1. Fuerst, Mark L.

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ATLANTA-Two chimeric antigen receptor (CAR) T-cell therapies show early signs of activity in solid tumors. In one study, a CAR that targets the protein mesothelin showed no evidence of major toxicity and had antitumor activity in patients with malignant pleural disease from mesothelioma. In the other study, a combination of chemotherapy and CAR T cells designed to target the protein HER2 was found to be safe and showed clinical responses in pediatric and adult patients with advanced HER2-positive sarcoma.


Treatment with CAR T cells has led to dramatic successes in blood cancers, but results have been disappointing to date for solid tumors. "Patients with advanced-stage solid tumors, such as mesothelioma, and lung and breast cancers, that are metastatic to the chest cavity have poor outcomes despite treatment," said Prasad S. Adusumilli, MD, Deputy Chief of Thoracic Surgery at Memorial Sloan Kettering Cancer Center.


He presented the results of the first study at a press briefing before the 2019 American Association for Cancer Research (AACR) annual meeting (Abstract CT036).


The researchers engineered the mesothelin-targeted CAR T cells, called IcasM28z, using completely human components, which includes the Icaspase-9 safety "suicide" switch that can be activated to kill all CAR T cells in case of an unexpected toxicity.


"The novelty of our study is that the CAR T cells target the cancer cell-surface protein, mesothelin, which is expressed on the majority of cancer cells, and they are delivered directly to the tumor site using regional delivery techniques," noted Adusumilli. "If this approach is successful, 2 million patients with mesothelin-expressing solid tumors per year in the U.S. will be eligible for this treatment."


The study included 21 patients with malignant pleural disease (19 with malignant pleural mesothelioma, one with metastatic lung cancer, and one with metastatic breast cancer); 40 percent of them had received three or more lines of prior therapy.


CAR T-cell transduction was successful in all patients. "A single dose of CAR T cells was administered intrapleurally following cyclophosphamide preconditioning," said Adusumilli. "We found no evidence of CAR T-cell related toxicity higher than grade 2, no neurotoxicity, no cytokine release syndrome (CRS), and no on-target, off-tumor toxicity."


CAR T cells persisted in the peripheral blood of 13 patients during the 38-week evaluation, and their presence was associated with more than 50 percent decrease in the levels of a mesothelin-related peptide in the blood and evidence of tumor regression on imaging studies.


The researchers found objective responses in 10 of 21 (72%) patients, including eight of 11 (73%) patients who received preconditioning therapy.


Preclinical studies found that anti-PD-1 agents could reactivate exhausted CAR T cells and eradicate tumors. On the basis of these studies, 14 patients went on to receive anti-PD1 checkpoint blockade agents. After up to 21 cycles of treatment, two patients had complete metabolic response on PET scans at 60 and 32 weeks, respectively, and these responses are ongoing at this time; five patients had partial response and four patients had stable disease.


"Combining rationally developed strategies-such as interventional radiology, T-cell genetic engineering, and newer immunotherapy agents-has produced encouraging results and provides rationale to further investigate this approach in aggressive, therapy-resistant cancers such as mesothelioma, for which the currently available treatment options are not optimal," Adusumilli stated.


HER2-Targeted CAR T-Cell Therapy

At the same press briefing, Shoba Navai, MD, Assistant Professor of Pediatrics at the Center for Cell and Gene Therapy at Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, noted that curative salvage chemotherapy regimens for sarcoma have low success rates and can be quite toxic.


Osteosarcoma, one of the most common types of sarcoma, has been reported to be HER2-positive in up to 40 percent of patients, and HER2 positivity is associated with a higher likelihood of tumor metastasis, said Navai. Prior clinical studies have shown that HER2-targeted antibodies such as trastuzumab are not effective for these patients.


"Our group has previously shown in the laboratory that HER2-directed CAR T cells are better at targeting low levels of HER2 on tumor cells compared with trastuzumab, so these CAR T cells may have antitumor activity in patients with sarcoma even when HER2-antibody therapies do not," she explained.


In a new study presented at AACR, Navai noted: "Our study shows that HER2-targeted CAR T-cell therapy can be safely given in combination with lymphodepletion chemotherapy, which enhances T-cell expansion and persistence. HER2 CAR T cells induce objective clinical responses in some patients with advanced HER2-positive sarcomas. Engagement of endogenous immunity may aid in generation of tumor response."


In this trial, the researchers treated 10 patients, ages 4-54, with refractory/metastatic HER2-positive sarcoma (five with osteosarcoma, three with rhabdomyosarcoma, and one each with Ewing sarcoma and synovial sarcoma). Patients had received up to five prior salvage therapies (Abstract LB-147).


The patients received up to three infusions of HER2-targeted CAR T cells after lymphodepletion with either fludarabine or fludarabine and cyclophosphamide. Responders received up to an additional five infusions of CAR T cells without lymphodepletion.


The results show CAR T cells expanded in all but two patients with a median peak expansion on day 7. CAR T cells were detected in all patients 6 weeks after infusion.


Overall, the patients had limited treatment-related toxicities. "We found no dose-limiting toxicities and there were no transfusions, no opportunistic infections, and no lasting pulmonary or cardiac toxicities. CRS was maximum grade 2 and with no neurotoxicity," said Navai. The most common grade 3/4 toxicities were lymphopenia in 10 patients and neutropenia in eight patients.


Six of 11 patients with advanced sarcomas achieved objective responses or stable disease. One pediatric patient with osteosarcoma that had metastasized to the lungs has an ongoing complete response (CR) for 32 months. Three patients had stable disease and five patients had progressive disease.


One pediatric patient whose rhabdomyosarcoma had metastasized to the bone marrow had a CR for 12 months but relapsed later; retreatment with CAR T cells resulted in a CR that has been ongoing for 17 months.


"Responses without lymphodepletion tended to have been among those with less disease or more accessible disease in the lungs. They may be more amenable to this treatment," Navai stated. The next step is to expand the research to other HER2-positive tumors and other sarcomas.


Mark L. Fuerst is a contributing writer.