CAR-T has seen a host of successes in blood cancers, but translating that into solid tumors has proven much more difficult. Now, early data out of the AACR cancer conference (and all the caveats that brings) may be offering some hope for that direction.
Two separate, small trials out of the American Association for Cancer Research (AACR) show that CAR-T therapy could impact several types of cancer: HER2-positive sarcomas and the difficult-to-treat pleural disease from mesothelioma, typically associated with asbestos-related disease.
First up is a small phase 1 for younger patients and adults with HER2-expressing sarcoma, which can affect bone and soft tissues.
Typically, when you think of HER2-positive cancers you tend to think of breast cancer, but it’s believed that around 40% of osteosarcomas, the most common kind of sarcoma, can harbor this expression.
You’d think you could turn to Roche’s long-standing HER2-positive stalwart Herceptin, but it has no effect on this particular patient population, with treatment usually consisting of chemotherapy agents, which have high side effects and often low treatment success.
So, Shoba Navai, M.D., 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 in Houston, and her team used HER2-targeted CAR-T cells, combined with a form of chemo. The result, Navi said, was found to be safe and effective in some patients.
It’s still early doors: The test was in just 10 patients, aged 4 to 54, with refractory/metastatic HER2-positive sarcoma (five with osteosarcoma, three with rhabdomyosarcoma, and one each with Ewing sarcoma and synovial sarcoma). These patients had already been through the ringer, receiving up to five prior salvage therapies.
The investigators found that the CAR-T cells expanded in all but two patients, with a median peak expansion after a week, and that they could detect the CAR-T cells in all patients six weeks after infusion.
One pediatric patient whose rhabdomyosarcoma had spread to the bone marrow had a complete response (CR) for 12 months, but relapsed later; retreatment with CAR-T cells resulted in a CR that has been ongoing for 7 months.
And one pediatric patient with osteosarcoma that had metastasized to the lungs has an ongoing CR for 32 months. Three patients had stable disease, and five had progressive disease.
The team acknowledged the limitation of the study, given its size, but were still encouraged by some of the activity; they also note that safety appeared strong, with no pulmonary toxicities detected, something that can occur with CAR-T cells infusion.
In another, separate trial, Prasad Adusumilli, M.D., deputy chief of thoracic surgery at Memorial Sloan Kettering Cancer Center, and his team focused their small phase 1 (of 21 patients) on a particularly aggressive form of lung cancer: malignant pleural disease from mesothelioma, essentially a cancer of the protective lining of the lung, which comes typically from inhaling asbestos and has a poor prognosis.
The MSK team tested mesothelin-targeted CAR T cells called IcasM28z, using completely human components, which includes the so-called safety “suicide” switch that can be activated to kill all CAR-T cells in case of a spike in toxicity.
The investigators recruited 21 patients with malignant pleural disease (19 with malignant pleural mesothelioma, one with metastatic lung cancer, and one with metastatic breast cancer), with 40% of them having had received three or more lines of prior therapy.
This approach saw the CAR T cells to be persistent in the peripheral blood of 13 patients during the 38-week evaluation, and their presence was associated with more than 50% decrease in the levels of a mesothelin-related peptide in the blood and evidence of tumor regression on imaging study.
One patient with mesothelioma underwent curative-intent surgery followed by radiation therapy to the chest. “Twenty months from diagnosis, the patient is doing well, with no further treatment,” Adusumilli noted.
Meanwhile, 14 patients were given PD-1 checkpoint inhibitors. This is because CAR-T cells can get dampened, or functionally exhausted, in large tumors; preclinical tests show they can be reinvigorated by PD-1 agents.
This only worked in mice, but Adusumilli said they would take try this out on the patients to see its effect. After up to 21 cycles of treatment with an anti -PD1 agent, two patients had complete metabolic response on PET scans at 60 and 32 weeks, respectively, and these responses are ongoing; five patients had partial response, while four 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 rational to further investigate this approach in aggressive, therapy-resistant cancers such as mesothelioma, for which the currently available treatment options are not optimal ,” Adusumilli concluded.