A Phase I Trial of Regional Mesothelin-Targeted CAR T-cell Therapy in Patients with Malignant Pleural Disease, in Combination with the Anti–PD-1 Agent Pembrolizumab

Adusumilli, Prasad S.; Zauderer, Marjorie G.; Rivière, Isabelle; Solomon, Stephen B.; Rusch, Valerie W.; O’Cearbhaill, Roisin E.; Zhu, Amy; Cheema, Waseem; Chintala, Navin K.; Halton, Elizabeth; Pineda, John; Pérez-Johnston, Rocío; Tan, Kay See; Daly, Bobby; Filho, Jose A. Araujo; Ngai, Daniel; McGee, Erin; Vincent, A.; Diamonte, Claudia; Sauter, Jennifer L.; Modi, Shanu; Sikder, Devanjan; Sénéchal, Brigitte; Wang, Xiuyan; Travis, William D.; Gönen, Mithat; Rudin, Charles M.; Brentjens, Renier J.; Jones, David R.; Sadelain, Michel

doi:10.1158/2159-8290.cd-21-0407

Cited by 307 publications

(219 citation statements)

References 37 publications

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“…No major toxicities were reported in these patients. Interestingly, this trial also tested CAR T cells in combination with an anti-PD-1 inhibitor, pembrolizumab, and results suggest that there may be synergy and clinical benefit in combining CAR T cells with immune checkpoint inhibitors to overcome CAR T cell exhaustion and prolong functional persistence [141,142]. This strategy is also being tested in another clinical trial (NCT03907852) that uses a different type of T cell genetic modification to recognize MSLN, which is called TCR fusion Construct (TRuC).…”

Section: Mesothelin-targeted Cellular Therapymentioning

confidence: 99%

Hitting the Bull’s-Eye: Mesothelin’s Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma

Yeo

Castelletti

Zandwijk

et al. 2021

Cancers

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Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited treatment options and poor prognosis. MPM originates from the mesothelial lining of the pleura. Mesothelin (MSLN) is a glycoprotein expressed at low levels in normal tissues and at high levels in MPM. Many other solid cancers overexpress MSLN, and this is associated with worse survival rates. However, this association has not been found in MPM, and the exact biological role of MSLN in MPM requires further exploration. Here, we discuss the current research on the diagnostic and prognostic value of MSLN in MPM patients. Furthermore, MSLN has become an attractive immunotherapy target in MPM, where better treatment strategies are urgently needed. Several MSLN-targeted monoclonal antibodies, antibody–drug conjugates, immunotoxins, cancer vaccines, and cellular therapies have been tested in the clinical setting. The biological rationale underpinning MSLN-targeted immunotherapies and their potential to improve MPM patient outcomes are reviewed.

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Section: Mesothelin-targeted Cellular Therapymentioning

confidence: 99%

Hitting the Bull’s-Eye: Mesothelin’s Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma

Yeo

Castelletti

Zandwijk

et al. 2021

Cancers

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“…Engineered CAR-T cells undergo autologous re-injection into the patient and can identify specific tumor antigens without the requirement of an APC. Mesothelin-targeted CAR-T therapy in combination with pembrolizumab has demonstrated disease control [ 40 ]. Several early-stage trials are underway, as reviewed elsewhere [ 41 ], but likely require several more years of optimization before more widespread use.…”

Section: The Emerging Role Of Immunotherapy In Mpmmentioning

confidence: 99%

The Role of Immunotherapy in the Treatment of Malignant Pleural Mesothelioma

et al. 2021

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Malignant pleural mesothelioma is a rare and aggressive malignancy arising from mesothelial cells that line the serous membranes of the body. Cytotoxic chemotherapy has been a mainstay of therapy, resulting in a modest improvement in overall survival, but toxicity limits the eligible patient population. Few targeted agents beyond bevacizumab have demonstrated superior efficacy compared to placebos. With an improved understanding of the relationship between the immune system and cancer progression, immunotherapies are playing a greater role in the treatment of many cancers. Several early- and late-phase trials in malignant pleural mesothelioma, including assessments of the first-line efficacy of combination ipilimumab/nivolumab treatment, have now demonstrated promising results for both immune checkpoint inhibition and cell-based therapies. These immune therapies are likely to play a central role in the treatment of this disease going forward.

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“…To counter this, cell-based therapies could be combined with checkpoint inhibitors such as Pembrolizumab; indeed, preliminary results suggest a potential synergy in both preclinical experiments and early phase clinical trials [ 74 , 75 ]. A number of studies have also tested the feasibility of engineering CAR T cells to co-express secretable antibody or antibody-like molecules capable of neutralising PD-1 signalling.…”

Section: Solid Tumour Targeting By Engineered Immune Cellsmentioning

confidence: 99%

Payload Delivery: Engineering Immune Cells to Disrupt the Tumour Microenvironment

Fowler

Nattress

Navarrete

et al. 2021

Cancers

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Although chimeric antigen receptor (CAR) T cells have shown impressive clinical success against haematological malignancies such as B cell lymphoma and acute lymphoblastic leukaemia, their efficacy against non-haematological solid malignancies has been largely disappointing. Solid tumours pose many additional challenges for CAR T cells that have severely blunted their potency, including homing to the sites of disease, survival and persistence within the adverse conditions of the tumour microenvironment, and above all, the highly immunosuppressive nature of the tumour milieu. Gene engineering approaches for generating immune cells capable of overcoming these hurdles remain an unmet therapeutic need and ongoing area of research. Recent advances have involved gene constructs for membrane-bound and/or secretable proteins that provide added effector cell function over and above the benefits of classical CAR-mediated cytotoxicity, rendering immune cells not only as direct cytotoxic effectors against tumours, but also as vessels for payload delivery capable of both modulating the tumour microenvironment and orchestrating innate and adaptive anti-tumour immunity. We discuss here the novel concept of engineered immune cells as vessels for payload delivery into the tumour microenvironment, how these cells are better adapted to overcome the challenges faced in a solid tumour, and importantly, the novel gene engineering approaches required to deliver these more complex polycistronic gene constructs.

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A Phase I Trial of Regional Mesothelin-Targeted CAR T-cell Therapy in Patients with Malignant Pleural Disease, in Combination with the Anti–PD-1 Agent Pembrolizumab

Cited by 307 publications

References 37 publications

Hitting the Bull’s-Eye: Mesothelin’s Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma

Hitting the Bull’s-Eye: Mesothelin’s Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma

The Role of Immunotherapy in the Treatment of Malignant Pleural Mesothelioma

Payload Delivery: Engineering Immune Cells to Disrupt the Tumour Microenvironment

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