CAR T-cell Therapy: Toxicity and The Relevance of Preclinical Models

Kalaitsidou, Milena; Kueberuwa, Gray; Schütt, Antje; Gilham, David E.

doi:10.2217/imt.14.123

Cited by 77 publications

(55 citation statements)

References 61 publications

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“…4,5,7-11,13-16, [35][36][37][38][39][40] Neurologic toxicities due to CAR T-cell therapy may occur concurrently with CRS or occur in the absence of CRS. 4,5,15 Hypothetically, the gene-therapy vector could be capable of autonomous viral replication or cause a secondary malignancy through insertional mutagenesis.…”

Section: -30mentioning

confidence: 99%

Toxicities of chimeric antigen receptor T cells: recognition and management

Brudno

Kochenderfer

2016

Blood

1,087

956

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Chimeric antigen receptor (CAR) T cells can produce durable remissions in hematologic malignancies that are not responsive to standard therapies. Yet the use of CAR T cells is limited by potentially severe toxicities. Early case reports of unexpected organ damage and deaths following CAR T-cell therapy first highlighted the possible dangers of this new treatment. CAR T cells can potentially damage normal tissues by specifically targeting a tumor-associated antigen that is also expressed on those tissues. Cytokine release syndrome (CRS), a systemic inflammatory response caused by cytokines released by infused CAR T cells can lead to widespread reversible organ dysfunction. CRS is the most common type of toxicity caused by CAR T cells. Neurologic toxicity due to CAR T cells might in some cases have a different pathophysiology than CRS and requires different management. Aggressive supportive care is necessary for all patients experiencing CAR T-cell toxicities, with early intervention for hypotension and treatment of concurrent infections being essential. Interleukin-6 receptor blockade with tocilizumab remains the mainstay pharmacologic therapy for CRS, though indications for administration vary among centers. Corticosteroids should be reserved for neurologic toxicities and CRS not responsive to tocilizumab. Pharmacologic management is complicated by the risk of immunosuppressive therapy abrogating the antimalignancy activity of the CAR T cells. This review describes the toxicities caused by CAR T cells and reviews the published approaches used to manage toxicities. We present guidelines for treating patients experiencing CRS and other adverse events following CAR T-cell therapy.

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Section: -30mentioning

confidence: 99%

Toxicities of chimeric antigen receptor T cells: recognition and management

Brudno

Kochenderfer

2016

Blood

1,087

956

View full text Add to dashboard Cite

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“…Adverse events such as severe CRS have been associated with the administration of CAR-T cells to patients with high tumor burden, which likely triggers massive antigen-specific CAR-T-cell expansion and activation (4,41). Therefore, we next asked whether the switch could be dose-titrated to achieve a gradual tumor clearance to avoid the acute toxicity.…”

Section: Effect Of Fitc Conjugation Site and Valency On Anti-fitc Carmentioning

confidence: 99%

“…Collectively, our results demonstrate that the activity of sCAR-T cells can be controlled by switch dosage to minimize treatment-related toxicities while retaining potent antitumor activity. This ability to control the temporal activation of the CAR-T-cell response may be helpful clinically to ameliorate adverse events associated with the administration of CAR-T cells to patients with high tumor burden, such as severe CRS (4,41).…”

Section: Effect Of Fitc Conjugation Site and Valency On Anti-fitc Carmentioning

confidence: 99%

Versatile strategy for controlling the specificity and activity of engineered T cells

Jennifer

Kim

Kazane

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

237

231

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The adoptive transfer of autologous T cells engineered to express a chimeric antigen receptor (CAR) has emerged as a promising cancer therapy. Despite impressive clinical efficacy, the general application of current CAR–T-cell therapy is limited by serious treatment-related toxicities. One approach to improve the safety of CAR-T cells involves making their activation and proliferation dependent upon adaptor molecules that mediate formation of the immunological synapse between the target cancer cell and T-cell. Here, we describe the design and synthesis of structurally defined semisynthetic adaptors we refer to as “switch” molecules, in which anti-CD19 and anti-CD22 antibody fragments are site-specifically modified with FITC using genetically encoded noncanonical amino acids. This approach allows the precise control over the geometry and stoichiometry of complex formation between CD19- or CD22-expressing cancer cells and a “universal” anti-FITC–directed CAR-T cell. Optimization of this CAR–switch combination results in potent, dose-dependent in vivo antitumor activity in xenograft models. The advantage of being able to titrate CAR–T-cell in vivo activity was further evidenced by reduced in vivo toxicity and the elimination of persistent B-cell aplasia in immune-competent mice. The ability to control CAR-T cell and cancer cell interactions using intermediate switch molecules may expand the scope of engineered T-cell therapy to solid tumors, as well as indications beyond cancer therapy.

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“…Moreover, a preclinical study showed that 3rd-G CAR-T cells combining CD28 and 4-1BB co-receptors had superior in vitro activation and proliferation capacity compared with 2nd-G CAR-T cells carrying CD28 signal domains, and both kinds of cells displayed in vivo comparable efficacy in eliminating CD19+ B cells 35. Another preclinical study demonstrated that in vivo persistence of 3rd-G CAR-T cells was inferior to that of 2nd-G ones 41. But there is a lack of clinical data of 3rd-G CAR-T cells in patients.…”

Section: Discussionmentioning

confidence: 99%

“…For one, engrafted human CAR-T cells may be challenged by residual elements of the immune system from immunocompromised mice. For another, it is difficult to assess CAR-T toxicity because human CD19 expression profile may not be equivalent to that of mouse 41. Therefore, the ability to predict and manage severe CRS in clinical trials is vital to protect patients' interests because early interventions could limit the efficacy of CAR-T immunotherapy while the late ones could increase morbidity and mortality of treated patients.…”

Section: Discussionmentioning

confidence: 99%

Third-generation CD28/4-1BB chimeric antigen receptor T cells for chemotherapy relapsed or refractory acute lymphoblastic leukaemia: a non-randomised, open-label phase I trial protocol

et al. 2016

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IntroductionThere is no curative treatment available for patients with chemotherapy relapsed or refractory CD19+ B cells-derived acute lymphoblastic leukaemia (r/r B-ALL). Although CD19-targeting second-generation (2nd-G) chimeric antigen receptor (CAR)-modified T cells carrying CD28 or 4-1BB domains have demonstrated potency in patients with advanced B-ALL, these 2 signalling domains endow CAR-T cells with different and complementary functional properties. Preclinical results have shown that third-generation (3rd-G) CAR-T cells combining 4-1BB and CD28 signalling domains have superior activation and proliferation capacity compared with 2nd-G CAR-T cells carrying CD28 domain. The aim of the current study is therefore to investigate the safety and efficacy of 3rd-G CAR-T cells in adults with r/r B-ALL.Methods and analysisThis study is a phase I clinical trial for patients with r/r B-ALL to test the safety and preliminary efficacy of 3rd-G CAR-T cells. Before receiving lymphodepleting conditioning regimen, the peripheral blood mononuclear cells from eligible patients will be leukapheresed, and the T cells will be purified, activated, transduced and expanded ex vivo. On day 6 in the protocol, a single dose of 1 million CAR-T cells per kg will be administrated intravenously. The phenotypes of infused CAR-T cells, copy number of CAR transgene and plasma cytokines will be assayed for 2 years after CAR-T infusion using flow cytometry, real-time quantitative PCR and cytometric bead array, respectively. Moreover, several predictive plasma cytokines including interferon-γ, interleukin (IL)-6, IL-8, Soluble Interleukin (sIL)-2R-α, solubleglycoprotein (sgp)130, sIL-6R, Monocyte chemoattractant protein (MCP1), Macrophage inflammatory protein (MIP1)-α, MIP1-β and Granulocyte-macrophage colony-stimulating factor (GM-CSF), which are highly associated with severe cytokine release syndrome (CRS), will be used to forecast CRS to allow doing earlier intervention, and CRS will be managed based on a revised CRS grading system. In addition, patients with grade 3 or 4 neurotoxicities or persistent B-cell aplasia will be treated with dexamethasone (10 mg intravenously every 6 hours) or IgG, respectively. Descriptive and analytical analyses will be performed.Ethics and disseminationEthical approval for the study was granted on 10 July 2014 (YLJS-2014-7-10). Written informed consent will be taken from all participants. The results of the study will be reported, through peer-reviewed journals, conference presentations and an internal organisational report.Trial registration numberNCT02186860.

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CAR T-cell Therapy: Toxicity and The Relevance of Preclinical Models

Cited by 77 publications

References 61 publications

Toxicities of chimeric antigen receptor T cells: recognition and management

Toxicities of chimeric antigen receptor T cells: recognition and management

Versatile strategy for controlling the specificity and activity of engineered T cells

Third-generation CD28/4-1BB chimeric antigen receptor T cells for chemotherapy relapsed or refractory acute lymphoblastic leukaemia: a non-randomised, open-label phase I trial protocol

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