A Regional Approach for CAR T-Cell Therapy for Mesothelioma: From Mouse Models to Clinical Trial

Mayor, Marissa; Zeltsman, Masha; McGee, Erin; Adusumilli, Prasad S.

doi:10.2217/imt-2016-0008

Cited by 19 publications

(16 citation statements)

References 26 publications

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“…These products are Major Histocompatibility Complex (MHC)-independent, meaning they can be utilised in diverse populations. Anti-mesothelin and anti-fibroblast activation protein (FAP; which is expressed ubiquitously in the MPM tumour microenvironment) CAR T-lymphocytes have both been shown to induce regression in MPM xenograft tumour models and can be delivered locally, to the pleura, using an indwelling pleural catheter [78,79]. Several Phase I studies testing the safety of these approaches are currently underway.…”

Section: Immunotherapymentioning

confidence: 99%

Progress and challenges in Mesothelioma: From bench to bedside

Blyth

Murphy

2018

Respiratory Medicine

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Malignant Pleural Mesothelioma (MPM) is currently an incurable cancer with a typical survival of 1 year from the time of diagnosis. The recent genomic and transcriptomic characterization of MPM presents new opportunities and challenges for MPM researchers. Recent advances in clinical and laboratory diagnostics, and proposals for an updated, data-driven, staging system, also present new challenges for clinicians and hospital services involved in MPM care. The aim of this review is first to introduce the reader to the topic of MPM, a disease that is causally linked to prior, typically occupational, exposure to asbestos fibres. Secondly, we will discuss MPM from the clinical and laboratory perspectives, including reviews of current and evolving therapies and our present understanding of the molecular basis of the disease. Finally, we will attempt to identify critical knowledge gaps that currently prevent more effective treatment, including the challenges involved in early detection and chemoprophylaxis.

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Section: Immunotherapymentioning

confidence: 99%

Progress and challenges in Mesothelioma: From bench to bedside

Blyth

Murphy

2018

Respiratory Medicine

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“…Colon cancer (Sheen et al, 2003) Mesothelin surfaceglycoprotein Malignant pleural mesothelioma (Mayor et al, 2016), Ovarian cancer (O'Hara et al, 2016), pancreatic adenocarcinoma (Beatty et al, 2014), breast cancer (Tchou et al,…”

Section: Cd30mentioning

confidence: 99%

Genetically engineered CAR T-immune cells for cancer therapy: recent clinical developments, challenges, and future directions

El‐Daly¹,

Hussein²

2019

J Appl Biomed

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Cancer immunotherapy offers tremendous clinical outcomes in cancer management with the potential to induce sustained remission in patients with refractory disease. One of these immunotherapy modalities is the adoptive transfer of autologous T-cells that are genetically engineered ex vivo to express chimeric antigen receptors (CARs). These receptors can direct T-cells to the surface antigens of tumor cells to initiate an efficient and specific cytotoxic response against tumor cells. This review elucidates the structural features of CAR T-cells and their different generations reaching the recent 4th generation (TRUCK). The step-wise treatment process using CAR T-cell therapy and some of the updated prominent clinical applications of this treatment modality in both hematologic and solid malignancies are also covered in the present review. The success of CAR T-cell therapy is still encountered by several limitations for a widespread clinical application of this treatment modality, these challenges along with the recent innovative strategies that have been developed to overcome such drawbacks, as well as, the approaches and future directions aiming for a commercial low cost CAR T-cell immunotherapy modality, are all covered in the present review.

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“…Here, we demonstrate preclinical proof of concept for the utility of a related approach to treat mesothelioma. Mesothelioma is highly suited to intra-cavitary delivery since tumors are directly accessible using a pleural or peritoneal catheter [12,16,40].…”

Section: Repeated Administration Of Patient-derived Erbb Re-targeted mentioning

confidence: 99%

“…Preclinical data have provided strong support for this approach using CAR T-cells retargeted against mesothelin [12,13] and fibroblast activation protein [14,15]. Clinical trials employing both intra-pleural [16,17] and systemic delivery [18] are ongoing.…”

Section: Introductionmentioning

confidence: 99%

Intracavitary ‘T4 immunotherapy’ of malignant mesothelioma using pan-ErbB re-targeted CAR T-cells

et al. 2017

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Malignant mesothelioma remains an incurable cancer. We demonstrated that mesotheliomas expressed EGFR (79.2%), ErbB4 (49.0%) and HER2 (6.3%), but lacked ErbB3. At least one ErbB family member was expressed in 88% of tumors. To exploit ErbB dysregulation in this disease, patient T-cells were engineered by retroviral transduction to express a panErbB-targeted chimeric antigen receptor (CAR), co-expressed with a chimeric cytokine receptor that allows interleukin (IL)-4 mediated CAR T-cell proliferation. This combination is referred to as T4 immunotherapy. T-cells from mesothelioma patients were uniformly amenable to T4 genetic modification and expansion/enrichment thereafter using IL-4. Patient-derived T4 T-cells were activated upon contact with a panel of four mesothelioma cell lines, leading to cytotoxicity and cytokine release in all cases. Adoptive transfer of T4 immunotherapy to SCID Beige mice with an established bioluminescent LO68 mesothelioma xenograft was followed by regression or eradication of disease in all animals. Despite the established ability of T4 immunotherapy to elicit cytokine release syndrome in SCID Beige mice, therapy was very well tolerated. These findings provide a strong rationale for the clinical evaluation of intracavitary T4 immunotherapy to treat mesothelioma.

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A Regional Approach for CAR T-Cell Therapy for Mesothelioma: From Mouse Models to Clinical Trial

Cited by 19 publications

References 26 publications

Progress and challenges in Mesothelioma: From bench to bedside

Progress and challenges in Mesothelioma: From bench to bedside

Genetically engineered CAR T-immune cells for cancer therapy: recent clinical developments, challenges, and future directions

Intracavitary ‘T4 immunotherapy’ of malignant mesothelioma using pan-ErbB re-targeted CAR T-cells

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