Multi Targeted CAR-T Cell Therapies for B-Cell Malignancies

Shah, Nirav N.; Maatman, Theresa; Hari, Parameswaran; Johnson, Bryon D.

doi:10.3389/fonc.2019.00146

Cited by 142 publications

(123 citation statements)

References 45 publications

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“…The resistant mechanisms of CAR T cell therapy have been extensively reviewed elsewhere (Cheng et al, 2019). For the CAR T cell-treated relapsed B-cell lymphoma patients, tumors can escape the recognition of CAR T cells by losing the very antigens targeted by CAR T cells (Shalabi et al, 2018;Shah et al, 2019). We summarize the current approved immunotherapeutic agents for treating B-cell lymphomas (Table 1), including monoclonal antibodies, antibody-drug conjugates (e.g., Brentuximab vedotin and polatuzumab vedotin-piiq (Polivy)) (Chau et al, 2019), immune checkpoint inhibitors and CAR T cells (Shah et al, 2019).…”

Section: Cellmentioning

confidence: 99%

HDAC inhibitors overcome immunotherapy resistance in B-cell lymphoma

et al. 2020

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Immunotherapy has been applied successfully to treat B-cell lymphomas in preclinical models or clinical settings. However, immunotherapy resistance is a major challenge for B-cell lymphoma treatment. To overcome this issue, combinatorial therapeutic strategies have been pursued to achieve a better efficacy for treating B-cell lymphomas. One of such strategies is to combine immunotherapy with histone deacetylase (HDAC) inhibitors. HDAC inhibitors can potentially increase tumor immunogenicity, promote anti-tumor immune responses, or reverse immunosuppressive tumor environments. Thus, the combination of HDAC inhibitors and immunotherapy has drawn much attention in current cancer treatment. However, not all HDAC inhibitors are created equal and their net effects are highly dependent on the specific inhibitors used and the HDACs they target. Hence, we suggest that optimal treatment efficacy requires personalized design and rational combination based on prognostic biomarkers and unique profiles of HDAC inhibitors. Here, we discuss the possible mechanisms by which B-cell lymphomas acquire immunotherapy resistance and the effects of HDAC inhibitors on tumor cells and immune cells that could help overcome immunotherapy resistance.

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Section: Cellmentioning

confidence: 99%

HDAC inhibitors overcome immunotherapy resistance in B-cell lymphoma

et al. 2020

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“…Although LDH release significantly increased with Tg treatment, treatment with nelfinavir or lopinavir did not show significant increase, apparently due to the initial high lysis compared to the untreated cells owing to the potency of the CAR-T cells. It should be noted that while CAR-T is highly efficient for the treatment of B cell malignancies [48,49], resistance in solid tumor therapy has been documented [50]. The addition of drugs that will minimize the resistance is highly pursued.…”

Section: Discussionmentioning

confidence: 99%

The integrated stress response promotes B7H6 expression

et al. 2019

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The B7 family member, B7H6, is a ligand for the natural killer cell receptor NKp30. B7H6 is hardly expressed on normal tissues, but undergoes upregulation on different types of tumors, implicating it as an attractive target for cancer immunotherapy. The molecular mechanisms that control B7H6 expression are poorly understood. We report that in contrast to other NK cell ligands, endoplasmic reticulum (ER) stress upregulates B7H6 mRNA levels and surface expression. B7H6 induction by ER stress requires protein kinase R-like ER kinase (PERK), one of the three canonical sensors of the unfolded protein response. PERK phosphorylates eIF2α, which regulates protein synthesis and gene expression. Because eIF2α is phosphorylated by several kinases following different stress conditions, the program downstream to eIF2α phosphorylation is called the integrated stress response (ISR). Several drugs were reported to promote the ISR. Nelfinavir and lopinavir, two clinically approved HIV protease inhibitors, promote eIF2α phosphorylation by different mechanisms. We show that nelfinavir and lopinavir sustainably instigate B7H6 expression at their pharmacologically relevant concentrations. As such, ER stress and ISR conditions sensitize melanoma targets to CART cells directed against B7H6. Our study highlights a novel mechanism to induce B7H6 expression and suggests a pharmacological approach to improve B7H6-directed immunotherapy.

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“…Fry et al were the first to establish that r/r B-ALL patients experiencing an antigen-negative relapse after CD19-targeted CAR-T-cell therapy can be rescued by using CAR-T cells targeting an alternative antigen: CD22 [65]. This has fueled the development of dual antigen-targeted approaches to overcome antigen escape [66]. Several early-phase CAR-T-cell clinical trials investigating the combined targeting of CD19 and another antigen, such as CD22 and CD20, have now been initiated in patients with CD19 + B-cell malignancies [67,68].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data

Roex

Feys²,

Béguin

et al. 2020

Pharmaceutics

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Chimeric antigen receptor (CAR)-T-cell therapy is an innovative form of adoptive cell therapy that has revolutionized the treatment of certain hematological malignancies, including B-cell non-Hodgkin lymphoma (NHL) and B-cell acute lymphoblastic leukemia (ALL). The treatment is currently also being studied in other B-cell neoplasms, including multiple myeloma (MM) and chronic lymphocytic leukemia (CLL). CD19 and B-cell maturation antigen (BCMA) have been the most popular target antigens for CAR-T-cell immunotherapy of these malignancies. This review will discuss the efficacy and toxicity data from the pivotal clinical studies of CD19- and BCMA-targeted CAR-T-cell therapies in relapsed/refractory B-cell malignancies (NHL, ALL, CLL) and MM, respectively.

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Multi Targeted CAR-T Cell Therapies for B-Cell Malignancies

Cited by 142 publications

References 45 publications

HDAC inhibitors overcome immunotherapy resistance in B-cell lymphoma

HDAC inhibitors overcome immunotherapy resistance in B-cell lymphoma

The integrated stress response promotes B7H6 expression

Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data

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