Abstract CT036: A phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CAR T cells: Safety and efficacy

Adusumilli, Prasad S.; Zauderer, Marjorie G.; Rusch, Valerie W.; O’Cearbhaill, Roisin E.; Zhu, Amy; Ngai, Daniel; McGee, Erin; Chintala, Navin K.; Messinger, John C.; Vincent, A.; Halton, Elizabeth; Diamonte, Claudia; Pineda, J. Sebastian; Modi, Shanu; Solomon, Stephen B.; Jones, David R.; Brentjens, Renier J.; Rivière, Isabelle; Sadelain, Michel

doi:10.1158/1538-7445.sabcs18-ct036

Cited by 18 publications

(18 citation statements)

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“…Immune checkpoint inhibitors may improve the efficacy of ATC by releasing constitutive inhibition on T-cell function through depletion of subpopulations of immunosuppressive cells within the tumor microenvironment via F c -mediated antibody-dependent cellular cytotoxicity (ADCC) mechanisms (17). Several recent clinical trials have demonstrated the safety and efficacy of combining ATC with CTLA-4 and PD-1/PDL1 targeting strategies: for example, using anti-PD-1 as an immune booster after intrapleural CAR T-cell administration in patients with mesothelin-positive malignant pleural disease (18), novel thirdgeneration CAR T-cells with the capability for expressing and secreting CTLA-4 and PD-1 antibodies into the tumor microenvironment (19), and CRISPR/Cas9 PD-1 knockout CAR T-cells (20). Many of these ATC methods utilize prior lymphodepletion to reset the regulatory components of the immune system and promote the engraftment and long-term persistence of transferred T-cells.…”

Section: Introductionmentioning

confidence: 99%

Intravital Imaging of Adoptive T-Cell Morphology, Mobility and Trafficking Following Immune Checkpoint Inhibition in a Mouse Melanoma Model

et al. 2020

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Section: Introductionmentioning

confidence: 99%

Intravital Imaging of Adoptive T-Cell Morphology, Mobility and Trafficking Following Immune Checkpoint Inhibition in a Mouse Melanoma Model

et al. 2020

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“…Preliminary results (AACR 2019, ASCO 2019): positive results on safety, 2/19 patients with CR, 5/19 with PR, 4/19 with SD (Ref. 36 , 37 ). NCT04577326 I anti-MSLN CAR T cells with intrinsic anti-PD1 inhibition (M28z1XXPD1DNR) cyclophosphamide MPM Intrapleural Memorial Sloan Kettering Cancer Center, USA Sep-22 anti-MSLN scFv linked to the CD28 and CD3ζ signaling domains plus PD-1 DNR and 1XX ITAM modification Recruiting.…”

Section: Clinical Trials Using Anti-mesothelin Car T Cell Therapy Inmentioning

confidence: 99%

Anti-Mesothelin CAR T cell therapy for malignant mesothelioma

et al. 2021

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Malignant mesothelioma (MM) is a treatment-resistant tumor originating in the mesothelial lining of the pleura or the abdominal cavity with very limited treatment options. More effective therapeutic approaches are urgently needed to improve the poor prognosis of MM patients. Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a novel potential treatment for this incurable solid tumor. The tumor-associated antigen mesothelin (MSLN) is an attractive target for cell therapy in MM, as this antigen is expressed at high levels in the diseased pleura or peritoneum in the majority of MM patients and not (or very modestly) present in healthy tissues. Clinical trials using anti-MSLN CAR T cells in MM have shown that this potential therapeutic is relatively safe. However, efficacy remains modest, likely due to the MM tumor microenvironment (TME), which creates strong immunosuppressive conditions and thus reduces anti-MSLN CAR T cell tumor infiltration, efficacy and persistence. Various approaches to overcome these challenges are reviewed here. They include local (intratumoral) delivery of anti-MSLN CAR T cells, improved CAR design and co-stimulation, and measures to avoid T cell exhaustion. Combination therapies with checkpoint inhibitors as well as oncolytic viruses are also discussed. Preclinical studies have confirmed that increased efficacy of anti-MSLN CAR T cells is within reach and offer hope that this form of cellular immunotherapy may soon improve the prognosis of MM patients.

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“…The requirement for neoantigens is bypassed by directing the CAR T-cell receptor to a tumor-associated antigen, such as mesothelin. The fibrous stroma can be circumvented by locoregional administration (100, 101), or designing CAR T-cells to target antigens that are expressed by both the tumor and cancer-associated stroma such as Fibroblast Activation Protein (102), or by adding chemokine receptors such as CCR2 to enhance trafficking to tumor (103). T-cell metabolism can be manipulated by the choice of costimulatory molecules, such as 4-1BB (104, 105).…”

Section: Immune Cell Infiltratementioning

confidence: 99%

“…T-cell metabolism can be manipulated by the choice of costimulatory molecules, such as 4-1BB (104, 105). Exhaustion can also be ameliorated by the concomitant use of PD-1 inhibitors (100, 101), or designing CAR T-cells with dominant negative PD-1 receptors to prevent signaling via native PD-1 (100). Switch receptors have also been designed for mesothelin CAR T-cells with extracellular PD-1 linked to intracellular CD28 (106).…”

Section: Immune Cell Infiltratementioning

confidence: 99%

The Immune Microenvironment in Mesothelioma: Mechanisms of Resistance to Immunotherapy

2019

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Although mesothelioma is the consequence of a protracted immune response to asbestos fibers and characterized by a clear immune infiltrate, novel immunotherapy approaches show less convincing results as compared to those seen in melanoma and non-small cell lung cancer. The immune suppressive microenvironment in mesothelioma is likely contributing to this therapy resistance. Therefore, it is important to explore the characteristics of the tumor microenvironment for explanations for this recalcitrant behavior. This review describes the stromal, cytokine, metabolic, and cellular milieu of mesothelioma, and attempts to make connection with the outcome of immunotherapy trials.

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Abstract CT036: A phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CAR T cells: Safety and efficacy

Cited by 18 publications

References 0 publications

Intravital Imaging of Adoptive T-Cell Morphology, Mobility and Trafficking Following Immune Checkpoint Inhibition in a Mouse Melanoma Model

Intravital Imaging of Adoptive T-Cell Morphology, Mobility and Trafficking Following Immune Checkpoint Inhibition in a Mouse Melanoma Model

Anti-Mesothelin CAR T cell therapy for malignant mesothelioma

The Immune Microenvironment in Mesothelioma: Mechanisms of Resistance to Immunotherapy

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