Revving the CAR – Combination strategies to enhance CAR T cell effectiveness

Bansal, Rajat; Reshef, Ran

doi:10.1016/j.blre.2020.100695

Cited by 26 publications

(25 citation statements)

References 186 publications

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“…Moreover, combination therapies of CAR-T cells with various small molecules and monoclonal antibodies to circumvent tumor escape and increase anti-tumor activity are already clinically tested in many hematologic tumors (reviewed in detail in [171]). Such combinations also hold great promise for the treatment of solid tumors and need to be tested in clinical trials in the near future.…”

Section: Discussionmentioning

confidence: 99%

“…Several resistance mechanisms to CAR-T-cell therapy in solid tumors may play a role in the observed lower effectiveness compared to CAR-T cells in hematologic malignancies [171][172][173][174]. For example, the tumor microenvironment can be hostile for CAR-T cells (e.g., unfavorable pH or oxygen levels) or unfavorable electrolyte or cytokine concentrations, inhibiting an effective immune response [175][176][177].…”

Section: Extra Features Introduced Into Car-t Cellsmentioning

confidence: 99%

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The Landscape of CAR-T Cell Clinical Trials against Solid Tumors—A Comprehensive Overview

Schaft

2020

Cancers

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CAR-T cells showed great potential in the treatment of patients with hematologic tumors. However, the clinical efficacy of CAR-T cells against solid tumors lags behind. To obtain a comprehensive overview of the landscape of CAR-T cell clinical trials against this type of cancer, this review summarizes all the 196 studies registered at clinicaltrials.gov. Special focus is on: (1) geographical distribution; (2) targeted organs, tumor entities, and antigens; (3) CAR transfer methods, CAR formats, and extra features introduced into the T cells; and (4) patient pretreatments, injection sites, and safety measurements. Finally, the few data on clinical outcome are reported. The last assessment of clinicaltrials.gov for the data summarized in this paper was on 4 August 2020.

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Section: Discussionmentioning

confidence: 99%

Section: Extra Features Introduced Into Car-t Cellsmentioning

confidence: 99%

The Landscape of CAR-T Cell Clinical Trials against Solid Tumors—A Comprehensive Overview

Schaft

2020

Cancers

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“…Chimeric antigen receptor (CAR)-T cell therapy has rapidly emerged as a highly promising immunotherapy, having achieved remarkable results for the treatment of B cell malignancies. In this personalized therapy, autologous T cells are genetically engineered to produce an antigen receptor that specifically binds to surface markers of cancer cells, triggering an antitumor immune response [140]. CD19-directed CAR-T cells, including axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel, have demonstrated potent clinical efficacy, achieving durable responses and improving patient survival outcomes, which led to subsequent FDA approval for treatment of R/R B cell malignancies, including high-grade B cell lymphomas, DLBCL and transformed FL [141,142].…”

Section: Car-t Cell Therapymentioning

confidence: 99%

Immunomodulatory Drugs for the Treatment of B Cell Malignancies

Ioannou

Jain

Ramsay

2021

IJMS

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Accumulating evidence suggests that the tumor microenvironment (TME) is involved in disease progression and drug resistance in B cell malignancies, by supporting tumor growth and facilitating the ability of malignant cells to avoid immune recognition. Immunomodulatory drugs (IMiDs) such as lenalidomide have some direct anti-tumor activity, but critically also target various cellular compartments of the TME including T cells, NK cells, and stromal cells, which interfere with pro-tumor signaling while activating anti-tumor immune responses. Lenalidomide has delivered favorable clinical outcomes as a single-agent, and in combination therapy leads to durable responses in chronic lymphocytic leukemia (CLL) and several non-Hodgkin lymphomas (NHLs) including follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), and mantle cell lymphoma (MCL). Recently, avadomide, a next generation cereblon E3 ligase modulator (CELMoD), has shown potent anti-tumor and TME immunomodulatory effects, as well as promising clinical efficacy in DLBCL. This review describes how the pleiotropic effects of IMiDs and CELMoDs could make them excellent candidates for combination therapy in the immuno-oncology era—a concept supported by preclinical data, as well as the recent approval of lenalidomide in combination with rituximab for the treatment of relapsed/refractory (R/R) FL.

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“…The success of T cell based immunotherapy in solid tumors is limited to checkpoint blockade therapies, with adoptive cell therapy lagging behind [18,19]. Anticancer strategies targeting CTLA-4, PD-1, PD-L1 demonstrated clinical efficacy in many cancer types [20] leading to several FDA-approved antibodies for treating melanoma [21,22], lung carcinoma (mainly, non-squamous non-small-cell lung carcinoma, NSCLC) [23] and DNA-mismatch repair-deficient cancers [24,25].…”

Section: Immunotherapy For Solid Tumorsmentioning

confidence: 99%

Hematopoietic versus Solid Cancers and T Cell Dysfunction: Looking for Similarities and Distinctions

Montironi

Muñoz-Pinedo

Eldering

2021

Cancers

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Cancer cells escape, suppress and exploit the host immune system to sustain themselves, and the tumor microenvironment (TME) actively dampens T cell function by various mechanisms. Over the last years, new immunotherapeutic approaches, such as adoptive chimeric antigen receptor (CAR) T cell therapy and immune checkpoint inhibitors, have been successfully applied for refractory malignancies that could only be treated in a palliative manner previously. Engaging the anti-tumor activity of the immune system, including CAR T cell therapy to target the CD19 B cell antigen, proved to be effective in acute lymphocytic leukemia. In low-grade hematopoietic B cell malignancies, such as chronic lymphocytic leukemia, clinical outcomes have been tempered by cancer-induced T cell dysfunction characterized in part by a state of metabolic lethargy. In multiple myeloma, novel antigens such as BCMA and CD38 are being explored for CAR T cells. In solid cancers, T cell-based immunotherapies have been applied successfully to melanoma and lung cancers, whereas application in e.g., breast cancer lags behind and is modestly effective as yet. The main hurdles for CAR T cell immunotherapy in solid tumors are the lack of suitable antigens, anatomical inaccessibility, and T cell anergy due to immunosuppressive TME. Given the wide range of success and failure of immunotherapies in various cancer types, it is crucial to comprehend the underlying similarities and distinctions in T cell dysfunction. Hence, this review aims at comparing selected, distinct B cell-derived versus solid cancer types and at describing means by which malignant cells and TME might dampen T cell anti-tumor activity, with special focus on immunometabolism. Drawing a meaningful parallel between the efficacy of immunotherapy and the extent of T cell dysfunction will shed light on areas where we can improve immune function to battle cancer.

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Revving the CAR – Combination strategies to enhance CAR T cell effectiveness

Cited by 26 publications

References 186 publications

The Landscape of CAR-T Cell Clinical Trials against Solid Tumors—A Comprehensive Overview

The Landscape of CAR-T Cell Clinical Trials against Solid Tumors—A Comprehensive Overview

Immunomodulatory Drugs for the Treatment of B Cell Malignancies

Hematopoietic versus Solid Cancers and T Cell Dysfunction: Looking for Similarities and Distinctions

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