Prasad Adusumilli and colleagues have shown that CAR T cells that start to lose power can be revived by immunotherapy drugs given several weeks later.
Mesothelioma is a rare cancer that affects the lining surrounding organs, usually in the chest and abdomen. Treating this disease has been challenging because in most cases it is not possible to remove all the cancer with surgery. The FDA has approved only two new therapies since 2000, both improving survival by only a few months.
Researchers at Memorial Sloan Kettering Cancer Center have been exploring the use of chimeric antigen receptor (CAR) T cell therapy to treat patients with pleural mesothelioma, which arises in the tissue surrounding the lungs. The CAR T approach involves removing a patient’s immune cells, altering them so they can recognize cancer, and then infusing them back into the patient.
Physician-scientist Prasad Adusumilli is leading a clinical trial at MSK testing this therapy. Here, he discusses encouraging results from a study published July 15, 2021, in Cancer Discovery and explains why he is optimistic this treatment will be effective against the disease.
What did the clinical trial show about this treatment?
This was a phase I trial, which means it was mainly testing whether the treatment is safe for people. There were no CAR T-related side effects. For example, there were no cases of severe cytokine release syndrome, which is characterized by dangerously high fevers and has complicated CAR therapy for other cancers. In addition, we saw signs that the T cells were having the desired effect.
How is CAR T therapy designed to work against mesothelioma?
CAR T therapy has worked well against some blood cancers, but we’ve had less success treating solid tumors like those found in mesothelioma as well as lung, breast, and other cancers. The T cells have to get into the tumor and stay there long enough to kill the cancer cells. Also, solid tumors are surrounded by cells and molecules that cause the T cells to lose their power after a while — what we call T cell exhaustion.
We studied thousands of MSK patient tumors and identified a molecule called mesothelin that’s found on the surface of the cancer cells. This protein is abundant in solid tumor cells compared with normal cells. Mesothelin is present not just in mesothelioma cells but also in lung cancer, breast cancer, pancreatic cancer, and ovarian cancer. I worked with physician-scientist Michel Sadelain, who pioneered CAR T cells for treating blood cancers, to develop mesothelin-targeted CARs.
How do you overcome the challenges that are specific to solid tumors?
From our laboratory experiments, we knew that we could increase the effectiveness by injecting the T cells directly into the chest rather than doing it intravenously, as is done for treating blood cancers. Mesothelioma almost always stays within the chest. When you infuse T cells specifically to that spot, they seem to recognize the cancer cells right away and start multiplying.
The combination immunotherapy treatment could be one of the first successful CAR T cell therapies for treating solid tumors.
For most patients, the space was too small to inject the cells using a catheter. But MSK has highly skilled interventional radiologists, led by Stephen Solomon, Chief of the Interventional Radiology Service, who are experts at using image-guided techniques to target parts of the body with great precision. It shows the importance of having multidisciplinary expertise — MSK’s cell manufacturing facility, led by Isabelle Rivière, successfully made the CAR T cells, and our interventional radiology physicians were able to refine ways to deliver them.
How do you avoid T cell exhaustion and make sure that the CAR T cells stay active enough to finish off the cancer cells?
We developed a way to reactivate the T cells. In 2016, we published research in the Journal of Clinical Investigation showing in mice that exhausted CAR T cells could be revived by drugs called checkpoint inhibitors — a form of combination immunotherapy. Checkpoint inhibitors had already been tested in many cancers and approved for some, so we knew the drugs were safe.
We tested this combination immunotherapy approach in 18 patients who had already received multiple prior treatments. Guided by the expertise of medical oncologist Marjorie Zauderer, a few weeks after we infused the CAR T cells into the patients, we gave them the checkpoint inhibitor drug pembrolizumab (Keytruda®). The drugs rescued the T cells and boosted their effectiveness. The patients’ median survival from the time of infusion was 24 months — compared with 18 months using current standard treatment methods — with 83% of participants living at least one year.
What is the next step for this type of treatment?
We have already converted this study into a phase II trial. We also have begun a separate clinical trial for mesothelioma using CAR T cells that have the checkpoint inhibitor component contained within them. The goal is to have a stronger, more sustained response from the CAR T cells and avoid having to give checkpoint blockade drugs for years.
Although we are starting with mesothelioma, we hope this strategy of combining CAR T cells with checkpoint inhibitors will work for other solid tumors, such as lung cancer, pancreatic cancer, and breast cancer.
- Better treatments are needed for mesothelioma.
- CAR T cell therapy can be injected into the chest to treat the disease.
- A key part of the therapy is giving checkpoint blockade drugs to “revive” the CAR T cells.
- A recent clinical trial suggests this approach could be effective, but more work is needed.
