such as ibrutinib or lenalidomide, or with immune-checkpoint inhibitors can be explored to improve CAR-T-cell activation or suppress the endogenous T-cell-inhibitory microenvironment, which might enhance treatment efficacy 84–86 .…”

Section: Engineered Car T Cellsmentioning

confidence: 99%

Novel immunotherapies in lymphoid malignancies

et al. 2015

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The success of the anti-CD20 monoclonal antibody rituximab in the treatment of lymphoid malignancies provided proof-of-principle for exploiting the immune system therapeutically. Since the FDA approval of rituximab in 1997, several novel strategies that harness the ability of T cells to target cancer cells have emerged. Reflecting on the promising clinical efficacy of these novel immunotherapy approaches, the FDA has recently granted ‘breakthrough’ designation to three novel treatments with distinct mechanisms. First, chimeric antigen receptor (CAR)-T-cell therapy is promising for the treatment of adult and paediatric relapsed and/or refractory acute lymphoblastic leukaemia (ALL). Second, blinatumomab, a bispecific T-cell engager (BiTE®) antibody, is now approved for the treatment of adults with Philadelphia-chromosome-negative relapsed and/or refractory B-precursor ALL. Finally, the monoclonal antibody nivolumab, which targets the PD-1 immune-checkpoint receptor with high affinity, is used for the treatment of Hodgkin lymphoma following treatment failure with autologous-stem-cell transplantation and brentuximab vedotin. Herein, we review the background and development of these three distinct immunotherapy platforms, address the scientific advances in understanding the mechanism of action of each therapy, and assess the current clinical knowledge of their efficacy and safety. We also discuss future strategies to improve these immunotherapies through enhanced engineering, biomarker selection, and mechanism-based combination regimens.

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Combining CAR T cells and the Bcl-2 family apoptosis inhibitor ABT-737 for treating B-cell malignancy

Cited by 51 publications

References 25 publications

In Vitro Pre-Clinical Validation of Suicide Gene Modified Anti-CD33 Redirected Chimeric Antigen Receptor T-Cells for Acute Myeloid Leukemia

In Vitro Pre-Clinical Validation of Suicide Gene Modified Anti-CD33 Redirected Chimeric Antigen Receptor T-Cells for Acute Myeloid Leukemia

Approaches to augment CAR T-cell therapy by targeting the apoptotic machinery

Novel immunotherapies in lymphoid malignancies

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