Why doesn’t immunotherapy work for everyone?

In the last decade, immunotherapy has become a viable treatment option for many cancer patients. Unlike radiation and chemotherapy, immunotherapy does not target the cancer itself. Instead, it enables a patient’s own immune system to attack the disease. In most cases, immune-based treatments stimulate T cells, a specialized type of immune cell, to fight cancer.

Immunotherapy drugs called immune checkpoint inhibitors accomplish this by blocking checkpoint proteins that live on the surface of T cells and act as “brakes” to prevent the T cells from accidentally attacking healthy cells. Now a standard treatment for a growing list of cancers, checkpoint inhibitors have proven effective for treating several types of cancers, including melanoma, small cell lung cancer and non-small cell lung cancer, bladder cancer, kidney cancer, stomach cancer, liver cancer, head and neck cancers, and lymphoma.

“The survival outlook for patients with metastatic bladder cancer used to be less than one year, but I’m now seeing some of my patients coming back to the clinic over and over again, five years and longer,” says Padmanee Sharma, M.D., Ph.D., co-leader of MD Anderson’s immunotherapy platform. “It’s very rewarding to see that stage IV cancer patients can have hope.”

However, checkpoint inhibitors don’t yet work for everyone. Certain cancers, including pancreatic cancer, prostate cancer and glioblastoma, have been especially resistant to this approach.

“The idea that these agents work for some patients but not others is a huge research question we’re still trying to understand,” says Sharma.

Learning why cancers may not respond to immunotherapy

Jim Allison, Ph.D., discovered the first known immune checkpoint, CTLA-4, in 1995. By blocking CTLA-4 in the laboratory, Allison learned that T cells could be set free to attack cancer.

Allison’s work led to the development of the first immune checkpoint inhibitor drug, ipilimumab, which was approved by the Food and Drug Administration (FDA) in 2011 for treating advanced melanoma. Since then, the FDA has approved several new checkpoint inhibitors for a growing list of cancer types.

For checkpoint blockade to work, T cells must be present within a tumor and able to perform their jobs. A growing body of evidence has begun to clarify how some tumors resist this treatment approach, explains Sharma. These explanations include:

• Tumors can develop mutations or mechanisms that prevent T cells from penetrating the tumor.
• Tumors may respond to the immune system by turning down signaling pathways that normally stimulate T cells, thereby dampening the anti-tumor immune response.
• Higher numbers of suppressive immune cells, such as myeloid cells, may be present in some tumors, which counter the activity of T cells.
• In advanced cancers, the sites of metastasis have very different cellular environments than where the primary cancer developed. T cells may not function as well in those environments.

“The interplay between a tumor and the immune system is extremely dynamic,” says Sharma. “So strategies to make the best use of checkpoint inhibitors require a complex understanding of this evolving back-and-forth.”

That is precisely the goal of MD Anderson’s immunotherapy platform, an engine of the Moon Shots Program®.

Innovative research drives immunotherapy breakthroughs

Under the leadership of Sharma and Allison, the immunotherapy platform strives for a deeper understanding of how cancers respond to immune-based treatments, so that more patients can benefit.

Its research is built around a reverse translation concept, which was developed by Sharma in 2004 during the earliest immunotherapy clinical trials in bladder and kidney cancer. The platform’s research is designed to learn from patients in real time as they participate in the more than 100 clinical trials run through the platform. Patients are asked to provide samples before, during and after treatment so the research team can learn about the evolving immune response as it happens.

“As I explain to my patients what we’re trying to do – that we want to develop immunotherapy for more people – they understand the importance of the work,” Sharma says. “They know we may not find a cure for them, but their participation could lead to a cure for someone else, maybe even someone in their family down the road.”

New immunotherapy combination may yield new discoveries and treatments

The approach already has revealed important insights and led to the development of new combination treatments.

For example, an ongoing clinical trial with the Prostate Cancer Moon Shot® is showing promising early results by using multiple checkpoint inhibitors to treat advanced prostate cancer. Insights from this work also showed when prostate cancer spreads to the bone, it leads to massive destruction of bone tissue. This sparks production of a protein called TGF-β that can suppress the immune response. To better treat bone metastases, the platform is planning to launch a clinical trial that combines a checkpoint inhibitor together with a therapy that blocks TGF-β.

Platform researchers also worked with the Glioblastoma Moon Shot® team and learned that glioblastomas can overcome checkpoint blockade with another type of immune cell called macrophages. The researchers found that certain macrophages in the brain express high levels of the CD73 protein that thwart the activity of T cells in a tumor. Future studies will test a combination of checkpoint inhibitors and a CD73 inhibitor.

These projects are proving that the immunotherapy platform, an entity unique to MD Anderson, can drive important discoveries that will bring immunotherapy to more patients.

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