Prasad S. Adusumilli, MD, surgeon, deputy chief of Thoracic Service, co-director of the Mesothelioma Program, head of Solid Tumors Cell Therapy, Cellular Therapeutics Center, at Memorial Sloan Kettering Cancer Center, discusses the rationale for an autologous mesothelin-targeted CAR T-cell therapy in advanced solid tumors.

Surface antigens, such as CD19, are more easily targeted in hematologic malignancies than they are in solid tumors, explains Adusumilli. Prior to the phase I study that investigated the use of an autologous mesothelin-targeted CAR T-cell therapy, investigators studied approximately 2,000 thoracic cancers and noticed that mesothelin is overexpressed in mesothelioma, lung cancer, triple-negative breast cancer, and pancreatic cancer.

Most importantly, investigators realized that mesothelin was partially responsible for the aggressiveness of the disease, making it unlikely that the cancer cell will shed the antigen under immune attack. They realized that if they were able to target mesothelin, approximately 2,000,000 patients could be treated in the United States alone, says Adusumilli. Moreover, they learned that by targeting mesothelin, they could target the tumor cells and spare the patient’s normal cells.

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Dr. Adusumilli on the Rationale for Mesothelin-Targeted CAR T-Cell Therapy

Prasad S. Adusumilli, MD, surgeon, deputy chief of Thoracic Service, co-director of the Mesothelioma Program, head of Solid Tumors Cell Therapy, Cellular Therapeutics Center, at Memorial Sloan Kettering Cancer Center, discussed the results of a phase I study exploring mesothelin-targeted CAR T-cell therapy in patients with advanced solid tumors during the 2019 AACR Annual Meeting.

Results from the phase I clinical trial (NCT02414269) showed that the CAR T-cell therapy had antitumor activity in patients with malignant pleural disease from mesothelioma without any evidence of major toxicity.

There is a lot of concern regarding on-target off-tumor toxicity, says Adusumilli. However, if there had been any unexpected toxicities, the therapy was designed with completely human components, including an Icaspase-9 safety “suicide” switch. If initiated, all CAR T cells in the patient’s body would be eliminated. Adusumilli and his team used clinical laboratory imaging to look for this kind of toxicity and they did not find it following extensive investigation, he says.

Due to the lack of toxicity, investigators added checkpoint blockade to patients who had been given a single dose of CAR T cells intrapleurally, and they noticed durable responses. These responses lasted for ≥6 months without the need of additional therapies, says Adusumilli.

The next step for research is to find a way to allow for patients to stop treatment eventually instead of having to receive anti—PD-1 therapy every 3 weeks for the remainder of their lives. To this end, Adusumilli and his team have genetically engineered a PD-1 dominant negative receptor. This is essentially a decoy receptor that can be placed within the CAR, thus the T cell can then bind to PD-L1 without exhausting the CAR T cell through intracellular signaling. This clinical trial is slated to launch in 2020.

Dr. Adusumilli on Autologous Mesothelin-Targeted CAR T Cells in Advanced Solid Tumors

Although malignant pleural mesothelioma (MPM) remains a rare disease, Memorial Sloan Kettering Cancer Center has considerable experience with this malignancy, and our specialists are at the forefront of translating new approaches for the treatment of patients with mesothelioma into the clinic.

At Memorial Sloan Kettering, patients with mesothelioma are managed by a working group that consists of specialists from multiple disciplines who use a personalized approach to achieve accurate diagnosis, stage, and treatment stratification. In general, patients with suspected mesothelioma are often misdiagnosed, owing to a lack of pathological expertise and the selection of inappropriate biopsies.

Memorial Sloan Kettering is one of the nation’s largest tertiary referral centers for this disease, and our mesothelioma working group, which meets regularly to discuss all patients with mesothelioma undergoing treatment at our center, has the skills and knowledge to ensure optimal management is consistently achieved.

Our experience with this rare tumor includes the largest study published to date (945 patients) on long-term outcomes among patients with mesothelioma at a single center. The development and maintenance of this vast and meticulous database enables us to design a customized management algorithm for each patient.

For example, to determine the most appropriate surgical resection for each patient, we employ an algorithm that takes into account the potential resectability of the tumor and the individual’s cardiopulmonary reserve—an approach that ensures tolerance of the planned surgical approach and results in better functional outcomes.

		A hemithoracic pleural intensity-modulated radiation therapy plan (coronal view) for a right-sided malignant pleural mesothelioma is used for targeted treatments that spare healthy lung tissue

The database has also enabled us to establish patient-management paradigms that have subsequently been adopted by physicians and official medical associations throughout the world.

Through our approach of systematically evaluating each patient with mesothelioma by CT scan, PET scan, and lung function tests, we are able to optimize patients for surgical resection and avoid unnecessary surgery that may delay treatment. Our preoperative assessment skills reflect our extensive research on these imaging modalities.

 With the assistance of Memorial Sloan Kettering radiologists, we are now developing advanced imaging techniques to accurately quantify tumor burden and monitor therapy response.

Working in concert with Memorial Sloan Kettering pathologists, our mesothelioma researchers have identified the key morphological characteristics that drive progression of mesothelioma. These developments have helped inform the efforts of the World Health Organization and other international associations to reclassify mesothelioma.

Mesothelioma patients with early-stage disease are managed by curative-intent surgical resection, using either extrapleural pneumonectomy or pleurectomy and decortication. Our surgeons pioneered these techniques and have trained surgeons across the globe on using them.

In carefully selected patients, extrapleural pneumonectomy— which involves the removal of the involved lung lining, heart lining, nearby lymph nodes, and diaphragm&mdash;provides an excellent option. The expertise of our nursing and surgical floor staff is key in successfully managing these patients in the immediate postoperative period.

The majority of mesothelioma patients undergo pleurectomy and decortication—a lung-sparing surgical procedure that aggressively and carefully removes the tumor&mdash;so that they can quickly recover and then undergo chemotherapy and/or radiation therapy.

To prevent recurrence of cancer following surgical resection, our radiation oncologists have developed an intensity-modulated radiation technique that precisely targets the tumor while sparing the underlying healthy tissue—namely, the lung (

We continue to lead efforts to elucidate the biological profile of MPM and advance imaging modalities and therapies. Landmark publications from our center have shed light on the biology of this aggressive disease.

 We are currently working to translate new imaging modalities developed in clinically relevant mouse models (

		An intraoperative fluorescence technique for visualizing pleural mesothelioma, developed for a mouse model, will be evaluated in a clinical trial.

In addition, in an ongoing clinical trial of an oncolytic vaccinia virus (which uses genetically modified smallpox virus to kill cancer cells), we are investigating real-time fluorescent techniques to visualize the microscopic deposits of the tumor in the operating room; this will enable us to accurately assess and remove the entire tumor.

Even more promising, our researchers have identified the beneficial role of antitumor immune responses

 and have discovered candidate cancer antigens to effectively target the tumor.

 We anticipate the initiation of a novel adoptive T-cell immunotherapy clinical trial for mesothelioma patients later this year. In this clinical trial, we will administer the patient’s own immune cells, genetically engineered to target and kill cancer cells, through tunneled pleural catheters that we pioneered for use in mesothelioma patients.

			Kadota K, Kachala SS, Nitadori J, et al. High SUVmax on FDG-PET indicates pleomorphic subtype in epithelioid malignant pleural mesothelioma: supportive evidence to reclassify pleomorphic as nonepithelioid histology. J Thorac Oncol. 2012;7(7):1192-1197.

			Kadota K, Suzuki K, Sima CS, et al. Pleomorphic epithelioid diffuse malignant pleural mesothelioma: a clinicopathological review and conceptual proposal to reclassify as biphasic or sarcomatoid mesothelioma. J Thorac Oncol. 2011;6(5):896-904.

			Kadota K, Suzuki K, Colovos C, et al. A nuclear grading system is a strong predictor of survival in epithelioid diffuse malignant pleural mesothelioma [published online October 7, 2011]. Mod Pathol. 2012;25(2):260-271.

			López-Ríos F, Illei PB, Rusch V, Ladanyi M. Evidence against a role for SV40 infection in human mesotheliomas and high risk of false-positive PCR results owing to presence of SV40 sequences in common laboratory plasmids. Lancet. 2004;364(9440):1157-1166.

			López-Ríos F, Chuai S, Flores R, et al. Global gene expression profiling of pleural mesotheliomas: overexpression of aurora kinases and P16/CDKN2A deletion as prognostic factors and critical evaluation of microarray-based prognostic prediction. Cancer Res. 2006;66(6):2970-2979.

			Bott M, Brevet M, Taylor BS, et al. The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma. Nat Genet. 2011;43(7):668-672.

			Bograd AJ, Suzuki K, Vertes E, et al. Immune responses and immunotherapeutic interventions in malignant pleural mesothelioma [published online September 13, 2011]. Cancer Immunol Immunother. 2011;60(11):1509-1527.

			Servais EL, Colovos C, Rodriguez L, et al. Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion in an orthotopic mouse model and in epithelioid pleural mesothelioma patients [published online February 27, 2012]. Clin Cancer Res. 2012;18(9):2478-2489.

			Suzuki K, Servais EL, Rizk NP, et al. Palliation and pleurodesis in malignant pleural effusion: the role for tunneled pleural catheters. J Thorac Oncol. 2011;6(4):762-767.

Prasad S. Adusumilli, MD

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